https://t.

me/Anesthesia_Books
Primary FRCA in a Box, 2nd Ed
Sarah Armstrong MA MB BS FRCA
Consultant anaesthetist
Frimley Health NHS Foundation Trust
Barry Clifton MB ChB FRCA
Consultant anaesthetist
Barts Health NHS Trust
Lionel Davis MB BS FRCA
Consultant anaesthetist
Barts Health NHS Trust and Homerton University NHS Trust
CRC Press
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For Mark, Jamie and Alex
Sarah Armstrong

For Subha and Matilda

Barry Clifton

For my family
Lionel Davis
Introduction

The Primary FRCA exam is a daunting task facing any trainee anaesthetist. Many currently available
books cover the enormous syllabus in detail, and we have not attempted to duplicate these. The sec-
ond edition of these revision flashcards is precisely mapped to the FRCA curriculum. We have added
a new anatomy section and clinical ‘nuggets’ to relate the basic sciences to clinical practice. The
cards focus on the premise that structuring your answers into an initial definition followed by a catego-
rization of the topic will increase your chances of saying something sensible and reduce that feeling
of impending doom in a viva situation. The cards are designed to fit into a scrubs pocket for quick
reference and thus act as a more convenient revision aid than conventional texts. They will also be of
use to those studying for the Final FRCA who wish to have a concise summary of Primary FRCA topics.

We wish you the best of luck in your exam!

SA, BC and LD
Contents

Physics
Basic Principles of Measurement
1 Measuring system characteristics
Measurement systems – static
characteristics
2 Measurement systems –
dynamic characteristics
Basic measurement concepts
3 Resonance and damping,
frequency response
  4 Calibration
Calibration and damping
athematical Concepts and
M anaesthesia
Statistics
5 Mathematical concepts
6 Logarithms and exponentials
7 Exponential processes
Hierarchy of evidence
8 Randomised controlled trials
  9 Errors
Power
Sensitivity
Specificity
PPV
Accuracy
RRR
ARR
NNT
  10 Types of data and their
representation
  11 Choice of simple statistical tests
for different data types
Frequency distributions
SI Units
  12 Base SI units
Derived SI units
  13 Electrical and magnetic
derived units
Non-SI units of relevance to
Simple Mechanics and Pressure
  14 Simple mechanics
Pressure definitions
  15 The gas laws – for ideal gases
Pressures and temperatures
  16 Pressure measurement in
gases
Bourdon pressure gauge
Piezo-electric effect
  17 Pressures of anaesthetic
equipment
Manufacture and storage of
gases
  18 Gases and vapours
Isotherms for nitrous oxide
Thermodynamics
  19 Heat and laws of
thermodynamics
Heat definitions
  20 Temperature definitions
  21 Measurement of temperature
Graphs relating to temperature
  22 Clinical aspects of heat and
temperature
Patient warming systems
 23 Humidity
 24 Humidifiers
Electricity and Magnetism
  25 Basic concepts
  26 Electrical interference
Biological signals
  27 Measurement of neuromuscular
blockade
  28 Electrical hazards – causes
  29 Electrical hazards – prevention
  30 Principles of lasers
  31 Laser safety
Electrical symbols
  32 Wheatstone bridge
Circuit breakers, fuses,
transformers, transistors,
diodes
  33 MRI scanners and anaesthesia
  34 Principles of cardiac   48 Measurement of cardiac output Physiology
pacemakers  49 Capnography General Principles
 35 Defibrillators   50 Pulse oximetry   62 Effects of old age on
 36 Diathermy   51 Measurement of gas and anaesthesia
Problems with diathermy vapour concentrations Paediatric anatomy and
  52 Measurement of gas and physiology
Fluids and Flow vapour concentrations   63 The cell
  37 Laminar and turbulent flow Measurement of pH   64 Cell membrane characteristics
  38 Bernoulli principle   53 Measurement of pCO2 Genes and their expression
Venturi masks Measurement of PO2
  39 Surface tension   54 Derived measurements – Biochemistry
Surfactant bicarbonate and   65 Acid–base balance
  40 Measurement of volume and base excess  66 Buffers
flow in gases and liquids Oxygen consumption, carbon  67 Sodium
  41 The rotameter dioxide production and  68 Potassium
  42 Ultrasound and the Doppler effect respiratory quotient   69 Causes of acid-base
  43 Simple tests of disturbances
pulmonary function Equipment   70 Bicarbonate and phosphate
  44 Tests of gas exchange   55 Classification of vaporizers  71 Calcium
Coanda effect Factors that affect delivered  72 Magnesium
concentration of anaesthetic  73 Chloride
Clincal Monitoring and Measurement agent Enzymes
  45 Minimum (essential) monitoring   56 Types of vaporizers
standards   57 Methods of killing Body Fluids
ECG – principles contaminating   74 Body fluid compartments
Placement of leads organisms Measurement of fluid
  46 Principles of pressure Classification of ventilators compartment volumes
transducers   58 Breathing systems   75 Osmolality and osmolarity
NIBP measurement  59 Scavenging Starling’s forces
  47 Principles of pulmonary   60 Carbon dioxide absorbers   76 Cerebrospinal fluid
artery and wedge pressure  61 Suction Blood–brain barrier
measurement CO2 removal systems Specific gravity
Contents (Continued)
  77 Other body fluids: Pleural,
Pericardial
  78 Other body fluids: Lymph,
Intraocular
Haematology and Immunology
  79 Blood groups
  80 Immune responses
Hypersensitivity
 81 Inflammation
 82 Haemostasis
Peripheral circulation
  83 Clotting cascade
Coagulation – cell-based
model
 84 Haemoglobin
Red blood cells
Nervous System
  85 Resting membrane potential
Neurones and nerve fibres
  86 Action potentials
  87 Organisation of the nervous
system
Motor pathways
  88 Special senses
Somatic sensation
  89 Intracranial pressure and
cerebral blood flow
  90 The vasomotor centre
Autonomic nervous system
  91 Sympathetic nervous system
Parasympathetic nervous system
  92 Spinal cord
  93 Spinal cord anatomy
Spinal cord injury
  94 Pain pathways
Gate control theory of pain
  95 Intraocular pressure
Pupillary responses
  96 Nausea and vomiting
Muscle
  97 Neuromuscular junction
  98 Muscle types and contraction
  99 Muscle components
100 Sarcomere
Disorders of neuromuscular
function
101 Myopathies
Sphincters
Heart and Circulation
102 Cardiac action potentials
103 Cardiac definitions
104 Control of blood pressure
105 Cardiac cycle
106 Pressure–volume loop for the left
ventricle
Autoregulation
107 Cardiovascular response to
haemorrhage
Response to the rapid infusion
of 1000 mL saline
108 Frank–Starling law of the heart
Heart failure
109 Valsalva manoeuvre
110 Exercise
111 Pressures within the normal heart
and pulmonary circulation
Shock
112 Coronary artery blood supply
113 Special circulations
114 Pulmonary vascular resistance
Factors that affect pulmonary
vascular resistance
115 Central venous pressure
Venous waveform
Renal
116 Structure and function of the
kidney
Renin–angiotensin–aldosterone
system
117 The glomerulus
118 Renal tubular function
Proximal convoluted tubule
119 Loop of Henle, DCT and
collecting duct
120 Renal glucose handling
Sodium and potassium handling
by the kidney
121 Renal blood flow
Clearance
122 Assessment of renal function
Micturition
123 Pathophysiology of acute
kidney injury
Respiration Liver, GI and Metabolism 150 Hypothalamus
124 Oxygen dissociation curve 138 The liver Pituitary gland
125 Work of breathing Functions of the liver 151 Adrenal gland
Shunt 139 The pancreas 152 Catecholamines
126 FRC and closing capacity 140 Gastric secretion Adrenergic receptors
Functions of FRC 141 Gut motility – functional 153 Thyroid gland
127 Hyperbaric pressure anatomy Thyroid hormones
Hypobaric pressure 142 Nutrition overview
128 Carbon dioxide stores Carbohydrates, proteins Pregnancy
and transport and fats 154 Changes in pregnancy
129 Oxygen stores and transport 143 Essential amino acids and 155 Placenta
130 Control of breathing fatty acids 156 Fetal circulation
131 Ventilation–perfusion Vitamins and minerals Changes in fetal circulation
relationships in the lungs 144 Carbohydrate metabolism – at birth
West’s zones overview 157 Lactation
132 Dead space 145 Metabolism Massive obstetric
133 Lung volumes and capacities Starvation haemorrhage
134 Respiratory failure 146 Obesity
Treatment of respiratory failure Anaesthesia for
135 Oxygen cascade and alveolar obese patients
gas equation 147 Temperature regulation Pharmacology
2,3-Diphosphoglycerate Hypothermia Principles
and myoglobin 148 Control of blood glucose 158 Drug interactions
136 Airways resistance Stress response 159 Lipid solubility and
and compliance protein binding
Compliance curve Drug mechanism of action
Intrapleural pressure Endocrinology 160 Isomerism
137 Flow-volume loops of the lungs 149 Hormones 161 Malignant Hyperpyrexia
Non-respiratory functions of Control of secretion 162 Materno-fetal drug distribution
the lungs of hormones 163 Addiction and dependence
Contents (Continued)
Pharmacokinetics 180 Propofol 192 Rocuronium and atracurium
164 Absorption of drugs Thiopentone Sugammadex
Drug entry into cells 181 Ketamine 193 Suxamethonium
165 Drug distribution Etomidate Suxamethonium apnoea
Dose–response curves 182 Benzodiazepines – general 194 Local anaesthetics
Compartmental models principles 195 Local anaesthetic toxicity
166 Drug metabolism 183 Midazolam
167 Elimination and excretion Diazepam Cardiovascular System Drugs
196 Inotropes
Pharmacodynamics Inhaled Anaesthetics 197 Adrenaline and noradrenaline
168 Agonists and antagonists 184 Inhalational anaesthetics – 198 Phosphodiesterase III inhibitors
169 Ionization and pKa general principles 199 Alpha-antagonists
170 Receptors Theories of anaesthetic action 200 Alpha agonists
171 G protein–coupled receptor 185 Minimum alveolar 201 Antihypertensive drugs
NMDA receptors concentration 202 Glyceryl trinitrate
172 GABA 186 Speed of onset of volatile Sodium nitroprusside
Adverse drug reactions anaesthetics 203 Hydralazine
187 Important structures – inhaled Nifedipine
Analgesia
anaesthetics 204 Beta blockers
173 Aspirin
Important structures – 205 Drugs used in ischaemic
Paracetamol
IV anaesthetics heart disease
174 Opioids – definitions and receptors
188 Inhaled anaesthetics – 206 Antiarrhythmics
175 Opioids – common effects
common properties 207 Digoxin
Opioids – dosage and
Inhaled anaesthetics –
other properties
noticeable differences Central Nervous System Drugs
176 Comparative features
189 Oxygen 208 Antidepressants
of opioids
190 Nitrous oxide Amitriptyline
177 NSAIDs
Nitric oxide 209 Phenytoin
IV Anaesthetics Carbamazepine and
178 General principles Other Anaesthetic Drugs sodium valproate
179 TIVA and context-sensitive 191 Non-depolarizing muscle 210 Antiemetics
half-time relaxants Anticholinergics
Miscellaneous Drugs
211 Cyclizine
Drugs acting on the uterus
212 Anticholinesterases
Neostigmine
213 Warfarin
Heparin
214 Oral drugs used in diabetes
Insulin
215 Antimicrobial drugs
216 Diuretics
217 Corticosteroids
Drugs used in thyroid disease
218 Colloids
Crystalloids
219 Drugs that act on
gastrointestinal tract
220 Antiparkinsonian drugs
Respiratory stimulants
Anatomy 230 Cutaneous nerves of
Respiratory System upper limb
221 Anatomy of the larynx Cutaneous nerves of lower limb
222 Anatomy of the nose 231 Brachial plexus
223 Mediastinum Stellate ganglion
Diaphragm 232 Anatomy of the vagus nerve
224 Tracheobronchial tree 233 Trigeminal nerve
225 Thoracic inlet and first rib 234 Anatomy of the orbit
Intercostal space 235 Cranial nerves
236 Internal jugular vein
Cardiovascular System
226 Structure of the heart and great Vertebral Column
vessels 237 Sacral anatomy and caudals
Cross section of the neck at C6
Nervous System 238 Vertebrae
227 Bones of the skull
Base of the skull Surface Anatomy
228 Cerebral arterial supply 239 Antecubital fossa
Venous drainage of head and Axilla
neck 240 Abdominal wall
229 Epidural and paravertebral Femoral triangle and lumbar
space plexus
241 Sacral plexus and sciatic nerve
242 Lower limb blocks
 Physics

Basic Principles of Measurement 1

Measuring system characteristics
Measurement
Measurement converts a value of a physical quantity into a form that can be observed and
recorded and that is repeatable and calibrated
●● In medical monitoring, data can be collected directly if it is electrical
●● Data may also be an evoked signal, such as in monitoring of neuromuscular blockade, or it may
be a transduced signal
●● A transducer will convert the input into usable data or a signal, usually an electrical signal, e.g. a
thermistor (temperature to electrical) or a piezoelectric device (pressure changes to electrical)

Signal-to-noise ratio (SNR)

Signal-to-noise ratio is a measure of the amplitude of the electrical signal compared with the
amplitude of the background interference (noise)
●● It is defined as a ratio of the signal power to the noise power
●● The noise is mainly the result of power line frequency signals and radiofrequency signals as well as
muscle activity added to the ECG
●● A poor SNR can be improved by eliminating the noise, differential amplifiers, filters and averaging
a repetitive signal
●● When the amplitudes are measured in Volts or Amperes:
signal amplitude
SNR = 20 log10
noise amplitude
Measurement systems – static characteristics
●● Static characteristics define the performance when the input is not changing
●● Accuracy is the degree of conformity of a measured or calculated quantity to its actual (true)
value. This is often quoted as a percentage
●● Precision (also called reproducibility) is the degree to which further measurements or calculations
will show the same or similar results. If a result is accurate and precise, it is called validity
●● Sensitivity is the relationship between the change in output reading and the measured quantity.
Less sensitive systems allow for a greater range
●● Linearity is a measure of the degree to which the displayed value is proportional to the true value.
On a graph of input against output, the ideal shape would be a straight line with the gradient
being the sensitivity
●● Non-linearity can be expressed as the maximum difference between the displayed and the actual
value or as this difference as a percentage of the maximum output. The rotameter is an example
of an instrument which is intrinsically non-linear
●● Hysteresis is a measure of the difference between the displayed value and the true value depend-
ing upon whether the true value is increasing or decreasing. It is seen with stretching and relaxing
of solid materials (e.g. in pressure transducers) and is due to loss of energy as friction and heat.
A graph of true value versus displayed value will have two lines: one for the true value increasing
and one for it decreasing
●● Drift is a measure of the degree to which the displayed value changes over time and is usually
caused by temperature changes or unstable components in the system. Drift is corrected by
zeroing
 Physics

Basic Principles of Measurement 2

Measurement systems – dynamic characteristics
Dynamic characteristics reflect the ability of the measuring system to respond to rapidly changing
inputs:
●● The dynamic response can be one of three types:
■■ Zero-order response – the displayed value tracks the measured value exactly
■■ First-order response – the displayed value moves towards the true value exponentially (e.g. in
a temperature probe)
■■ Second order – the displayed value may approach the true value like a first-order response or
may oscillate around the true value (for example, in invasive blood pressure monitoring)
●● Step response:
■■ The response to a rapid increase of the system being measured
■■ It is reflected by the:
● Response time – the time from the ‘step’ increase in the system being measured to 90% of
the output being displayed
● Rise time – the time taken for the output measurement to increase from 10%–90% of the final
value
●● Phase shift response:
■■ Any signal can be broken down into component frequencies (Fourier analysis)
■■ Each of these frequencies will undergo a different time delay as it passes through the measur-
ing system and this can distort the measurement
●● Damping
●● Frequency response
Basic measurement concepts

Input

Transducer Device to convert one form of

energy into another

Transmission path

Amplification
Signal conditioning – Processes signal for
Filtering
unit display/storage
Conversion
analogue digital
Display/storage
component

Output
 Physics

Basic Principles of Measurement 3

Resonance and damping, frequency response
●● Any system that oscillates (such as a pendulum) does so at a natural frequency; it is known as the
resonant frequency and is determined by inertial and compliance elements
●● Energy imparted to a system at its resonant frequency will amplify the signal. In invasive blood
pressure measurement, resonance must be avoided because it causes distortion of the wave-
form and leads to errors in measurement
●● Fourier analysis is the mathematical separation of waveforms into sine wave components at the
fundamental (slowest) frequency and harmonics (multiples of the fundamental frequency). The
more harmonics reproduced, the more accurate the signal breakdown. Analysis up to the tenth
harmonic is required for accurate invasive BP measurement
●● In order to avoid distortion, the resonant frequency of the invasive blood pressure measurement
system must be manipulated so that it is out of range of the operating frequency. This manipulation
must include the fundamental frequency and all harmonics to the tenth harmonic of the blood
pressure waveform. This is achieved by using short, stiff-walled, wide catheters with no blood
clots or air bubbles and minimal connections
●● The bandwidth is the range of frequencies over which the measurement system will respond and
should be 0–20 Hz for invasive arterial blood pressure
Resonance and damping, frequency response (cont.)
●● Frequency response is the response of the system (gain) plotted against the signal frequency.
As the frequency response is variable, there may be inaccuracy in the measured output; this is
maximal at the resonant frequency
●● Damping is a progressive decrease in the amplitude of oscillations because of dissipation of
energy. Mechanical damping is necessary with direct arterial blood pressure monitoring to pre-
vent amplification of the waveform by subsequent pulsations
●● With an underdamped system, the oscillations continue for a long time; falsely high systolic and
falsely low diastolic pressures will be displayed with invasive blood pressure monitoring
●● Critical damping occurs when there is a rapid fall in pressure just avoiding overshoot; the damp-
ing factor, D, is 1.0
●● Although overdamping avoids overshoot, the system will be slow to respond, therefore causing
falsely low systolic and falsely high diastolic pressures but with accurate mean arterial pres-
sure (MAP). Overdamping is common and is caused by air bubbles or blood clots
●● Optimal damping occurs when the damping factor, D, is 0.64; this produces the most rapid
response while avoiding excessive oscillations
 Physics

Basic Principles of Measurement 4

Calibration
Calibration is the setting up or correction of a measuring device or base level, usually by adjust-
ing it to conform to a dependably known and unvarying measure
●● A calibration curve is the graphical representation of the functioning relationship between
the expected value of the observed signal to the measured amount
●● Calibration aims to remove the effects of drift on the measurement. Drift may be gradient drift
(measurement value increases disproportionately to increasing input value) or offset drift (where
every measured value has a constant drift). These require one-point calibration. A combination of
offset and gradient drift requires two-point calibration
Calibration and damping

Underdamped
Offset + gradient drift
Gradient drift Critical damping
Displayed value

Overdamped

Pressure
Offset drift

Valid measurement

True value Time

Physics

Mathematical Concepts and Statistics 5

Mathematical concepts Physics
Sinusoids Repetitive processes of the body, such as traces from ECGs or invasive blood
pressure, can be represented by waveforms. These waveforms can be formed by
combining sine waves of different amplitude and frequency
Amplitude The maximum displacement of the wave from the horizontal axis
Wavelength Literally, the length of one wave from one corresponding peak to the next or one
trough to the next. One cycle is one complete wavelength. This corresponds to
360° (that is, one complete revolution). One sine wave that is 360° after another
identical sine wave will superimpose on the first and is therefore in phase. Two
otherwise identical sine waves that are 180° out of phase will cancel each other out
Frequency The number of complete cycles in one second; the SI unit of frequency is hertz.
The period is the time taken for one cycle to occur and is the reciprocal of the
frequency (Period = 1/Frequency)
Velocity Frequency × Wavelength
Parabolas Conic section (as are the circle, ellipse and hyperbola) that has an equation of
the form y = Ax2 + Bx + C. A reflector with a parabolic cross-section may be used
to focus light into a parallel beam. This is used in theatre lights
Mathematical concepts (cont.)
Differentiation and integration Equations can help us understand and demon-
strate how relationships behave in the natural
Differentiation will find the slope of the curve
world. Equations can be plotted on a graph to
(the rate of change at a given point in time)
give a visual image
d n d d x
x = nx n−1 sin x = cosx e = ex Straight line y = mx + c Parabola y = ax 2 + c
dx dx dx
y
Integration will find the area under the curve Circle
c Ellipse
1
∫ n
x dx =
n +1
x n+1 + c Parabola

Example: o x
Hyperbola

1
∫ x 5 dx = x 6 + c
6
100
Concentration (µg/mL)

80 Sinusoidal y = sin x Rectangular hyperbola

AUC
y
60 AUC segment 1
y=
x

40

20 x

0
0 2 4 6 8 10
Time (hour)
 Physics

Mathematical Concepts and Statistics 6

Logarithms and exponentials
Logarithm ●● The general form of a negative exponential
●● If y = ax, the logarithm to the base a is defined equation is y = Ae−kt
●● With a true negative exponential process, the
by x = logay
■■ For example, the log10 of 10 is 1, the log10 quantity will never reach zero because the
of 100 is 2, the log10 of 1000 is 3, etc. rate of change becomes smaller and smaller,
●● The natural logarithm (loge) is also denoted therefore the process goes on indefinitely
●● Taking the natural logarithm of both sides of
ln, where e = 2.718 and is known as Euler’s
the negative exponential equation y = Ae −kt
number
gives:
Exponential ln(y) = ln(Ae−kt) = lnA + ln(e−kt) = lnA – kt
●● As this is an equation for a straight line, a
●● In an exponential process, the rate of
graph of the natural logarithm of an exponen-
change of a quantity at any given time is
tial function against time will be a straight line
proportional to the quantity at that time
Exponential build-up
Exponential decay
●● An example of a wash-in or build-up expo-
●● An example of a negative exponential pro-
nential processes is the intake of volatile
cess is the rate of metabolism of certain
anaesthetic agents, in which the concen-
drugs being directly proportional to their
tration of agent in the alveoli exponentially
concentration in the plasma; this produces
approaches that in the inspired gas
a wash-out curve
●● Another example is lung volume during infla-
●● In normal lungs, the rate of ‘wash out’ of
tion with a pressure generator ventilator
nitrogen in pulmonary function tests is pro-
●● This follows the equation y = (1 – Ae−kt)
portional to its concentration
Logarithms and exponentials (cont.)
Exponential (cont.) ●● Time constant for the lung = compliance mul-
Positive exponential tiplied by resistance
●● The reciprocal of the time constant is equal
●● Bacterial growth is a tear-away (positive)
to the rate constant, k
exponential function, because the rate of
●● The rate constant, k, is also known as the con-
growth is proportional to the concentration at
stant of proportionality, because the prod-
any given time
uct of the quantity and k is equal to the rate of
●● The general form of an exponential equation
change of the quantity
for a tear-away function is: y = Aekt

Rate of exponential processes

●● Half-life is the time taken for the quantity to
decrease to half the current value
●● Time constant (τ, tau) is the time that it would
have taken to complete the process had the
initial rate of change continued
●● After one time constant, the quantity has
decreased to 37% of its initial value; time con-
stant is therefore longer than half-life
Clinical nugget
Lungs with high compliance (e.g. emphy-
sema) and high resistance (e.g. broncho-
constriction) will have an abnormally high
time constant and will need additional
time for gas emptying.
 Physics

Mathematical Concepts and Statistics 7

Exponential processes
Wash out/exponential decay y

For example y = Ae–kt

●● most drug elimination
●● wash-out of nitrogen when a patient switches to breathing
oxygen from a non-rebreathing circuit

y = (1 – Ae–kt) Wash in/build up t

●    Preoxygenation (wash-in of oxygen)

t
y = Aekt

Positive exponential
For example
●● development of action potential
●● growth of bacterial colony
t
Hierarchy of evidence
1. Systematic reviews/meta-analyses
2. Randomised controlled trials
3. Cohort studies
4. Case-control studies
5. Cross-sectional surveys
6. Case reports
THE COCHRANE
Systemic review COLLABORATION®

●● Explicit objectives using stated methods and

materials
●● Explicit and reproducible methodology
●● Clear question to be answered
●● Widespread search
●● Assess quality of studies found, apply eligibil-
ity criteria and exclude without prejudice
●● Gain as much raw data as possible (contact
authors)
●● Apply meta-analysis, plot findings (see
Funnel plot
A funnel plot is a scatterplot of treatment effect
against a measure of study precision. It is used
primarily as a visual aid for detecting bias or sys-
tematic heterogeneity. A symmetric inverted fun-
nel shape arises from a ‘well-behaved’ data set,
in which publication bias is unlikely.
0

‘Forest plot’) 0.2

●● Publication bias? (funnel plot)

Standard error
0.4
●● Find explanation for findings 0.6

Forest plot 0.8

The logo for the Cochrane Collaboration is a for- 1

est plot which represents the meta-analysis of a 1.2
systemic review of multiple studies testing ante- –4 –3 –2 –1 0 1 2 3 4
natal steroids and respiratory distress in neonates Log risk ratio
 Physics

Mathematical Concepts and Statistics 8

Randomised controlled trials
The gold standard design of clinical trials because it is considered the best known way of eliminating bias

Requirements ●● Clearly defined aims, methods and statistical analysis

●● Relevant
●● Original
●● Robust methods
Ethics committee ●● Must be obtained before patients recruited to a trial
approval ●● Committee has professional and lay members who determine whether the trial is
justified
●● Patients must be given relevant explanation of the purpose of the study and a
consent form
Power analysis ●● Calculation of the sample size necessary to detect a certain statistical difference
between treatment groups if a true difference exists
●● Part of the design of the study
●● Required result must be clinically significant as well as statistically significant
Recruitment ●● Strict inclusion and exclusion criteria
Randomisation ●● Carried out to make sure that all participants are equally likely to end up in any
treatment group, i.e. to minimise bias
●● Stratified randomisation can be used to minimise the differences in age, weight,
ASA status, etc.
●● Treatment compared with placebo, existing treatment or no treatment
Randomised controlled trials (cont.)
Blinding ●● Used to reduce the chance of ascertainment bias
●● In single-blind studies, the patient does not know what treatment they are
receiving
●● In double-blind studies, neither the patient nor the investigator knows which
treatment is being given
Possible causes ●● Selection bias: methodical difference in acceptance or rejection for inclusion in
of errors a trial or treatment group
●● Ascertainment bias: knowledge of treatment given
●● Drop-out bias: drop out more common in one treatment group
●● Poor randomisation
●● Unreliable data collection
●● Poor choice of statistical tool
Variability ●● May result from instrument precision or observer variability
●● May be reduced by using identical techniques, healthcare professionals,
surroundings, etc. for all patients
Data collection ●● Guidelines should be drawn up and available, and data collectors appropriately
trained
●● The means of data collection and analysis should be established before the study
is started
●● Machinery and monitors must be tested and calibrated
Endpoint ●● Must be determined with the total number studied or by periodic analysis and
termination of the trial when results become significant
Publication ●● Should include a comprehensive account of the methods used so that readers
can assess their validity
 Physics

Mathematical Concepts and Statistics 9

Errors Sensitivity
●● α is a type I error or false positive The number of true positives divided by the
■■ The probability of a positive finding from a total number with the condition
study being wrong ●● Describes the ability of a test to identify true
■■ Represented as the p value and 0.05 is positives (or exclude false negatives)
usually the maximum accepted
■■ As the p value is reduced, the risk of reject- Condition Condition
ing a statistically significant result (false present absent
negative) increases
●● β is a type II error or false negative Test positive a b
■■ The chance of not picking up a difference Test negative c d
when a difference actually exists
■■ Highest acceptable value is usually 0.2 ●● Sensitivity = a ÷ (a + c)

Power
Likelihood of the null hypothesis being cor- Specificity
rectly rejected The number of true negatives divided by the
●● Equals 1 − b total without the condition
●● With a power of 0.8, there is an 80% chance of ●● Describes the ability of a test to identify true
showing a statistical difference if such a differ- negatives (or exclude false positives)
ence actually exists ●● Specificity = d ÷ (b + d)
Positive predictive value (PPV)
The number of true positives divided by the
total number with an abnormal test
●● Describes the ability of a test to predict true
abnormality
●● Positive predictive value = a ÷ (a + b)
●● Negative predictive value = d ÷ (d + c)
Accuracy
The sum of the true positives and true nega-
tives divided by the total
Relative risk reduction (RRR)
Ratio of the probability of an adverse event
occurring in a treatment group versus the
­control group
●● If the risk of the event is reduced from A% to
B%, the relative risk reduction is [(A − B) ÷ A]
●● If events are rare (i.e. A is small), relative risk
reduction overestimates the treatment effect
●● If events are common (i.e. A is large), relative
risk reduction underestimates the treatment
effect
Absolute risk reduction (ARR)
The absolute decrease in percentage risk of
an adverse event by giving a certain treatment
●● If the risk of the event is reduced from A% to
B%, the absolute risk reduction is (A – B)%
Number needed to treat (NNT)
The number of patients needed to be given a
certain treatment for one patient to have the
desired effect
●● Number needed to treat = 1 ÷ absolute risk
reduction
 Physics

Mathematical Concepts and Statistics 10

Types of data and their representation
Statistics describe data from samples that are Distribution
parts of a population of similar items, events ●● Central tendency
or observations ■■ Median
■■ Mode
Null hypothesis ■■ Median
●● There is no difference between two ●● Scatter
­samples – they are both taken from the same ■■ Percentiles
population ■■ Standard deviation
●● The object of trials is to reject the null
hypothesis Types
●● Descriptive statistics simply describe the
The p value sample data
●● The probability of a given result occurring by ●● Inferential statistics are used to infer some-
chance thing about the population itself
●● p < 0.05 means that there is a less than 1 ●● Qualitative data are names or labels
in 20 probability of that result occurring by ●● Quantitative data are numerical
chance; it is the usual value required for sta-
tistical significance and to reject the null
hypothesis
Types of data and their representation (cont.)
Qualitative data
●● Nominal or categorical data have no partic-
ular order, e.g. type of operation; represented
by the mode (most common category)
●● Ordinal data are sequential but not numeri-
cal in that, for example, twice the value is
not double the magnitude, e.g. pain scores;
represented by the median (middle value
­ ●● Variance = Σ(x − x )2 ÷ (n − 1)
when placed in ascending order) and
­p ercentiles (percentage at or below a
­p articular value)
Quantitative data
●● Continuous data can be any number includ-
ing fractions, e.g. age
●● Discrete data can only be a whole number,
e.g. heart rate
●● Ratio data – the zero value is truly equal to
naught, e.g. degrees Kelvin
●● Interval data does not include a true zero,
e.g. degrees Celsius
Parametric or normally
distributed data
●● Characteristic symmetrical bell-shaped curve
●● Mean is sum of values divided by number of
values
●● Standard deviation is equal to the square
root of the variance
●● Approximately 68% of the data lies within one
standard deviation on either side of the mean
and about 95% within two standard deviations
●● Mean = mode = median
●● The standard error of the mean represents
how certain we can be that the mean of a
sample corresponds to the population mean
■■ It equals the standard deviation divided
by the square root of the number of
observations
■■ There is a 95% chance of the true mean
lying within two standard errors of the
population mean; this is known as the
95% confidence interval
 Physics

Mathematical Concepts and Statistics 11

Choice of simple statistical tests for different data types
● Qualitative data may be compared using the chi-squared test, which compares the frequency
of observed results to the expected frequency if there were no difference between groups. Fisher’s
exact test is used if any expected frequency is less than five
● The type of test used to compare quantitative data depends upon whether or not it is normally
distributed
■ Normally distributed data from two groups may be analysed with the Student’s t-test, which
compares the mean and standard deviation for each group
■ Non-normally distributed data from two groups may be compared with the Mann–Whitney
U-test
● With more than two groups, multiple comparisons are made and there is a 5% chance of obtain-
ing statistical significance by chance alone if the above tests are used
■ For normally distributed data, therefore, analysis of variance (ANOVA) is used instead
■ For non-normally distributed data of more than two groups, the Kruskal–Wallis test is used
● If paired data is used, paired Student’s t-test or paired ANOVA tests may be used for normally
distributed data
● For non-normally distributed paired data, the Wilcoxon signed-rank test can be used or the
Friedman’s test can be used for more than two groups
Frequency distributions
Normal (Gaussian) distribution Parametric (skewed) distribution

Mode
Median

34.1% 34.1% Mean

2.1% 2.1%
0.1%
13.6% 13.6%
0.1% f

–3σ –2σ –1σ µ 1σ 2σ 3σ

Outliers

The mean, median and mode are identical in a

normal distribution.
Physics

SI Units 12
Base SI units
Measure SI unit Description

Length Metre (m) The distance light travels in a vacuum in a specified time
Mass Kilogram (kg) The mass of a specific piece of platinum–iridium alloy kept at
Sèvres near Paris
Time Second (s) The frequency of radiation emitted by caesium-133
Current Ampere (A) The current that produces a force of 2 × 10−7 N/m between two
straight parallel wires of infinite length that are one metre apart in a
vacuum
Temperature Kelvin (K) 1/273.16 of the temperature of the triple point of water – the point
at which water vapour, ice and liquid water exist in equilibrium.
Temperature is the property of a substance that determines
whether heat is transferred to or from it
Luminous Candela (cd) A description of a physical process that will produce one candela
intensity of luminous intensity
Amount of Mole (mol) The quantity of substance that contains as many particles as there
Substance are atoms in 12 g of carbon-12
Derived SI units
Measure Derived SI unit Description

Temperature Degree Celsius The magnitude of a degree Celsius is equal to that of a degree
Kelvin. The relationship is °C = K − 273.15
Force Newton The force required to accelerate a mass of one kilogram at one
metre per second per second. 1 N = 1 kg ⋅ m ⋅ s−2
Pressure Pascal One pascal is equal to one newton per square metre. 1 Pa = 1 N ⋅ m−2
Energy Joule The amount of energy required to move the point of application
(or work) of a force of one Newton a distance of one metre. 1 J = 1 N ⋅ m
Electronvolt (eV) The work done moving one electron through a potential
difference of one volt in a vacuum
Power Watt (W) The rate of expenditure of energy in joules per second. 1 W = 1 J ⋅ s−1
Frequency Hertz (Hz) The rate in cycles per second
3
Volume Cubic metre (m )
Litre (L) One thousandth of a cubic metre
Density Kilograms per cubic metre (kg ⋅ m−3)
Velocity Metre per second (m ⋅ s−1)
Acceleration Metre per second per second (m ⋅ s−2)
Physics

SI Units 13
Electrical and magnetic derived units
Measure Derived SI unit Description

Charge Coulomb (C) One coulomb is the amount of charge transported in

one second by a current of one ampere. C = A ⋅ s
Electrical potential/ Volt (V) The potential difference between two points that imparts an
electromotive force energy of one joule per coulomb.
V = J/C. But C = A ⋅ s and W = J ⋅ s−1 so V = W ⋅ A−1
(Power = Current × Potential difference)
Resistance Ohm (Ω) A potential difference drop of one volt producing a current of
(also reactance one ampere gives the conductor a resistance of one ohm.
and impedance) Ω = V ⋅ A−1
Capacitance Farad (F) A capacitance of one farad produces one volt of potential
difference for an electric charge of one coulomb.
F = C ⋅ V−1
Induction Henry (H) When an electric current that is changing at one ampere per
second causes an electromotive force across the inductor of
one volt, the circuit has an inductance of one henry.
H = V ⋅ s ⋅ A−1
Magnetic flux/ Weber (Wb)/ A magnetic flux of one weber, passing through a conducting
magnetic flux tesla (T) loop and reduced to zero at a uniform rate in 1 second,
density induces an electric potential of one volt in the loop. One weber
is equal to one volt second.
Wb = V ⋅ s. T = Wb ⋅ m−2
Non-SI units of relevance to anaesthesia
Name of unit Symbol Quantity Definition

Calorie cal Energy 1000 cal = 1 Kcal = 4.184 kJ

Electron volt eV Energy 1 eV = 1.602 × 10−19 J
Dyne dyn Force 1 dyn = g ⋅ cm ⋅ s−2
Barye (cgs unit) Pressure 1 dyn ⋅ cm−2 = 0.1 Pa
Torr torr Pressure 1 torr = 1/760 standard atmosphere
Bar bar Pressure 1 bar = 105 Pa
Atmosphere atm Pressure 1 atm = 101325 Pa
Pounds per square inch psi Pressure 1 psi = 6.894 × 103 Pa
Millimetres of mercury mmHg Pressure 1 mmHg = 133.332 Pa
Centimetres of water cmH2O Pressure 1 cmH2O = 98.06 Pa
Gauss Gs Magnetic flux density 1 Gs = 10−4 tesla
Maxwell Mx Magnetic flux 1 Mx = 10−8 weber
 Physics

Simple Mechanics and Pressure 14

Simple mechanics
●● Mass is the quantity of matter in a substance and is measured in kilograms
●● Force is a physical influence that changes the state of rest or motion of a body. It causes the
body to accelerate in the direction of the force and is a vector (i.e. has both direction and magni-
tude). The SI unit of force is the newton
●● Work is a form of energy; whenever energy is expended work is done. The amount of work
done is equal to the force multiplied by the distance moved in the direction of the force. The SI unit
of work is the joule
●● Power is the rate of working. It can therefore be measured in joules per second, also known as
watts
●● Newton’s first law states that a body remains at rest at a state of constant velocity unless acted
on by a force
●● Newton’s second law states that Force = Mass × Acceleration
■■ Hence N = kg ⋅ m ⋅ s−2; J = kg ⋅ m2 ⋅ s−2 and W = kg ⋅ m2 ⋅ s−3
●● Newton’s third law states that for every action there is an equal and opposite reaction
Pressure definitions
Pressure = Force ÷ Area
●● The derived SI unit of pressure is the pascal, Clinical nugget – Myocardial
which is equal to one newton per square metre pressure/volume loops
● 1 Pa = 1 N ⋅ m −2
P = F/A. Then multiplying top and bottom
by D
Pressure equivalents
●● Atmospheric pressure is the pressure in the P = (F × D)/(A × D)
Earth’s atmosphere caused by the weight of air
● 1 atmosphere ≈ 101.3 kPa ≈ 760 mmHg ≈ But F × D = Work and A × D = Volume
760 torr 1033 cm of H2O 1.013 bar, so that:
P = Work/Volume. Thus Pressure × Volume =
● 1 kPa ≈ 7.6 mmHg ≈ 10 cmH2O
Work (energy)
Partial pressure That is demands on the myocardium is
● Partial pressure is the pressure exerted by determined by pressure and stroke volume
each gas in a mixture of gases
● It is equal to the pressure the single gas
would exert if alone (Dalton’s law of partial
pressures)
● Tension is the partial pressure of a gas in
­solution, for example oxygen in blood
Physics

Simple Mechanics and Pressure 15

The gas laws – for ideal gases
Boyle’s law At a constant temperature, the volume of a fixed mass of gas is V ∝ 1/P
inversely proportional to the absolute pressure
Charles’ law At a constant pressure, the volume of a fixed mass of gas is directly V∝T
proportional to the absolute temperature
Gay-Lussac’s law At a constant volume, the absolute pressure of a fixed mass of gas P∝T
is directly proportional to the absolute temperature
Avogadro’s Equal volumes of ideal gases at constant temperature and pressure
hypothesis contain equal numbers of molecules
At standard temperature and pressure, one mole of a substance
contains 6.023 × 1023 particles and one mole of gas occupies
22.4 litres
The ideal gas A combination of the above PV = nRT
equation
Dalton’s law The pressure exerted by a fixed mass of gas in a mixture of gases is
the same as the pressure it would exert alone
Henry’s law At a constant temperature, the amount of gas dissolved in a solvent
is proportional to its partial pressure above the solvent

Abbreviations: P = pressure, V = volume, n = number of moles of gas, R = universal gas constant (8.3),
T = temperature
Standard temperature and pressure = 273.15 K and 100 kPa.
Pressures and temperatures
●● Gauge pressure is total pressure minus atmospheric pressure. For example, the gauge pressure of
an ‘empty’ oxygen cylinder is 0, but the cylinder contains gas at atmospheric pressure
●● Absolute pressure = Gauge pressure + Atmospheric pressure (that is, true total pressure)
●● Critical temperature is the temperature above which a substance cannot be liquefied no mat-
ter how much pressure is applied. Below this temperature, the substance is a vapour; above this
temperature, it is a gas
●● Critical pressure is the pressure required to liquefy a vapour at its critical temperature
●● Pseudocritical temperature, at a given pressure, is the temperature above which a mixture of
gases will not separate out into its constituents
●● At a pipeline pressure of 4.1 bar, the pseudocritical temperature of an equal mixture of nitrous
oxide and oxygen is −30°C whereas for Entonox cylinders (137 bar) it is −5.5°C

Clinical nugget
If the ambient temperature is above the critical temperature (which it could be with N2O of
36.5°C), then the cylinder could be in danger of pressure damage or even exploding. If the
ambient temperature, is below the pseudocritical temperature which is feasible for Entonox
in cold conditions, (< −5.5°C) then there is a danger of separating to oxygen gas and liquid
nitrous oxide.
 Physics

Simple Mechanics and Pressure 16

Pressure measurement in gases
The manometer ●● One type is the Bourdon gauge:
■■ Spiral tube of oval cross-section
●● The simplest method of pressure measurement
■■ The tube uncoils as it becomes circular in
●● It does not need calibration, so it can be used
cross-section with increasing pressure
to calibrate other devices
●● Does not require a power supply
●● The pressure is balanced against a column of
●● Mechanically tough
liquid of known density – usually water for low
●● Cannot be used for very low pressures
pressures and mercury for higher pressures
●● Difficult to recalibrate
●● The pressure is equal to the depth multiplied
by the liquid density multiplied by the accel-
eration due to gravity, hence the commonly Piezoresistive strain gauge
used units are cmH2O and mmHg ●● Piezoelectric effect is the generation of
●● Mercury is 13 times more dense than water
charge in some solid materials, e.g. crystals,
●● The vertical height gives the pressure value;
when they undergo mechanical stress
the tube itself does not need to be vertical ●● Resistance varies with mechanical strain,
●● It is bulky and does not provide a direct
and the gauge forms one arm of a bridge
reading
circuit that produces a small current that is
amplified and transduced
Aneroid gauges ●● Versatile and suitable for measuring high and
●● Mechanical devices that contain a mecha- low pressures
nism that moves a pointer according to the ●● Requires a power supply and is susceptible
pressure, e.g. by expansion of a sealed cap- to interference
sule of gas
Bourdon pressure gauge Piezo-electric effect
●● The generation of electricity by some materi-
als (e.g. crystals) when undergoing mechani-
cal stress
●● The reverse effect is seen when an electric
Direction
of movement
charge is passed across this material and
with increase there is a change in its size and shape
in pressure ●● Used in the ultrasonic transducer for
ultrasonography

Piezo-electric
material

Pressure

Cross section of tube changes from

Pressure

applied

Flattened to circular on exposure to

high pressure
 Physics

Simple Mechanics and Pressure 17

Pressures of anaesthetic equipment
Cylinder pressures
Pressure

Gas Phase in cylinder (kPa) (bar)

Oxygen Gas 13,700 137
Nitrous oxide Mixed liquid and vapour 4,400 44
Entonox (50:50 O2:N2O) Gas 13,700 137

Anaesthetic machine pressures

Pipeline pressure ●● Gases supplied at 400 kPa (4 bar) except medical air for driving surgical
instruments, which is supplied at 700 kPa (7 bar)
Pressure regulating valves* ●● 400 kPa (4 bar)
Flow restrictors* ●● Placed upstream of flow meters
●● Protect machine from damaging surges in pipeline pressure (100–200 kPa)
Flow control valves ●● Govern transition from high to low pressure
Non-return pressure relief ●● Downstream of vaporizers on the back bar and prevent damage to flow meters
safety valves* ●● Open at 35 kPa
Emergency oxygen flush ●● Supplied by high pressure system directly
●● Provides 37–75 L/min at 400 kPa
Oxygen failure alarm ●● Sounds at pressures lower than 200 kPa
Adjustable pressure limiting ●● Needs <0.1 kPa (<1 cmH2O) to actuate in the open position and produces maximal
valve (Heidbrink valve)† pressures of 7.0 kPa (70 cmH2O) when closed
Reservoir bag† ●● Maximal attainable pressure 60 cmH2O
*Protect the machine from barotrauma
†
Protect the patient from barotrauma
Manufacture and storage of gases
Manufacture of gases
●● Oxygen
■■ Fractional distillation of liquefied air (industry)
■■ Oxygen concentrators. Aluminium silicate
(‘The Zeolite’), which must be dust-free, is used
as a molecular sieve to adsorb nitrogen from
the air leaving approximately 93% oxygen
●● Nitrous oxide
■■ Heating ammonium nitrate to 250°C
■■ NH4NO3 → N2O + 2H2O; other gaseous impuri-
ties will need to be filtered out
●● Carbon dioxide
■■ A by-product of many manufacturing reactions
■ For example the thermal (850°C) decom-
position of limestone to produce quicklime
CaCO3 → CaO + CO2
Storage of gases – Cylinders
●● Manufactured from molybdenum steel
●● Quality assurance (BOC) includes visualization
of cylinders both without and within, and hydrau-
lic testing every 5 years
●● Oxygen and air are stored as compressed gases
(critical temperature of O2 is −118.4°C)
●● Nitrous oxide and carbon dioxide are vapours
(critical temperatures of 36.5°C and 31°C
respectively)
●● The filling ratio (0.75 in temperate climates) will
need to be reduced (0.67) if the ambient temper-
ature can exceed the critical temperature
●● Volume of oxygen in the cylinder is proportional
to the pressure; fluctuations due to temperature
changes will be insignificant
●● Volume of nitrous oxide can be calculated by
weighing the cylinder and knowing the tare (the
weight of the empty cylinder)
●● Cylinders are identified by their colours and by the
pin-index system which should ensure that pres-
surised gases are not connected to the wrong yoke
●● Gases/vapours can be stored in manifolds,
banks of cylinders, one ‘duty’ and one ‘reserve‘
and connected to the users through a piped
medical gas and vacuum (PMGV) system
Storage of oxygen – The VIE
(vacuum-insulated evaporator)
●● Liquid oxygen is transported in a specially insu-
lated tanker and is delivered to the VIE which is kept
at −183°C by a vacuum between two layers of steel
●● Gas boils off through a restrictor and superheater
at the top of the cylinder
●● The inefficiency in the vacuum insulation is offset
by slow evaporation of liquid oxygen, thus cool-
ing the remainder
●● The VIE rests on a weighing device in order to
measure the contents (as in N2O cylinders)
 Physics

Simple Mechanics and Pressure 18

Gases and vapours
Gaseous state is the form of matter in which molecules are far apart and constantly moving
● Gases exert pressure as a result of the collisions of molecules against the walls of a container
● Gas
■ A gas is a substance in the gaseous state above its critical temperature
■ A gas cannot therefore exist as a liquid at that temperature
● Vapour
■ A vapour is a substance in the gaseous state below its critical temperature
■ At the saturated vapour pressure, it will exist in equilibrium with the liquid phase
● Gases, vapours and liquids are all fluids that behave similarly under flow conditions
● Both gases and liquids fill the shape of containers
● Liquids are more affected by gravity because of their increased density
● The density and viscosity of fluids affect how they flow
● Flow of fluids through tubes are inversely proportional to their viscosity, whereas through an orifice,
flow is inversely proportional to the square root of the density
Isotherms for nitrous oxide
Temp. < Critical Temp. >
critical temp. critical
temp. temp.

Liquid Gas
Pressure

Liquid
+
vapour
Vapour

Volume

● The critical pressure of a substance is the pressure needed to liquefy a vapour at its critical tem-
perature; for N2O this is 72 bar
● Critical temperature for N2O = 36.5°C
 Physics

Thermodynamics 19
Heat and laws of thermodynamics
●● Heat is a measure of the vibrational kinetic energy (K.E. = 1/2 mv2) of the particles of a substance
and is dependent on the number of particles involved. Heat may be transferred from one sub-
stance to another
●● Specific heat capacity is the amount of heat needed to increase the temperature of one kilo-
gram of a substance by one kelvin
●● Temperature is the thermal state of an object and is a measure of the ability to transfer heat to
another object. Therefore, a small object at a high temperature may contain less heat than a
larger one at a lower temperature
●● Calorimetry is the measurement of the chemical potential energy stored in the bonds of an
organic substance. It involves the combustion of the substance to carbon dioxide and water in an
oxygen-containing compartment surrounded by a quantity of water or ice. The amount of energy
released can be calculated by measuring the increase in the temperature of the water or the
quantity of ice that melts
●● Laws of thermodynamics
■■ Zeroth law: If system A and system B are both in thermal equilibrium with system C, then system
A is in thermal equilibrium with system B (this is the notion of temperature)
■■ First law: In a closed system the total amount of internal energy remains unchanged
■■ Second law: In a natural thermodynamic process the sum of entropy (a measure of disorder in
large systems) increases
■■ Third law: The entropy of a system approaches a constant value as the temperature approaches
absolute zero
Heat definitions
●● Conduction is the transfer of heat from one substance to another through the transfer of energy of
molecules to adjacent molecules; it occurs without movement of the substance itself. Clothes trap
a layer of air that acts as an insulator because air is a poor conductor of heat
●● Convection is the transfer of heat through a liquid or gas by movement of the fluid or gas itself
●● Radiation is the transfer of heat by means of electromagnetic waves
●● Evaporation is the change of state from liquid to vapour that occurs as a result of molecules break-
ing free of intermolecular bonds. Loss of latent heat of vaporization on the skin surface leads to
cooling, which may be increased by a factor of 10 when sweating
●● Linear coefficient of expansion is a measure of the amount a specific metal expands by increas-
ing its temperature and forms the basis of the bimetallic strip
 Physics

Thermodynamics 20
Temperature definitions
●● Freezing point is the temperature at which a cooling liquid becomes solid at a given pressure. With
increasing pressure, freezing point increases
●● Boiling point is the temperature at which a heated liquid becomes a gas at a given pressure. It is
the point at which the saturated vapour pressure equals the ambient pressure
●● Latent heat of fusion is the energy needed to change a substance from solid to liquid state with-
out changing its temperature (unit J kg −1)
●● Latent heat of vaporization is the energy needed to change a substance from the liquid to the
gaseous state without changing its temperature (unit J kg −1). Latent heat is needed to break the
bonds holding the substance together in either its solid or liquid state. In an isolated system, there-
fore, as a liquid evaporates, the temperature of the remaining liquid will fall because of the energy
needed for vaporization
●● Vapour pressure is the pressure caused by the molecules of a liquid that escape from its surface
and exert pressure on the walls of a closed container. Increasing the temperature increases the
kinetic energy of the molecules, thus increasing the vapour pressure in a non-linear manner
●● Saturated vapour pressure (SVP) at a given temperature is the vapour pressure at equilibrium
when the number of particles escaping the liquid is equal to the number entering it and the ambi-
ent air is saturated
●● Colligative properties of a solution are the change in its properties due to the number of solute
particles present. As the molar concentration of solute increases, there is a proportional
■■ increase in osmotic pressure
■■ decrease in freezing point (1.86 K per osmol of solute per kg solvent); hence, salting the roads
in winter and the principle of how an osmometer works
■■ increase in boiling point (0.52 K per osmol per kg)
■■ decrease in vapour pressure of solvent – this is Raoult’s law
Measurement of osmolarity or osmolality can use any of the above colligative properties
Temperature definitions (cont.)
●● OsmolaRity = number of osmoles of solute per litre of solution
●● OsmolaLity = number of osmoles of solute per kg of solvent
●● Below 500 mOsm the mass of the solute is negligible and these terms are interchangeable
●● Tonicity=the effective osmolarity of a solution. This takes into account the particles able to exert an
osmotic pressure across a particular membrane

Clinical nugget – Osmolality of plasma and urine

By comparing abnormal results of urine and/or plasma osmolality the clinician can be guided
as to the underlying condition of the patient. For example, high or normal plasma osmolality
with high urine osmolality could indicate dehydration, renal disease or congestive cardiac
failure, whereas low plasma osmolality with high urine osmolality could indicate SIADH (syn-
drome of inappropriate antidiuretic hormone secretion).

●● The triple point of water is the single combination of pressure and temperature at which the three
phases of ice, water and water vapour coexist in equilibrium. It is at 0.006 atmospheres (611.7 Pa)
and 0.01°C. It forms part of the definition of the degree Kelvin
 Physics
Measurement of temperature
●● A thermometer works by using the change in a physi-
cal property of a substance brought about by tem-
perature. For accuracy, this change must be reliable,
reproducible and quantifiable
●● Contact thermometers work by equilibrating with the
temperature of the body to be measured, so they
must be in direct contact with the body
●● Non-contact thermometers work from a distance
Non-contact thermometers
A thermophile measures the infrared radiation emitted
by the eardrum to form the basis of the tympanic thermom-
eter. It is made from several thermocouples connected in
series to increase the generated voltage. The reference
junctions are connected to a temperature-stable mass
at room temperature, and the measuring junctions are
exposed to the infrared radiation from the eardrum
Contact thermometers
Physical thermometers
●● These may use change in density of a
■■ metal (bimetallic strip)
■■ liquid (alcohol or mercury in glass)
■■ liquid crystal thermometers – contain heat-sensitive
liquids crystals that change colour with change in
temperature
Thermodynamics 21
■■ gas (constant volume gas thermometer)
●● The Bourdon gauge thermometer actually mea­sures pres-
sure but is calibrated to show temperature
Electrical thermometers
●● In the platinum resistance thermometer, increasing
temperature causes a measurable increased resis-
tance. This is usually incorporated into a Wheatstone
bridge circuit
●● A thermistor contains a metal oxide semiconductor
bead in which resistance decreases with increasing
temperature. This is also often used with a Wheatstone
bridge. As they respond rapidly, thermistors are used
to measure core temperature in the operating theatre
and blood temperature in the pulmonary artery cath-
eter. Autoclaving changes the calibration, which leads
to inaccuracy
●● In a thermocouple, a voltage, which is proportional to
the temperature (the Seebeck effect), is generated
at the junction of two different conductors. The total
generated voltage is the difference between the two
voltages generated by each conductor. A reference
junction is kept at constant temperature to enable
calibration of the thermocouple. Thermocouples are
simple, cheap, tough, small and work over a wide
range of temperatures
Graphs relating to temperature
Seebeck effect Graph showing heat versus
●● Tc = (cool) reference temperature at thermo- temperature (water at 1 atmosphere)
couple A and change of phases
●● Th = (hot) measured temperature at thermo-

Temp (°C)
couple B
Material X
Tc Th

A Mat Y Mat Y B
110
100
Vo 90
●● Vo = Seebeck electromotive force (emf) can 80

Latent heat of evaporation

be used to express Th

Latent heat of fusion

70
60
Plot of resistance/temperature for 50
thermistor showing near linearity 40
30
28
24 20
Resistance (kΩ)

20 10
16
12
0
8 –10
4
10 20 30 40 50 60 Energy imparted
Temperature °C
 Physics

Thermodynamics 22
Clinical aspects of heat and temperature
The proportion of heat lost in an anaesthetized Consequences of hypothermia
patient is approximately: ●● ↑ risk of surgical site infections
●● Conduction 3%–5% ●● ↑ risk of adverse myocardial events
●● Convection 30% ●● Shift of O2 dissociation curve to left
●● Radiation 40%–50% ●● Prolongation of drugs effect
●● Evaporation 20%–25% ●● ↓ in minimum alveolar concentration (MAC) of
●● Respiration 0%–10% volatiles
●● Bleeding disorders
General anaesthesia effects on a patient’s temperature ●● Shivering post-op
●● Cold theatre
●● Lack of behaviour adaptation (e.g. putting on Sites to measure core temperature
clothes) ●● Naso-pharynx (approximates to brain)
●● Depression of thermoregulatory centre ●● Lower third of oesophagus (approximates to heart)
●● Blood diverted to periphery and expansion of ●● PA catheter (blood)
core ●● Bladder (with high flow urine)
●● Cold IV fluids and surgical irrigation fluids ●● CPB machine (blood)
●● Latent heat of evaporation from medical gases Sites to measure near-core temperature
●● Axillary
Neuraxial anaesthesia effects on a patient’s ●● Oral (e.g. pre-operative)
temperature ●● Bladder (low flow urine)
●● Lack of afferent temperature signals from anaes- ●● Rectal (tends to lag behind, unreliable due to
thetized patient presence of faeces)
●● Decrease of shivering and behaviour adaptations Peripheral (skin) temperature should be about 2°C–4°C
●● Sedative drugs lower than core temperature
●● Cold IV fluids and surgical irrigation fluids

20% of surgical patients experience peri-operative

hypothermia (<36°C)
Patient warming systems
Prevention of heat loss during anaesthesia can
improve outcomes (e.g. surgical site infection
rates, blood loss, mortality) and is particularly
important in neonates and the frail elderly
Blankets and mattresses
● Covering as much as the patient as possible
with warm blankets and gamgee. Expose as
little as possible for as short as time a possible.
Hypothermia can set in even before induc-
tion of anaesthesia so use covers whilst the
patient is waiting
● Forced air warmers (FAWs) advocated on
operations >30 minutes. They use convection
to prevent and treat hypothermia. In children
and neonates it is best done by placing the
patient on the blanket and forcing the warm
air up around the baby
● Complications from FAWs include burns
(especially if used incorrectly (e.g. hosing or
major vascular operations during aortic cross
clamping), pressure ulcers (in arteriopaths)
and increase infections (not evidenced)
● Electrical blankets can interfere with
monitoring
● Others include water-filled mattresses/blan-
kets, resistive polymer blankets, electric heat-
ing pads
Ambient temperature and
humidification
● Aim for ambient temperature 22°C–24°C and
humidity about 50%. This will be a fair compro-
mise between patient cooling and bearable
working conditions
● Use humidified inspired gases (e.g. using
heat–moisture exchanger [HME])
● Overhead heaters can be used for neonates
but they are impractical for long operations
as they also heat the anaesthetists/surgeons
Fluid warming devices
● Recommended for all adult fluid administra-
tion in excess of 500 mL
● Divided into pre-warming (using warming
cabinet) and warming during administration
■ Dry warming systems
■ Counter-current heat exchange systems
(good for low-flow, e.g. in neonates)
■ Water baths
■ Convective air systems
■■ Insulators
Invasive methods
● Warmed irrigation of cavities (e.g. peritoneal)
and organs (e.g. stomach, bladder)
● ECMO and CPB (cardiopulmonary bypass)
 Physics

Thermodynamics 23
Humidity
●● Absolute humidity is the mass of water vapour in a given volume of gas at a given temperature
and pressure in gm−3 or mg ⋅ L−1
●● The following table shows normal values for absolute humidity

Inspired air at 20°C 17 gm−3

Upper trachea, fully saturated at 34°C 34 gm−3
Alveoli, fully saturated at 37°C 44 gm−3

●● Relative humidity is the mass of water vapour present in a given volume of gas as a percentage
of the total mass that would saturate that volume of gas at the same temperature and pressure
●● As the partial pressure of water is proportional to its mass, the relative humidity is also equal to the
water vapour pressure divided by the saturated water vapour pressure
●● The amount of water required to saturate a gas increases with increasing temperature
●● A hair hygrometer measures relative humidity. As the relative humidity increases, the length of the
hair increases, which moves a pointer
Humidity (cont.)
● A wet-and-dry-bulb hygrometer uses two mercury-in-glass thermometers. One reads the ambient
temperature of the surroundings. The bulb of the second thermometer sits in an open container
of water, which cools as the water evaporates because of loss of latent heat of vaporization. The
humidity of the surroundings varies the rate of evaporation and therefore the difference in the
temperatures measured by the two thermometers. Tables can be used to determine the relative
humidity for a given temperature difference
● In Regnault’s hygrometer, air is bubbled through a silver-coated tube containing ether, and the
temperature at which condensation occurs on the outside of the tube is noted. This is called the
dew point and is the temperature at which the ambient air is fully saturated. The saturated vapour
pressure (SVP) at dew point divided by the SVP at ambient temperature is equal to the relative
humidity. The relative and absolute humidities can be determined by using tables
● Absolute humidity can also be measured by change in resistance or capacitance of a substance
because of absorption of water vapour from the atmosphere. The mass spectrometer or ultraviolet
light absorption can also be used to measure humidity
 Physics

Thermodynamics 24
Humidifiers
●● Humidification is important to prevent the following:
■■ drying of the respiratory mucosa
■■ thickening of mucus resulting in airway plugging
■■ decreased ciliary activity
■■ keratinization and ulceration
■■ heat loss (reduces loss of latent heat of vaporization)
●● Methods may be active or passive
Passive
Tracheal water/ ●● Potentially dangerous
saline instillation ●● Inefficient
Bottle humidifier ●● Oxygen is bubbled through water at room temperature
●● At best this will achieve a relative humidity of 40%
Soda lime in the ●● Reaction of soda lime with CO2 produces water as a side product
breathing system ●● Can achieve 60%–70% relative humidity
Heat and moisture ●● Hygroscopic, consisting of a foam or chemically coated membrane
exchanger (HME) ●● Expired gases pass through the capsule and allow water and heat to be retained through
conservation of latent heat of vaporization
●● Efficiency is up to 90%
Active
Hot water bath ●● Thermostatically controlled water tank with a large surface area through which the inspired
gas is passed through
●● 100% humidity (full saturation) can be achieved
●● Risk of scalding, electrocution and colonization by micro-organisms
Nebulizers ●● Produce a fine mist in the delivered gas
●● No saturation limit
●● Excess amounts of water may be deposited in the trachea
Humidifiers (cont.)
Fires and explosions
For a fire or an explosion to occur there needs to
be three prerequisites
● A combustible material
● A source of ignition–the activation energy
● Oxygen (or another oxidizing agent like N2O)
to support the combustion
The end result will be reaction products and
heat energy which causes the temperature of
the mixture to increase
Ratio Pressure Temperature Speed
Fire Flammability 1 bar 200°C–500°C Ms–1
Explosion Stoichiometric 25 bar 3000°C 8 Mach
Definitions
● Flammability limits: The ratio of the fuel and
the oxygen beyond which (in either direction)
the mixture will not ignite. The flammability lim-
its will hence differ if the fuel is in oxygen or air
●● Stoichiometric mixtures: This is the combina-
tion of the fuel and the oxygen in such a ratio
that all the ingredients are used up. The reac-
tions that take place at this ratio provide the
most energy and are more likely to be explosions
Sources of ignition
● Static electricity (theatres and equipment
were all provided with anti-static precautions
but with the phasing out of ether and cyclo-
propane this is no longer necessary)
●● Other sources of sparks (e.g. faulty equipment)
● Diathermy
● Lasers
● X-ray equipment
● Hot surfaces/heat (see below)
Combustible material
● Anaesthetic agents (mostly historical, e.g.
cyclopropane, diethyl ether)
● Ethyl chloride
● Surgical spirit
● Methane and hydrogen from patient’s gut
● Oil and grease on cylinders (the sudden
exposure of grease or oil on an oxygen cylin-
der to the high pressures in the cylinder, e.g.
when it is opened, can cause enough heat to
ignite it and cause an explosion)
 Physics

Electricity and Magnetism 25

Basic concepts
Electricity and magnetism
● The outer layer of electrons in conductors is loosely bound and will easily move under an electro-
motive force. Insulators have tightly bound electrons. Semiconductors will conduct when external
energy is applied (light, heat, electricity) allowing some electron movement
● A potential difference (V) across a conductor causes a current (I) to flow by the movement of
electrons or ions. One volt is the potential difference between two points when one joule of work is
done per coulomb of electricity flowing from one point to the other
● The resistance (R) of the conductor is caused by collisions of the electrons and is given by
V
■ Ohm’s law: R =
I
● Direct current (DC) flows in one direction only, whereas alternating current (AC) alternates
between one direction and its opposite
● Two resistors in series have a total resistance given by the sum of the two individual resistances
● Two resistors (R1 and R2) in parallel have combined resistance (R) given by
1 1 1
■ = =
R R1 R2
● Power (W, watts) is the rate of expenditure of energy (in joules per second) and is given by the
current multiplied by the potential difference
● Electrical charge is measured in coulombs and is the product of the current and the time for which
it flows. A current of one ampere is one coulomb per second
Basic concepts (cont.)
Impedance is the term used to describe the resis-
tance of capacitors and inductors in an AC cir-
cuit and indicates that the resistance depends
upon the frequency of the alternating current.
Impedance is measured, like resistance, in ohms but
has the symbol Z.
A high frequency AC current passes more eas-
ily through capacitors, whereas a low frequency
current passes more easily through inductors, the
basis of bandwidth filters
Capacitors and capacitance
A capacitor is an electrical component that, when
a potential difference is applied across it, stores
charge on two conductive plates separated by an
insulator. The amount of charge stored depends
on the capacitance
●● The unit of capacitance is the Farad, which is the
amount of charge stored per volt applied across the
capacitor. Therefore: C = Q/V, where C = capaci-
tance, V = potential difference and Q = charge
●● Alternating current can flow across a capacitor
by cyclical charging and discharging, but direct
current cannot flow
●● Factors affecting capacitance
■■ Size of capacitor plates
■■ Separation of capacitor plates
■■ Dielectric medium used (the thin layer of insu-
lating material separating the plates)
Inductors and inductance
●● Magnetic fields surround magnets and conduc-
tors in which current is flowing. These fields cause
attraction or repulsion of magnets and mag-
netizable metal because of the force known as
magnetism
●● A changing magnetic field will induce a current
in a conductor
●● An inductor is a conductor formed into coils
wound around a core of ferrous material
●● Inductance is the generation of a current in
an electrical circuit by a changing current in
the circuit or a nearby one. The original current
causes an electromagnetic field to form, which
induces the second current. This causes interfer-
ence in electrical equipment and is the basis for
transformers
●● The unit of inductance is henry (H)
●● Magnetic field strength is the strength of the
field in a vacuum
●● Magnetic flux is the strength of the field in any
material and is ↑ in ferromagnetic materials and
↓ in diamagnetic materials
●● The unit of magnetic flux is the weber, and the
unit of flux density is the tesla
●● The earth’s magnetic flux density is 60 mT. The
­magnetic flux density in an MRI scanner is 0.4–4 T
 Physics

Electricity and Magnetism 26

Electrical interference
● Electrical interference may come from the mains electricity supply, traffic ignition systems, radio,
television and mobile phone signals. The mains supply produces an electrical field at 50 Hz, and
a magnetic field that is dependent on the current. A conductor in an electric field or a fluctuating
magnetic field will have a potential difference induced in it
● This interference may come from capacitance, for example the patient’s body acts as one plate
and is linked to local AC currents
● Surgical diathermy causes heating, charring or explosions conditional on the waveform, cur-
rent density and power used. High frequency (0.5–1 MHz) causes little effect on excitable tissue,
such as muscle and nerve, other than heating. The wire acts as an aerial and induces a current
in nearby conductors that is easily filtered because of its high frequency
● The MRI scanner uses a powerful magnet, radio transmitter and receiver. Thus interference may
be induced in patient monitoring. Pulse oximetry with fibre-optic leads may be used. The elec-
trical fields generated by the monitoring equipment may also reduce the quality of the images
produced. A small radio transmitter that uses a non-interfering frequency can be used to transmit
the ECG signal to a monitor outside of the MRI room
● The whole MRI room is enclosed by a Faraday cage of conductive copper mesh to prevent radio
waves getting in or out
Biological signals
● Biological signals are too small to measure directly and require amplification
● Amplifiers are devices that convert a small weak electrical signal to a more powerful signal
output
● Bandwidth is the range of frequencies an amplifier accurately works over
● Filters are used to block certain frequencies of an electrical signal. They can block interference
from the unwanted signal if the frequencies are suitably different. For example, a notch filter blocks
the 48–52 Hz signal to remove interference in the ECG signal caused by 50 Hz mains; it has an insig-
nificant effect on the accuracy of the recording

Signal Frequency (Hz) Voltage

EEG 0.5–100 (routine) 0.5–100 µV

0.05–150 (diagnostic) Up to 1 mV on surface of brain
ECG 0.5–30 (theatre monitor) 100 µV–3 mV
0.05–100 (diagnostic)
EMG 1–20,000 Around 1 mV

● Periodic complex waves can be conceived of as being a summation of simpler sine waves (Fourier
analysis) and have a fundamental and a series of harmonic waves
 Physics

Electricity and Magnetism 27

Measurement of neuromuscular blockade
●● Clinical signs: coughing, absence of respiratory effort, abdominal muscle relaxation, head lift for
5 seconds, eye opening, tongue protrusion, swallowing and grip strength
●● Nerve stimulator: supramaximal, square wave, DC 0.1–0.3 ms stimulus through proximally placed
anode and distally placed cathode. Ulnar nerve stimulation contracts adductor pollicis. Facial
nerve stimulation contracts orbicularis oculi. Common peroneal nerve stimulation at the fibular
head causes dorsiflexion of the ankle. Posterior tibial nerve stimulation at the ankle causes
plantar flexion
●● 80% of the neuromuscular receptors must be blocked to paralyse the diaphragm. Recovery of
the diaphragm from neuromuscular block occurs quicker than that of the adductor pollicis
muscle. Therefore, if this muscle is used to monitor neuromuscular blockade, overestimation of the
blockade of the diaphragm can occur
●● Single-twitch stimulation provides single twitches between 1 and 10 seconds apart
●● Train of four (TOF) applies four stimuli 0.5 seconds apart (2 Hz). Depolarizing blockade reduces
the amplitude of all four contractions with no fade. Non-depolarizing blockade causes fade of
the train of four. Therefore 75% blockade leads to TOF count of 3, 80% blockade to TOF count of 2,
90% blockade to TOF count of 1 and 100% to no response to TOF. The train of four ratio is the ratio
of the amplitude of the last response to the first response. A TOF ratio >0.7 is required for clinical
recovery from neuromuscular blockade
Measurement of neuromuscular blockade (cont.)
●● Tetanic stimulation is 5 seconds of 50 Hz stimulation. Normally, no fade in tetanic stimulation
occurs. With non-depolarizing blockade, there is fade and post-tetanic facilitation. This is
used clinically when there is no response to the train of four. After applying tetanic stimulation
for 5 seconds, the post-tetanic count is the number of muscle responses to 1 Hz single twitches.
Depolarizing blockade does not cause fade or post-tetanic facilitation
●● Double-burst stimulation applies two short bursts of 50 Hz tetanic stimulation 0.75 s apart. The
tetanic stimuli used elicit a bigger response and reportedly make fade easier to detect than with
train of four
●● Objective measurement of neuromuscular blockade
■■ Acceleromyography uses a piezoelectric crystal attached to the thumb to measure accelera-
tion of the crystal because of thumb movement in response to ulnar nerve stimulation
■■ Mechanomyography measures the force of thumb contraction after ulnar nerve stimulation
■■ Evoked electromyography measures the evoked compound muscle action potential in
response to nerve stimulation
 Physics
Electrical hazards – causes
Mains electrical current
●● AC at 50 Hz with the live wire at 240 V
and the neutral connected to earth at the
sub-station
●● If a patient or member of staff forms a con-
nection between the live wire and earth, a
current will flow through.
●● Electricity may cause
■■ electrocution
■■ burns – see diathermy
■■ a fire or explosion
Electrocution
●● Causes damage according to
■■ the current
■■ the path it takes
■■ its density
■■ the type of current (AC or DC)
■■ its duration
Electricity and Magnetism 28
●● According to Ohm’s law: the higher the volt-
age or lower the resistance, the greater the
current and therefore the damage
●● The path of the current will determine its pos-
sible effects. Current through the chest may
cause respiratory arrest or ventricular fibril-
lation (VF). Current passing up and down the
body may cause unconsciousness or spinal
cord damage
●● With a 50 Hz current conducted across the
chest from one hand to the other, the effects
would depend on the magnitude
■■ 1 mA causes tingling
■■ 5 mA is the maximum safe current
■■ 15 mA causes tetany (‘let go’ current),
pain and asphyxia
■■ 75 mA may cause VF
Electrical hazards – causes (cont.)
Electrocution (cont.) a connection from the electrical source to
earth. This may result in burns to or electrocu-
● With AC current, mains frequency is the most
tion of the patient or a member of staff
dangerous, because it is the frequency most
likely to cause arrhythmias and it also causes
Capacitive coupling
muscle spasm, which prevents release from
● If the body acts as the plate of a capacitor,
the source. The longer the duration, the more
capacitive conductance occurs
damage is done
■ With DC, current flows only very briefly
● A microshock of only 50 mA could induce
until the plate is charged to the same
VF through a central venous catheter or
potential as the electrical source
pacemaker, because bypassing the skin
■ With AC current, the capacitor is
impedance causes high current density in
charged but then changes polarity at
the heart. Impedance is the AC equivalent to
the frequency of the electrical source; a
resistance
current will therefore continue to flow
Sparks ■ The changing magnetic fields in an MRI
scanner may induce currents in the wires
● May cause fires or explosions by igniting
of standard monitoring, which can, in turn,
inflammable vapours
cause a patient burn through capacitive
Resistive coupling coupling
● A direct physical connection results in resis-
tive coupling. Faulty equipment or leakage
currents can cause electricity to flow through
 Physics

Electricity and Magnetism 29

Electrical hazards – prevention
General measures
● Regular testing and maintenance of equipment
● High impedance shoes
● Ensuring that the patient is not in contact with earthed objects
● All medical equipment must comply with British standards for safety. These standards include two
classifications of electrical equipment
■ protection provided against electric shock caused by connection to the mains supply
■ maximum permissible leakage current

Protection from electric shock from the mains supply

● Class I equipment must have any conductible part accessible to the user connected to earth
through the earth wire. If the conductible part becomes connected to the live wire through a fault,
the current will be conducted through the lower resistance earth wire, which can result in breakage
of the fuse and removal of the source current
● Class II equipment has double or reinforced insulation of any conductible accessible part. It
does not have an earth wire
● Class III equipment uses batteries at voltages unlikely to cause electrocution but may result in
microshock
Electrical hazards – prevention (cont.)
Maximum permissible leakage current
● Type B equipment has a maximum leakage current of 100 mA for IIB and 500 mA for IB and
should not be directly connected to the heart. It may be class I, II or III
● Type BF is type B but also uses a floating circuit. Use of an isolating transformer that consists of two
coils electrically insulated from each other means there is no direct electrical connection between
the mains circuit and the patient circuit. The mains circuit is earthed, but the patient circuit is not.
Therefore, connection between the electrical source in the patient circuit and earth will not result
in completion of a circuit, and so no current will flow
● Type CF has a floating circuit and maximal leakage current of 10 mA for IICF and 50 mA for ICF
and therefore can be safely connected directly to the heart

Circuit breakers
Current-operated earth leakage circuit breakers have coils of the live wire around a transformer
● An equal number of coils of the neutral wire are also wound around the transformer
● A third coil connects to a relay that operates the circuit breaker
● With equal currents in the live and neutral wire, the magnetic fluxes are equal and opposite and
therefore there is no magnetic field
● With a small leakage current, the magnetic fluxes are different, and a magnetic field that induces
a current in the third winding results in the relay breaking the current
 Physics

Electricity and Magnetism 30

Principles of lasers
Laser stands for light amplification by the stimulated emission of radiation

Properties of laser light

● Monochromatic (single colour and frequency)
● Almost non-divergent
● High-intensity beam
● In phase
● May be of a very small cross-sectional area

Principles of laser light

● Electrons have energy but can exist only at certain energy levels according to quantum theory.
They can move between these energy levels by absorbing or emitting a specific amount (quanta)
of energy as radiation, which may be in the visible spectrum. With non-laser light, random pro-
cesses result in the light waves being out of phase or incoherent
● Energy is absorbed from a flashlight or high-voltage discharge and is released as a photon, with
energy equal to the difference in the two energy levels
● The photon is reflected back and stimulates an excitable electron (in a higher energy level) to fall
to a lower energy level, resulting in emission of a wave of energy equal to the stimulating photon,
which can go on to stimulate another
Principles of lasers (cont.)
● Amplification occurs through a chain reaction, and as the photons have equal energy (and thus
frequency), they are coherent
● If the photon stimulates an atom with a lower energy state into a higher energy state, the energy is
absorbed. If many more atoms have electrons in the higher energy state than in the lower state,
then, on average, more stimulated emission than absorption will occur
● Emission restricted to a single direction forms laser light

Types of lasers
● An argon gas laser produces blue–green light that passes through the humour of the eye and is
used for retinal surgery and also removal of birthmarks. It may be used endoscopically with optical
fibres
● A carbon dioxide laser produces infrared light that vaporizes water in tissues, cutting with hae-
mostasis and low penetrance. It is the laser used most frequently in surgery. It is not suitable for
endoscopic use
● A neodymium-doped yttrium aluminium garnet (Nd:YAG) laser produces near infrared. As it is not
absorbed by water, it is used for coagulation and cutting with deep penetration into tissues. It may
be used endoscopically
 Physics

Electricity and Magnetism 31

Laser safety
Burns ■■ disconnect the circuit and remove the ET
●● High-intensity laser light may burn the tube if possible
■■ bag and mask the patient with air
■■ retina or optic nerve, which can result in
■■ inspect the airway with a rigid
a permanent blind spot or partial or total
bronchoscope
blindness; infrared light cannot be seen,
■■ observe patient in ITU, and keep intu-
so it may cause worse damage, especially
bated for several hours
to the cornea, lens, and aqueous and vit-
■■ give dexamethasone and humidified oxygen
reous humour
■■ repeat bronchoscopy in a few days
■■ skin
Safe use of lasers
Fire
●● The laser operator must ensure that it is used
The danger of fire can be reduced by
safely
●● using air and oxygen that is less flammable ●● An appropriate fire extinguisher and 50 mL
than nitrous oxide and oxygen syringe filled with saline should be available
●● a fraction of inspired oxygen (FiO2) ≤0.25 ●● Personnel should wear suitable eye
●● using non-flammable endotracheal (ET)
protection
tubes with cuffs inflated with saline ●● All doors should be locked and windows
●● using non-reflective, matte-black surgical
covered
instruments
●● protecting nearby tissue with wet swabs
●● If an airway fire occurs
■■ switch off the laser and flood the site with
saline
Electrical symbols

Cell A.C. supply

Battery Capacitor Ground

Resistor Inductor Fuse

Variable resistor Diode –

Thermocouple

Switch

Transistor
V Thermistor
Volt meter

A
Ammeter Transformer
 Physics

Electricity and Magnetism 32

Wheatstone bridge
A Wheatstone bridge contains four resistors (two Rmeasure
fixed, one adjustable and one strain gauge) arranged
with a battery and galvanometer
●● A strain gauge is a type of resistor in which the resis- Radjustable
tance alters when it is stretched or strained
●● In a pressure transducer, movements of the dia- Rmeasure R2
=
phragm result in changes in tension in strain gauges Radjustable R1
■■ Kinetic energy thus is converted to electrical A
energy
●● The variable resistor is used to balance the bridge so
R2
no current flows. It is therefore known as a null deflec- R1
tion system.
●● In practice, the four resistors are all strain gauges and
the Wheatstone bridge is arranged so that as the
resistances of two of the strain gauges on one side
of the bridge increase, the resistances of the two on
the other side of the bridge decrease. It thus works to
amplify the electrical signal
Circuit breakers, fuses, transformers, transistors, diodes
Resistors, fuses and circuit breakers
●● A rise in temperature in a resistor is the basis of the
resistance thermometer
●● As a resistor is stretched its resistance increases; this
is the basis of the strain gauge which transduces
mechanical energy to electrical energy
●● A fuse is a wire of a certain resistance that is chosen
to heat and melt at a certain current thus breaking
the circuit and preventing inadvertent electrocution
●● Circuit breakers act like fuses to protect circuits and
equipment from current surges but then can be reset
rather than replaced. They use the heating or magnetic
effects of the current to cause an interruption of flow
Transformers
Transformers are used to step up or step down the
voltage in alternating currents. They work on induc-
tion and do not work on direct current
●● A primary AC with a primary coil will induce a sec-
ondary current in a circuit with a secondary coil. This
induction can be made more efficient if the coils are
linked by a ferromagnetic core
●● The step up (or step-down) in voltage depends on
+ input
the ratio of the number of turns in each coil
●● Power lines have high voltage (400 kV–700 kV) from
step-up transformers in order to reduce energy loss
(the current will be very small) which are stepped
down by transformers to domestic voltages (240 V)
Diodes and transistors
A diode is a component of an electrical circuit which
only allows current to flow in one direction
●● It can be used to convert AC to DC and to protect
circuits from back currents, for example when motors
are turned off
●● Most are made from semiconductors (e.g. silicon)
with p-n junction (positive-negative)
●● A transistor is a semiconductor device that can be used
as a switch or to amplify small currents.The simplest type
are two diodes placed back to back (NPN or PNP)
1 watt audio amplifier
100k Ω 3 Speaker
Collector
MPSW45A
2 Base 50 Ω
10k Ω

●● As the primary voltage increases the current will

100k Ω + 9V
decrease by the same factor (so the overall energy Emitter
1
stays the same)
●● Chargers for small devices (e.g. mobile phones) – input

have transformers included in their leads

 Physics
MRI scanners and anaesthesia
History
●● Nuclear magnetic resonance (NMR) first described
in 1946 (Bloch and Purcell)
●● Wide-bore superconducting magnets introduced in
the 1970s
●● First clinical MRI imaging introduced in 1980
Principles
●● All atomic nuclei (protons in hydrogen atoms) have a pos-
itive charge and spin, thus behaving like a bar magnet
●● Application of a strong external uniform magnetic force
(B0) aligns some of the protons, either in a low-energy
(parallel) or high energy state (perpendicular to B0)
●● A second radiofrequency (RF) magnetic field (B1)
applied perpendicular to B0 will excite the nuclei that
possess spin
●● The RF is applied in short bursts (µs) causing absorp-
tion of the energy by the nucleus
●● This energy is emitted on relaxation and can be
detected and amplified; the voltage is displayed as
free induction delay (FIDs)
●● In practice multiple RF pulses are applied obtaining
multiple FIDs which are averaged thus improving SNR
The MRI scanner
●● Typically 1–3 tesla in the centre of the coil (c.f. Earth’s
magnetic field is 0.00005 T which is 0.5 gauss), the
fringe field around the scanner will be lower
Electricity and Magnetism 33
●● Open scanners (useful for claustrophobic patients or
for interventions) have lower strength
●● High magnetic flux density is achieved by cryogenic
superconducting magnets close to absolute zero
(0 K) by immersing in liquid helium
●● The receiver and transmitter coils for RF pulses and
detection can be separate or combined
T1 and T2 weighted MR imaging
●● After the RF pulse ceases the nuclei returns to thermal
equilibrium–relaxation
●● T1 is the time constant (time taken for 63% return to
equilibrium) for longitudinal relaxation, T2 for trans-
verse relaxation
●● Water and CSF have long T1s (3–5 s), whereas fat has
a much shorter T1 (260 ms); T1 is good for white/grey
matter contract, whereas T2 is good for tissue oedema
●● There are other groups of sequences which can be
used depending on what type of pathology and tis-
sue is being investigated; e.g.
■■ gradient echo for cardiac MRI
■■ inversion recovery (which can attenuate fat or
water signals)
■■ diffusion and perfusion weighted looking for
cerebral infarction
MRI scanners and anaesthesia (cont.)
Clinical applications of MRI scanners
●● Neuroimaging
●● MR angiography and cardiac MRI
●● Prostate and uterine cancer staging
●● MR spectroscopy to detect various metabolites in
body tissues
●● Operative MRI (hybrid theatres with attached MRI
scanners)
MRI scanners and anaesthetic
considerations
●● Sedation or anaesthesia can be chosen depending
on the availability of staff.
●● There needs to be clear guidelines dictating which
patients are appropriate for sedation and to ensure
sedation practitioners are all appropriately trained.
●● Drugs used for sedation – chloral hydrate, propofol,
midazolam, dexmedetomidine
●● If using general anaesthesia (GA) with laryngeal
mask airway (LMA) it is important to remember to
tape the pilot balloon to stop it being drawn into the
magnet next to the head and causing artefacts
Patient population
●● The patients who will require anaesthetic care for
their MRI carry their own particular challenges
●● Infants and children
●● ITU patients (especially neurological ITU)
●● Patients who are unable to lie flat (e.g. due to intrac-
table pain)
●● Psychiatric patients and extreme claustrophobia
Remote anaesthesia
●● MRI scanners are usually some distance from theatre
suites; help, drugs and equipment are not immediately
available
●● Recovery might not be easily available
●● Lack of familiarity with the environment unless there is
a regular team and list. Equally significant, radiogra-
phers are not familiar with the needs and priorities of
the anaesthetic team
●● Limited access to patient in the scanner; it is vital
that any airway/adjunct is secure before putting the
patient into the magnet; it will not be possible to bring
a laryngoscope (unless it is plastic) close to the mag-
net in an emergency
Dangers to the patient and staff
●● Projectiles causing trauma (e.g. cylinders, wheel-
chairs, syringe pumps)
●● Interference with implantable devices (e.g. pace-
makers, defibrillators, programmable pumps)
●● Interference with infusion devices (it might be neces-
sary to extend infusion pump lines so they are kept
outside the Faraday cage)
●● Monitoring interference–full monitoring is necessary
and the Association of Anaesthetists of Great Britain
and Ireland (AAGBI) suggests having the monitor in
the control room
●● Monitoring applied to the patient must be done in such
a way to avoid induction currents causing contact burns
●● Foreign bodies can shift (e.g. metal shards in the eye,
aneurysm clips if not titanium) and must by approved
by the supervising MRI radiographer (MRIsafety.com)
●● Acoustic damage
●● Risk of anaphylaxis and renal damage with IV con-
trast media (though much less with gadolinium)
 Physics
Principles of cardiac pacemakers
A cardiac pacemaker provides cyclical
electrical stimulation of cardiac activity for
­ and pulse duration of up to 50 ms to decrease
the treatment of bradyarrhythmias or tachyar-
rhythmias. It is indicated for disease of the
­conducting system of the heart
Temporary pacing
●● Transvenous pacing is achieved via a cen-
tral vein under x-ray control and may be
indicated after MI. The pulse duration is
less than 1 ms, and the potential difference
required is usually less than 4 V. There is a risk
of microshock. Transvenous pacing should be
considered preoperatively for
■■ bradyarrhythmias
■■ third-degree heart block
■■ second-degree heart block if it is Mobitz
II or if there are associated symptoms or
extensive surgery
■■ bundle branch block if it is bifascicular
or has a prolonged PR interval
●● Transcutaneous pacing is quicker and
prevents the complications of transvenous
Electricity and Magnetism 34
pacing. It uses large-area skin electrodes
nerve and muscle stimulation
Permanent pacing
●● Permanent pacing may be used for sick
sinus syndrome, heart block or after MI if
the arrhythmia causes dizziness, syncope
or heart failure. The pacing wire is usually
placed endocardially in the atrium or ven-
tricle, or both, and is connected to a subcu-
taneous battery-powered pulse generator
●● The pacemaker code consists of five letters
(in order) indicating
■■ chamber paced (0 = none, A = atrium,
V = ventricle, D = dual)
■■ chamber sensed (0 = none, A = atrium,
V = ventricle, D = dual)
■■ response (0 = none, T = triggered, I =
inhibited, D = dual, R = reverse)
■■ programmable functions
■■ antiarrhythmic function
Principles of cardiac pacemakers (cont.)
Demand-mode pacemakers
●● Demand-mode pacemakers have chamber-sensing electrodes. Interference by electromag-
netic fields external to the patient (electric motors, microwaves, antitheft devices, electrosur-
gical equipment, nerve stimulators and monitoring equipment) may be interpreted by the unit
as QRS complexes. An MRI scanner may cause it to move or malfunction
●● Pacemaker function may be changed externally by using magnets or radio-frequency genera-
tors. This may produce unpredictable results and should only be done by a qualified technician

Use of diathermy
●● Use of a diathermy in a patient with a pacemaker may result in asystole, ventricular fibrillation
or failure of the pacemaker. The risks may be reduced by:
■■ ensuring the pacemaker programmer is available and pacemaker checked preoperatively
■■ limiting the use of diathermy
■■ placing the indifferent electrode on the same side as the operation and as far as possible
from the pacemaker
■■ using the lowest effective current
■■ using bipolar diathermy
■■ continuously monitoring the ECG
■■ ensuring the pacemaker programmer is available
 Physics

Electricity and Magnetism 35

Defibrillators
A defibrillator applies an electrical current to the heart in order to convert ventricular fibrillation
to sinus rhythm
●● The current causes simultaneous contraction of the entire heart muscle, which results in a refrac-
tory period, after which sinus rhythm hopefully returns. In order for this to work, the defibrillator
must store electrical energy and release it in a controlled way. The capacitor has a potential differ-
ence of 5000 V applied across it. This results in a build-up of charge on the plates of the capacitor
●● The stored energy depends on the charge, the capacitance and the potential
■■ Stored energy, E = 12 QV
Q
■■ as C = ,E = 1
2 CV 2
V
Defibrillator circuit
Switch Inductor Paddle

Patient
5000 V Capacitor impedance
32 µF 50–150 Ω

Paddle
Defibrillators (cont.)
●● In a monophasic defibrillator, electrodes are placed on the patient’s chest (using conductive jelly
or pads to decrease impedance) under the right mid-clavicle and over the apex of the heart
●● The energy stored in the capacitor is delivered to the patient at, for example 35A for 3 ms
●● An inductor is used to lengthen the time of discharge and control the shape of the electric pulse.
It is the amount of energy that is delivered to the patient, not the total contained by the capacitor
that is important. Therefore, the defibrillator has a setting to adjust the total energy delivered to the
patient
●● Transthoracic impedance is reduced by the first shock, so the second will deliver more energy to
the heart without increasing the set delivered energy. Internal defibrillation direct to the heart will
require lower levels of energy in adults and children
●● Biphasic defibrillators use a pulse in one direction followed by a second in the opposite direc-
tion; there is evidence that they may achieve defibrillation with lower energy therefore causing
less damage to the heart
●● For the treatment of certain dysrhythmias, a defibrillator in synchronized mode will deliver a shock
only during the R wave; if not, there is a risk of causing ventricular fibrillation
 Physics

Electricity and Magnetism 36

Diathermy
Diathermy is the device used to pass electrical current through tissue to generate heat in order
to coagulate blood vessels or cut and destroy tissue
●● The heat produced is proportional to the power developed, typically 50–400 W
●● Unipolar diathermy uses the forceps as one electrode, with a large surface area plate attached
to the patient – usually on the leg. Current density is high at the forceps, which causes the coagu-
lation or cutting, but is low at the plate, so little heating occurs there
●● Bipolar diathermy uses current passing between two blades of the forceps; no plate is required.
The power used is smaller, so it may be used for eye surgery, digits and neurosurgery to localize
the current and prevent collateral tissue damage. However the range of available electrodes is
less and so it may not be suitable for some uses
●● Cutting diathermy uses an alternating sine-wave current at 0.5 mHz
●● Coagulation diathermy uses a pulsed sine-wave current at 1–1.5 mHz
●● Effects of diathermy depend on frequency
Problems with diathermy
●● Diathermy can cause interference with monitoring: pulse oximetry and ECG
●● Incorrect siting of plate (i.e. with a small surface area) may cause burns
●● Accidental activation of the diathermy causing burns, so an insulated holder is used, and a
buzzer warns when the diathermy is activated. Accidental burns can occur even if the diathermy
is not in physical contact with the patient through capacitance linkage, in which the patient acts
as one plate of a capacitor
●● Using unipolar diathermy in the locale of end arteries can cause collateral damage and infarction
●● Diathermy can cause ignition of flammable substances, such as skin preparation spirit, anaes-
thetic agents or bowel gases causing fire or even explosions
●● If the diathermy is earthed but the connection is faulty, current may flow to earth via another
earthed metal conductor, such as a drip stand or ECG lead, and cause burns. A floating circuit
prevents this
●● Pacemakers may malfunction, especially with unipolar diathermy
●● The risk of causing physical sensation, muscular contraction or ventricular fibrillation is negli-
gible above 1 MHz, so a frequency of around 0.5–1.5 MHz usually is used
 Physics

Fluids and Flow 37

Laminar and turbulent flow
Flow is the amount of fluid (liquid or gas) pass- Turbulent flow
ing a point per unit time ●● Results in uneven movement with eddies
●● It is likely to develop if the Reynolds number is
Laminar flow
greater than 2000
●● Smooth with no turbulence or eddies ●● Reynolds number = vρd/η
●● In a tube, the flow is fastest in the centre where v is the linear velocity, ρ is the density,
(about twice the mean flow) and slowest at d is the diameter of the tube and η is the
the edges, with a gradient between viscosity
●● Rate of laminar flow is given by the Hagen- ●● For a given fluid in a given tube, there is a
Poiseuille equation critical velocity above which laminar flow
■■ Laminar flow = Pd /128ηl
4
becomes turbulent
4
= Pr /8ηl ●● At a sharp bend or orifice, the velocity
increases and may exceed the critical veloc-
 w here P is the pressure difference across
ity, which results in turbulent flow
the tube, d is the diameter of the tube, r is
●● With turbulent flow, the flow is proportional to
the radius of the tube, η is the viscosity
the square root of the pressure difference,
of the fluid and l is the length of the tube
so that if the pressure difference is increased
●● Viscosity is the ‘stickiness’ of fluids or their ten-
by a factor of four, the flow will only double.
dency to resist flow. It decreases with increas-
Therefore, resistance is not constant and
ing temperatures
increases with increasing flow
●● Laminar flow is dependent on viscosity not
density
Turbulent flow (cont.) the diameter of the airway in millimetres.
Therefore, flow in an endotracheal tube with a
●● Turbulent flow depends on the density rather
diameter of 7 mm becomes turbulent at flows
than the viscosity of the fluid. With flow that is
above 7 L/min
a mixture of laminar and turbulent, viscosity
●● Peak flow is much faster, so turbulent flow is
also has an effect
usually present during peak flow and laminar
●● Turbulent flow in anaesthetic circuits is mini-
flow present at other times
mised by avoiding kinks, angles and constric-
●● Although the smaller airways have a much
tions in the tubing
smaller diameter, the gas velocity is much
Critical flow slower, so Reynolds number is not exceeded
and flow is usually laminar
●● Critical flow is the flow above which turbulent
flow occurs
●● For a typical anaesthetic gas mixture, the
critical flow in litres per minute is equal to

Clinical nugget – turbulent flow

In conditions where it is desirable to reduce turbulent flow and maintain laminar flow (e.g. upper
airway obstruction, croup, vocal cord pathology) replacing air (density 1.25 g/L) with heliox
(21% O2 in helium, density 0.5 g/L) can be beneficial. This is because velocity in turbulent flow
depends on the density. The viscosity of air and heliox are similar. Heliox is also available in
higher O2 concentrations (70/30 and 60/40).
 Physics

Fluids and Flow 38

Bernoulli principle
The Bernoulli effect is the name given to the reduction in pressure when a fluid increases in veloc-
ity, e.g. at a point of constriction in a tube
●● The fluid has kinetic energy (½ mv2) due to its flow and potential energy due to its pressure
●● As the fluid passes through the constriction, the flow increases, so the kinetic energy increases
●● The total energy must remain unchanged, so the potential energy reduces
●● Therefore the pressure at the constriction is lower and may be subatmospheric
●● This effect is used in a Venturi device, in which an opening at a constriction where the pressure is
subatmospheric results in air or another fluid being entrained. This is used for:
■■ Nebulizers – gas entrains liquid in droplets small enough to be inhaled and reach the lower
airways
■■ Venturi oxygen masks – use the driving oxygen to entrain room air; they also depend on jet
entrainment or viscous drag, which is the friction of the oxygen molecules pulling more air
molecules along with them
■■ Sanders injector – also uses jet entrainment
Venturi masks
●● Also known as HAFOE (high air flow oxygen
enrichment) masks
●● Work on the Bernoulli principle and jet
entrainment
●● Need to provide consistent FiO2 even during
peak inspiratory flow rate (40 L/min)
●● Will have a fixed entrainment ratio
Entrained flow
■■ Entrainment ratio =
Driving flow
●● Hence doubling the oxygen flow will not
change the FiO2
●● Clinical uses
■■ delivering low concentration O2 (24%) for
patients driven by hypoxic drive
■■ to check patient’s condition on a known
FiO2
■■ to monitor response to therapy
●● Flow rates of O2, entrainment ratio and final
FiO2. An example:
■■ Eventual flow rate delivered to patient
(enough for peak flow) = 40 L/min
■■ Entrainment ratio = 9:1
■■ Hence O2 flow needed = 4 L/min and this
will entrain 4 × 9 L/min giving a total of
40 L/min
■■ Overall O2 concentration is
{4 L (pure oxygen) + 36/5 (oxygen in air)}
40 (total volume)
= 11.2/ 40 = 28%
■■ This mask will provide 28% consistently if
4 L/min O2 or more is provided
■■ Similar calculations can be made for
other fixed FiO2 masks
 Physics

Fluids and Flow 39

Surface tension
Surface tension is the tangential force present
at air–liquid interfaces, which is caused by the
attraction between the liquid molecules
●● In a body of liquid, the molecules are all
attracted in all directions, resulting in no net
force. At the surface, the liquid molecules
are not attracted outwards (because of the
absence of liquid molecules) and therefore
have a net attraction inwards. This results in
the surface contracting to the smallest pos-
sible area and is why a droplet becomes
spherical
●● Similar forces between a liquid and its con-
tainer result in a meniscus forming
●● Mercury in a thermometer does not wet the
tube surface resulting in a convex meniscus
Laplace’s law
T
●● For a cylinder, P =
R
where P = transmural pressure, T = tension in
the wall and R = radius
●● For a sphere, because there are two planes
of curvature, P = 2T/R
●● Important in reducing the build-up of pres-
sure in an anaesthetic breathing system, as
the radius of the reservoir bag increases, so
does the tension
Surfactant
Surfactant is a phospholipid secreted by type II
alveoli cells which markedly reduces the sur-
face tension of the alveoli as they decrease in
radius
●● It is thought to work by causing repulsion
between adjacent molecules of surfactant
on the surface of the alveoli
●● When the alveoli become smaller during
expiration, the surfactant molecules get
closer together and the repulsion increases,
which helps to prevent collapse of alveoli
●● Surfactant increases compliance in smaller
alveoli that are more prone to collapse, which
evens out overall compliance
●● It reduces the energy lost as heat during
respiration
●● It helps to keep alveoli dry by reducing the
surface tension-induced negative interstitial
pressure that draws fluid from capillaries into
the air spaces
●● Production of fetal surfactant starts at
26 weeks’ gestation and is fully developed by
32 weeks’ gestation
●● Surfactant is under hormonal control and can
be stimulated by maternal hormones
●● It prevents respiratory distress syndrome
(RDS)
 Physics

Fluids and Flow 40

Measurement of volume and flow in gases and liquids
Volume measurement
●● A Benedict-Roth spirometer consists of a light bell that contains a closed volume of air over water.
The bell rises and falls as the patient breathes in and out, and a pen connected to the bell draws
a trace to measure volumes and flows
●● A vitalograph uses bellows connected to a motor-driven scriber on a chart
●● A Wright respirometer is an expiratory volume recorder that uses gas flow to spin a vane; it is
therefore an anemometer. Flow rates can be obtained by averaging volumes over time. It does
not need a power supply and is small and portable, but it can only measure gas volume flowing in
one direction. It underestimates at low volumes, but it overestimates at high volumes because
of the inertia of the vanes

Gas flow measurement

●● A rotameter is a variable orifice flow meter
●● A Wright peak flow meter uses rotation of a vane to open a circular slot allowing gas to escape
and is opposed by a constant force from a coiled spring. A ratchet stops the vane movement at its
maximum displacement and the flow is read from a dial
●● The mini-Wright peak flow meter (more common nowadays) works by the patient’s expiration mov-
ing a spring-loaded diaphragm this increasing the size of the outflow. It is thus a variable orifice
variable pressure (the spring tension changes as it is stretched) device
●● A mass flow meter keeps the temperature of a thermistor constant while gas flows over it and
extracts heat energy. The current required to maintain a constant depends on both the gas flow
and the temperature of the gas, so a second thermistor must be used to compensate for this
Measurement of volume and flow in gases and liquids (cont.)
Gas flow measurement (cont.)
●● A pneumotachograph is a constant-orifice, variable-pressure flow meter. It is used in anaes-
thetic circuits therefore must cause little low resistance to gas flow. It contains a pneumotacho-
graph head, of which there are several types
■■ The screen pneumotachograph has a gauze screen that the gas flows through; this produces
a pressure drop across the screen. Flow must be laminar for it to function correctly. Pressure
ports on either side of the screen deliver the pressure drop to a transducer
■■ The Fleisch pneumotachograph uses a series of fine-bore ducts to guarantee laminar flow
■■ The hot-wire pneumotachograph has two heated wires perpendicular to each other across
the lumen of the head. The gas flow cools the wires, which alters their resistance and produces
an electrical signal
■■ The modified Pitot tube pneumotachograph contains two small-pressure, open-ended sam-
pling tubes positioned in the centre of the gas flow channel. The pressure difference between
the upstream (dynamic) and downstream (static) ports depends on the kinetic energy of the
gas, which is proportional to the (velocity)2
 Physics

Fluids and Flow 41

The rotameter
A rotameter is a variable-orifice, constant-pressure flow meter that consists of a vertical tapered
glass tube containing a bobbin

Design and function

●● Gas flow is controlled by a needle valve at the base of the glass tube
●● The diameter of the tube is narrow at the bottom and wide at the top
●● The bobbin moves upwards into the widening orifice as the flow increases
●● The weight of the bobbin is balanced by the pressure of the gas flow pushing up on it
●● Readings are taken from the top of the bobbin
●● Each rotameter must be designed and calibrated for a specific gas because
■■ at low flows the orifice behaves like a tube, so flow is laminar and therefore depends upon
viscosity
■■ at high flows the orifice becomes like a constriction in a tube, so flow becomes turbulent and
therefore is dependent on density

Advantages
●● Reliable and does not need a power supply
●● No display to malfunction
The rotameter (cont.)
Safety features
●● Fins built into bobbin make it spin and prevent it sticking (due to build-up of dirt and static)
●● Internal conductive strip along the tube also prevents static build-up
●● In the UK, the oxygen control knob is larger, sticks out farther and is always on the far left
●● The oxygen inlet is downstream of the others to prevent leakage if one of the other flow meters is
cracked
●● A mechanical antihypoxia device prevents administration of <25% oxygen

Possible problems
●● Vaporizers positioned at the outlet of rotameters may increase the pressure in the rotameters and
affect their accuracy
●● Malfunction is potentially dangerous, as the rotameter is part of the anaesthetic circuit
●● To maintain accuracy, the rotameter must be vertical to prevent friction and to stop the bobbin
from sticking
●● It is accurate only for a specific gas at a specified temperature and pressure
 Physics

Fluids and Flow 42

Ultrasound and the Doppler effect
Ultrasound is a very high frequency (>20 kHz) sound that is inaudible to the human ear. Clinical
ultrasound operates between 1 and 10 MHz, which is 50,000 times higher frequency than the
audible range

Ultrasound
●● Produced by a vibrating crystal transmitter on the ultrasound probe
●● Waves are absorbed by the tissues they pass through, which is known as attenuation
●● Water causes low attenuation; bone and air cause the most attenuation
●● When ultrasound waves reach a boundary between two different substances, parts of the wave
are reflected, depending on the difference in tissue densities
●● Gel is used on the probe to decrease the difference in densities, which reduces the attenuation
and improves the image
●● The receiving transducer in the probe detects the reflected waves
●● By comparing the transmitted and reflected waves, an image can be formed
●● Lower frequency ultrasound achieves better tissue penetration, but the images it produces are
of lower resolution
●● The highest frequency that will penetrate the tissue just deeply enough is used to get maximal
resolution
●● Different areas of the body consequently require different frequencies
Ultrasound and the Doppler effect (cont.)
Types of ultrasound scans
●● Amplitude or A scan shows information about
tissue depth
●● M mode detects movement at tissue
interfaces
●● B mode – variation of the direction of the
ultrasound source allows a two-dimensional
picture to be formed
The Doppler effect
●● Sound waves are transmitted by oscillations
of particles in the direction of the wave itself
●● If they are reflected off a surface that is mov-
ing towards the waves, the peaks will be
closer together and therefore the wavelength
of the reflected waves will be shorter and the
frequency higher
●● This is known as the Doppler effect; it is why
the pitch of an ambulance siren changes as
it approaches or drives away
Uses
●● Ultrasound is used for diagnostic imaging
●● Doppler ultrasound is used to monitor
■■ flow in blood vessels for vascular surgery
■■ fetal heart rate
■■ estimates of stroke volume and cardiac
output in the oesophageal Doppler
■■ uterine blood flow
●● Duplex scanner combines ultrasound images
in real time with colour Doppler images indi-
cating velocity, e.g. echocardiography
 Physics

Fluids and Flow 43

Simple tests of pulmonary function
Pulmonary function tests are used to deter-
mine the extent of respiratory disease
Clinical tests
●● For example, the ability to blow out a match
or walk up stairs; imprecise and subjective
Tests of ventilation mechanics
1. Static lung volumes – for example, dead
space and closing capacity; requires bulky
apparatus
2. Spirometry to measure forced expiration
after maximal inhalation
■■ Useful in differentiating between obstruc-
tive and restrictive lung disorders
■■ In obstructive disorders (e.g. asthma),
forced expiratory volume in one second
(FEV1) usually is decreased, forced vital
capacity (FVC) usually is normal and the
ratio of FEV1 to FVC is decreased
■■ In restrictive disorders, (e.g. fibrosis) FEV1
and FVC are both decreased, leaving a
normal FEV1/FVC
The figure shows typical forced expiratory
patterns

Normal Obstructive Restrictive

FVC FVC
Expired volume

FEV 1 FVC
FEV 1 FEV 1

Time (s)
Simple tests of pulmonary function (cont.)
Tests of ventilation mechanics (cont.) Flow–volume loops
3. Flow–volume loops provide a graphical illus-

Flow
tration of a patient’s spirometric effort
Normal
■■ Flow is plotted against volume to display
a continuous loop from inspiration to
expiration

expiration
■■ In healthy patients, after a small amount of Restrictive
gas has been exhaled, the flow is limited
by airway compression and determined
by the elastic recoil of the lung and resis- Obstructive
tance upstream of that point 0
■■ In restrictive diseases, maximum flow rate Volume

inspiration
and total volume expired are decreased.
Increased recoil leads to high flow in late
expiration TLC RV
■■ In obstructive diseases, flow rate is low in
relation to lung volume, with a ‘scooped-
out’ appearance after maximal flow
 Physics

Fluids and Flow 44

Tests of gas exchange
●● Blood gas analysis and pulse oximetry
●● V/Q mismatch (usually by radioisotope scanning); also assesses pulmonary circulation
●● Diffusion capacity is the volume of a substance (CO) transferred across the alveoli per minute per
unit alveolar partial pressure
■■ CO is rapidly taken up by haemoglobin, so transfer is limited mainly by diffusion
■■ A single breath of 0.3% CO and 10% helium is held for 20 seconds
■■ Expired pCO is measured. Normal value is 17–25 mL/min/mmHg
■■ Decreases with
●● increasing alveolar membrane thickness (e.g. fibrosis)
●● decreasing alveolar membrane (e.g. pneumonectomy)
Coanda effect
The Coanda effect is the name given to the tendency for a flowing liquid to change direction by
attaching itself to a surface and clinging to it
●● On entering a constriction, the pressure decreases because of the Bernoulli effect
●● Entrainment of a second fluid cannot occur if the flow continues along a surface (or along the
wall of a tube)
●● The pressure therefore remains low, and flow clings to the surface
●● If there are two surfaces (or tubes), the flow continues along one but not the other
●● Proposed to explain uneven ventilation, in which a constriction precedes division of a bronchiole
●● May also be a mechanism for myocardial ischaemia distal to branching of a coronary artery

Fluid logic
●● Two side tubes positioned after the constriction can apply a small switching flow across the main
flow
●● The flow switches to the other limb and continues to flow down it until another switching flow is
applied
●● Ventilators that use fluid logic have fewer valves and moving parts but consume extra gas
 Physics

Clincal Monitoring and Measurement 45

Minimum (essential) monitoring standards
●● See current AAGBI guidelines Limits of minimum monitoring
●● The presence of the anaesthetist is paramount
●● Monitoring cannot prevent all adverse events but
●● Standards of monitoring should be adhered to
it is thought to minimise the impact by early warn-
throughout the anaesthetic care including for
ing and detecting the impact of human error
anaesthetic provision of transfers, sedation and
●● Monitoring devices will only give correct mea-
regional techniques
surements if they are maintained and used
●● Monitoring equipment needs to be checked
correctly. This means regular calibration and
before use and alarms set with appropriate limits
maintenance, and knowledge of how to apply
and audibly
correctly by the anaesthetic team (e.g. using the
●● Measurements should be recorded, ideally by
wrong size cuff for NIBP)
an automated electronic system at least every
●● Some monitors have good rationale for their use
5 minutes
but are still not providing reliable numbers consis-
●● Parameters that are essential monitoring (the
tently (e.g. cardiac output monitors)
anaesthetist may decide to add others depend-
●● Monitoring devices only supplement clinical
ing on the patient or the complexity of surgery)
observations. The anaesthetist should be con-
■■ Oxygen inspired concentration
stantly looking for clinical signs such as mucosal
■■ Capnography, concentration of volatiles
colour, pulse rate and strength, heart sounds
■■ Pulse oximetry and ECG
and breath sounds, pupil size and reactivity, and
■■ NIBP
signs of sweating
■■ Airway and cuff pressure on airways
●● In some situations it is not feasible to have the
■■ Temperature (if >30 minutes)
monitoring attached before induction, for exam-
■■ Nerve stimulator (ideally quantitative)
ple with some children
■■ TIVA patients should have some form of depth
●● Where it is impossible to be near the patient (e.g.
of anaesthesia monitor
in radiotherapy or MRI suites) then the measure-
ments will need to be visible on slave monitors or
relayed to control rooms by cameras
ECG – principles
●● The wave of depolarization which passes from Schematic diagram from Einthoven’s triangle
the SA node to the rest of the heart can be
detected through nearby structures aVF
●● As these potentials are attenuated the signal II –90° III
detected is only about 1–2 mV (the original will –120° –60°
be about 90 mV)
●● The size of the muscle bulk will determine the size aVR aVL
of the measured potential, hence the atrial sig- –150° –30°
nal (P wave) will be much smaller than the ven-
tricular signal (QRS complex)
●● The ECG signal is usually detected by a biologi- –180°
cal electrode system attached to the skin. This I 0° I
+180°
consists of a thin layer of silver on the electrode
and an electrolyte gel of silver chloride. There is
an adhesive surround to attach to the skin
+150° +30°
●● Leads can also be oesophageal and cardiac
aVL aVR
●● The ECG signal can be interfered with by noise
from, for example, muscle movement, diathermy, +120° +60°
MRI III +90° II
●● The leads will pick up a positive deflection if the aVF
majority of the cardiac depolarization lies in the
same vector plane as the lead
■■ Inferior leads – II, III, aVF
Placement of leads ■■ Anterior leads – V3, V4
●● For diagnostic purposes the majority of patients ■■ Lateral leads – I, aVL, V5, V6
will undergo a 12 lead ECG which is derived ■■ Septal – V1, V2
from 10 electrode placements (4 limb and 6 pre-­ ●● For monitoring purposes lead II or CM5 is gener-
cordial electrodes) ally used
 Physics
Clincal Monitoring and Measurement
Principles of pressure transducers
●● Pressure transducers convert a physi-
ological pressure into an electrical signal.
They either connect a fluid-filled tube in the
patient to a distant transducer (IBP) or have
a small sensor within the patient (ICP). The
latter type are more accurate, but they are
more expensive and cannot be recalibrated
in situ
●● The most common pressure transducer is the
strain gauge, four of which are commonly
arranged in pairs as part of a Wheatstone
bridge. Integrated chips contain circuitry for
amplification, temperature compensation
and calibration. Zero balancing before use
and at intervals to correct drift is required for
calibration
Invasive blood pressure
measurement
●● Requires cannulation of an artery connected
to a transducer via a column of fluid
●● Fluid is pressurised to 200–300 mmHg and
a valve allows a flush along the cannula at
2–4 mLhr−1 preventing clot formation at the
catheter tip
46
●● Transducer converts pressure into an electri-
cal signal, which is amplified and displayed
as a waveform and as numerical values
●● Calibration and zeroing are necessary
●● Gives continuous beat-to-beat monitoring
●● Cannula is also used for blood sampling but
may cause local tissue damage, and dis-
connection may result in massive blood loss
●● Peripheral measurement (e.g. radial) have a
higher systolic and lower diastolic (and a larger
pulse pressure) when compared with central
(e.g. aorta) sites. The mean arterial pressure
(MAP) remains constant
●● Other derived information from the waveform
includes
■■ outflow resistance and compliance from
the slope of the diastolic decay
■■ myocardial work and oxygen consump-
tion from the area under the curve of sys-
tolic pressure and time
■■ myocardial perfusion from the area under
the curve of diastolic pressure and time
■■ stroke volume and cardiac output from
the area under the curve
■■ contractility from the gradient of the upslope
NIBP measurement
Manual occlusive cuff techniques
●● Auscultation for Korotkoff sounds as the cuff
pressure is decreased
●● Sounds thought to be the result of turbulent arte-
rial blood flow
●● The phases are
I tapping sound at systolic pressure
II muffling or loss of sounds (auscultatory gap)
III reappearance or increased intensity of sounds
IV sudden muffling of sounds – diastolic pres-
sure in UK
V disappearance of sounds – diastolic pressure
in US
●● Simple equipment and no power supply
●● Cuff width should equal 40% of the mid-circum-
ference of the limb, and the cuff length should
equal twice the width
●● Reliant upon operator’s technique
●● Sources of error include
■■ narrow cuff over-reads and wide cuff under-
reads
■■ incorrect cuff length, which causes misalign-
ment of the bladder and artery
■■ failure of zeroing and calibration of the aner-
oid gauge
■■ difficulty in auscultating in patients with ath-
erosclerosis or hypotension
■■ arrhythmias (e.g. atrial fibrillation)
Automatic oscillometric occlusive cuff
techniques
●● Development of oscillotonometer
●● Single cuff inflates and detects transient pressure
changes which are analysed and systolic pres-
sure is derived
●● Mean and diastolic pressures are measured and
displayed
●● Allows alarms and data transfer to be used
●● Less accurate than the invasive method: over-
estimates low pressures, underestimates high
pressures and repeated measurements may
cause tissue damage
Continuous non-invasive blood pressure
●● Vascular unloading technique (also Penaz)
●● The volume of a digit is measured using a photo-
spectrometer and kept constant over the cardiac
cycle by a cuff. The pressure needed to keep the
volume constant is proportional to the arterial
blood pressure
●● Used in the Finapres and LiDCOrapid
 Physics

Clincal Monitoring and Measurement 47

Principles of pulmonary artery and wedge pressure measurement
The pulmonary artery catheter is a balloon-tipped Measurements
catheter used to measure pulmonary capillary wedge
●● Mixed venous, right atrial and ventricular gas ten-
pressure and cardiac output for perioperative or
sions and oxygen saturations, continuous mixed
intensive care monitoring
venous oxygen saturation, right ventricular ejec-
tion fraction and cardiac output
Components ●● Derives systemic and pulmonary vascular resis-
●● Distal lumen opening at the tip tance, stroke volume and cardiac index
●● Proximal lumen opening 30 cm from the tip
●● Balloon at tip is inflated with 1–1.5 mL of air during Complications
insertion and measurement of pulmonary capillary
wedge pressure During insertion ●● Complications associated with
●● Balloon should be kept deflated at other times central venous cannulation
●● A continuous pressure trace is displayed to aid with ●● Catheter knotting
insertion and afterwards to warn of accidental wedging ●● Pulmonary artery rupture
●● A thermistor a few centimetres from the tip is used to
monitor cardiac output Longer-term ●● Incorrect position and
●● Fibre-optic bundles are used for continuous mixed complications interpretation
venous oximetry ●● Infection
●● Contained within a plastic sheath to maintain sterility ●● Thrombocytopenia
during later manipulation ●● Pulmonary infarction or
thrombosis
Practical use ●● Damage to the valves,
myocardium or pulmonary
●● Inserted using an 8G introducer sheath, usually via
artery
the internal jugular vein
●● Use has not been shown to
●● Balloon inflated when in right atrium
decrease mortality
●● Pressure trace observed as catheter advanced
●● Floated until characteristic pulmonary capillary
wedge pressure displayed
●● The balloon is then deflated
Principles of pulmonary artery and wedge ­pressure measurement (cont.)
Pulmonary capillary wedge pressure ●● Placement in the dependent parts of the lung can
lead to inaccuracies due to the addition of hydro-
(PCWP) static pressure
●● Also known as pulmonary artery occlusion pressure
●● Indicator of left atrial filling pressure and, therefore,
Inaccuracies
left ventricular end diastolic pressure (LVEDP),
and, according to Starling’s law, left ventricular end ●● Inaccuracies may occur in situations where PCWP
diastolic volume exceeds LVEDP such as:
●● Indicator of the probability of development of pulmo- ■■ left ventricular failure
nary oedema ■■ non-compliant left ventricle – for example, with
●● Normally 6–12 mmHg; trends rather than absolute myocardial ischaemia, ventricular hypertrophy
values are used to guide treatment or pericardial tamponade
●● The tip must be in West zone 3 of the lung to ensure ■■ raised intrathoracic pressure – for example, posi-
accuracy (see West’s zones) tive end-expiratory pressure (PEEP)
■■ mitral valve disease
■■ aortic regurgitation

Clinical nugget – pulmonary hypertension (PH)

●● MPAP at rest >25 mmHg (with PCWP >12 mmHg)
●● Classification (WHO)
PH with lung COPD (chronic obstructive
Pulmonary arterial CTD (connective tissue disease)
disease pulmonary disease)
hypertension Left–right shunt
OSA (obstructive sleep apnea)
(PAH) – ↑MPAP Idiopathic
Chronic high altitude
without ↑LAP
PH due to Obstructed pulmonary artery
PH with left heart Chronic LVF (left ventricular
throm­boembolic
disease failure)
disease
Chronic mitral valve disease
Miscellaneous Sarcoidosis
Pulmonary veno-occlusive disease
 Physics

Clincal Monitoring and Measurement 48

Measurement of cardiac output
The Fick principle
●● States that the amount of substance taken up by an organ in unit time is equal to the arterial concentra-
tion minus venous concentration multiplied by the blood flow to the organ
●● Used to measure cardiac output by using oxygen or carbon dioxide

Oxygen consumption
Cardiac output =
Arterial − Mixed venous oxygen concentration
250 mL /min
=
200 − 150 mL /L
= 5 L /min
●● Kety-Schmidt technique is the application of the Fick principle to ascertain renal blood flow or cerebral blood
flow
●● Not routinely used because of inaccuracies in sampling and failure to maintain steady state conditions

Thermodilution
●● Involves intermittently injecting 5–10 mL of cold saline through the proximal port of a pulmonary artery catheter
and measuring the change in temperature by a thermistor at the catheter tip
●● A computer calculates the cardiac output using the Stewart-Hamilton equation. The cardiac output is inversely
proportional to the area under the graph of temperature versus time
●● Several readings should be taken and averaged as pulmonary artery blood flow varies with the ventilatory cycle
●● Imprecise readings may result from intracardiac shunts, tricuspid regurgitation, positive pressure ventilation, vari-
ations in the speed of injection and the thermistor being positioned against a vessel wall
●● A continuous version of the thermodilution technique uses a thermal filament in the pulmonary artery catheter to
heat the blood in pulses every 30–60 seconds.
●● Changes in temperature measured by the thermistor are compared with the thermal energy input to give a con-
stant cardiac output measurement
Measurement of cardiac output (cont.)
Indicator dilution
●● Indocyanine green dye and its concentration is measured peripherally using a photoelectric
spectrometer
●● Using indicator dilution (e.g. lithium) calibration of arterial wave form analysis allows CO measure-
ment continuously (e.g. LiDCOplus)
●● Some continuous CO measurement devices are uncalibrated (e.g. LiDCOrapid)

Echocardiography
●● Transthoracic or transoesophageal
●● Measuring the cross-sectional area and flow in the L ventricular outflow tract (LVOT) easily gives a
volume per unit time from which can be calculated the cardiac output
●● Three-dimensional echocardiography may be more accurate than two-dimensional

Oesophageal Doppler
●● Uses mean blood flow velocity through the descending aorta and assumes that a fixed proportion
of the cardiac output is going down the aorta
●● Multiplying by an estimate of the cross-sectional area obtained from a nomogram gives the
approximate stroke volume
●● Combining with heart rate gives an estimate of cardiac output

Clinical nugget – pulse pressure variation (PPV)

Hypovolaemia will affect venous return which shows variability during positive pressure ventilation.
Fluid responsiveness can thus be predicted by measuring PPV over the ventilatory cycle. Functional
parameters like PPV rather than static measurements are better predictors of fluid responsiveness.
 Physics

Clincal Monitoring and Measurement 49

Capnography
Capnography is the continuous analysis and ●● Calibration is with air (assumed zero) and a
graphical display of CO2 concentration known concentration from a gas cylinder

Principles
●● A molecule containing two or more different Clinical nugget – Capnography in
atoms will absorb infrared light at a wavelength a patient with bronchospasm
characteristic for that molecule Due to the lung units with long time constants
●● Interference from other gases, such as N2O, changes for emptying (= Compliance × Resistance)
the absorption spectrum but may be manually or dead space is still diluting the alveolar gas
automatically compensated for by the machine when the next inspiration occurs, hence no
●● A wire is heated to emit infrared radiation plateau.
●● Wavelength selection is achieved by filtering
●● Filters mounted on a rotating disc allow simulta-
neous analysis of several sample compounds
(alternating signal also reduces drift)
●● Carbon dioxide absorbs the infrared radiation
●● Wavelength of 4.28 mm is used to reduce inter-
ference from N2O

ETCO2
●● Sample chamber contains sapphire not glass
(which absorbs infrared)
●● Infrared radiation measured by photodetector
●● Double-beam instrument increases accuracy
by splitting through reference and sample gas
chambers
●● A capnometer displays the numerical value only Time
Capnography (cont.)
Types
Sidestream
●● Sample line takes 150 mL/minute from a
connector at the patient’s airway through
a water trap and into the analyser before
returning the gas to the circuit or scavenging
●● Transit time is the time taken to move the
sample to the analyser
●● Rise time is the time taken for the analyser to
register from 10% to 90% of a step change
after the sample has entered the measuring
chamber
●● Response time or delay time is the sum of
the transit time and the rise time
■■ Response time is less than one second
in a sidestream capnography
■■ May cause diffusion errors, and occlusion
is possible
■■ Expensive parts are protected in a strong
container
●● Useful in operations where there is a high risk
of air embolism (e.g. posterior fossa surgery in
sitting position)
●● Has a shorter delay time but is bulkier and
therefore difficult to support when using a
mask and is more vulnerable to damage
Capnography is useful to detect
●● estimated arterial PCO2
●● disconnection of the anaesthetic circuit
●● rebreathing – with raised baseline
●● malignant hyperthermia – gradual increase
in ETCO2
●● oesophageal intubation – decreased or no
ETCO2
●● pulmonary or air embolus or decreased
cardiac output – decreased ETCO2

Mainstream
●● Measures the CO2 concentration in the
breathing attachment, avoids turbulence
and does not extract gas from it
 Physics
Clincal Monitoring and Measurement
Pulse oximetry
Pulse oximetry uses a probe to measure per-
centage oxyhaemoglobin saturation in arterial
blood by detecting the absorption of infrared
and red light at two different wavelengths
Physical principles
●● The Beer-Lambert law states that the inten-
sity of light transmitted through a transpar-
ent substance decreases exponentially as
concentration of the substance and distance
travelled through it increases
●● Experimentally defined algorithms must be
used to give an accurate reading
●● An isosbestic point is found, at which the
absorptions of a certain wavelength of light
by two substances are equal
●● The isosbestic points for the oxygenated and
deoxygenated forms of haemoglobin are
590 nm and 805 nm
●● Modern pulse oximeters may or may not use
isosbestic points as a reference
50
Principles of pulse oximetry
●● Two light-emitting diodes (LEDs) emit pulses
of infrared and red light every 5–10 ms, and
a photodetector detects the light transmitted
through the finger
●● Oxygenated haemoglobin absorbs more infra-
red light (940 nm wavelength) and less red light
(660 nm) than deoxygenated haemoglobin
●● Comparison of absorption of the two wave-
lengths allows an estimated oxygen satura-
tion to be calculated
●● Cycling of the two wavelengths includes a
period with both off (to allow for subtraction
of ambient interference)
●● The pulsatile (AC) component of the signal
is separated from the constant (DC) compo-
nent, which is discarded
●● The signal is then amplified and an algorithm
calculated experimentally from healthy vol-
unteers is then used to estimate arterial oxy-
gen saturation
●● Therefore, it is increasingly inaccurate at
<85% saturation
Pulse oximetry (cont.)
Inaccuracies
●● Movement
●● Failure because of poor peripheral perfu-
sion or venous congestion
●● Interference from abnormal haemoglobin
(carboxyhaemoglobin – falsely high read-
ing, hyperbilirubinaemia – falsely low read-
ing, methaemoglobin – causes saturation to
approach 85%)
●● Irregular pulse rate (e.g. atrial fibrillation), or
non-pulsatile flow (e.g. on cardiopulmonary
bypass) or venous pulsations (e.g. tricuspid
regurgitation)
●● Nail varnish
●● Ambient light, especially if flickering
●● Diathermy, which causes electrical interference
●● Intravenous methylene blue or indocyanine
green may cause a transient decrease in the
reading
●● Fetal haemoglobin has no effect
Harmful effects
●● Prolonged response time
■■ instrumental delay (because of the aver-
aging time used to reduce movement
artefacts)
■■ circulatory delay (because of the inter-
val between changes in central and
peripheral saturation; <15 s for an ear
probe, >60 s for a finger probe). Response
time may rise 2–3 times because of vaso-
constriction or venous engorgement
●● Prolonged use may cause pressure dam-
age or burns, especially with finger probes
used on children
●● Burns may also occur if used in the MRI
scanner
●● Infection
 Physics

Clincal Monitoring and Measurement 51

Measurement of gas and vapour concentrations
Fuel cell
●● No battery needed
●● Cell produces a voltage itself and acts as a battery
●● Like all batteries, it will expire in time due to exhaustion of the lead anode
●● Made up of lead anode and gold mesh cathode linked by KOH electrolyte
●● At anode: Pb + 2OH − → PbO2 + H2O + 2e−
●● Reaction at cathode is same as for Clark electrode
●● Current flows at cathode proportional to oxygen concentration, as in Clark electrode
●● Response time is 30 s, which is slower than Clark electrode and makes it inappropriate for instant
ventilation analysis
●● In standard cells, N2O reacts with lead anode to give nitrogen, which may damage the fuel cell
●● Temperature compensation with thermistor

Infrared spectrophotometer
●● Uses the principle that molecules containing two or more dissimilar atoms absorb infrared light
●● Different gas molecules absorb specific wavelengths of infrared light
●● Capnograph specifically measures CO2
●● Pulse oximeter measures oxygen saturation
●● Nitrous oxide and volatile anaesthetics can also be measured
Measurement of gas and vapour concentrations (cont.)
Ultraviolet light absorption
●● Can be used in a similar way to infrared spectrophotometry to measure halothane concentration

Mass spectrometry
●● Measures the concentration of various gases by separating them according to their mass:charge
ratio
●● A cathode charges the particles, which are then accelerated and deflected by a magnetic field
by varying amounts according to their momentum and charge
●● The electrical charge detected depends on the number of particles in the original sample
●● Quadrupole mass spectrometer contains four beams of differing potential, which remove particles
unless they are of a certain mass

Paramagnetic cell
●● Oxygen is attracted into a magnetic field, that is it is paramagnetic
●● The sample gas flow and the reference gas flow are separated by a differential pressure transducer
●● Alternating magnetic field is applied
●● Difference in pressure represents the oxygen concentration of the sample
●● Fast response time allowing breath by breath analysis
●● Samples need to be dried by passing through silica gel as water vapour can affect accuracy
 Physics

Clincal Monitoring and Measurement 52

Measurement of gas and vapour concentrations (cont.)
Haldane apparatus depends upon the types of atomic bonds in
●● Measures gas volumes before and after the molecules of the gas
●● Can be used to measure the concentra-
removal of oxygen by pyrogallol absorbent
●● Version with potassium hydroxide absorbent tion of O2, N2O, N2, CO2 and the volatile
anaesthetics
can be used to measure CO2

Katharometer Interferometer
●● Light beam split into sample and reference
●● Electrical resistance of a heated wire falls
chambers
when a gas is passed over it
●● Differing velocity of light in chambers puts
●● Can be used to measure concentrations of
beams out of phase
CO2, N2O and O2, because different gases
●● Interference pattern dependent on concen-
conduct heat to differing degrees
tration of sample
Raman scattering ●● Cheap, portable and accurate
●● Used to calibrate vaporizers
●● Raman effect – a gas exposed to electro-
magnetic radiation may absorb the radiation
partially; the magnitude of the absorption
Measurement of pH
pH is the negative logarithm to base 10 of the
hydrogen ion concentration; a normal arterial
blood pH of 7.4 corresponds to a hydrogen ion
concentration of 40 nmol/L
●● Because it is a logarithmic scale, a difference
of 1 corresponds to a 10-fold difference in
pH; pH 7.0 is 100 nmol/L of H+ and pH 8.0 is
10 nmol/L of H+
Measurement – pH electrode
●● Reading electrode (Ag/AgCl) which sits in a
buffer solution separated by hydrogen ion-
sensitive glass from the sample
Glass electrode
Electrode 1
Liquid of known pH
Thin glass membrane
●● Buffer solution maintains constant concentra-
tion of H+ in reading electrode
●● Difference in concentration of H+ between
the sample and reading electrode generates
a potential difference
●● Reference electrode (Ag/AgCl in KCl) linked
to the sample via a semipermeable mem-
brane completes the circuit
●● Membrane prevents protein contamination of
the potassium chloride solution
●● Whole system is maintained at 37°C
●● Concentration of hydrogen ions is converted
to pH
Reference electrode
KCI solution
Electrode 2
External liquid junction
Sample
 Physics
Clincal Monitoring and Measurement
Measurement of pCO2
●● The Severinghaus carbon dioxide elec-
trode is a modified pH electrode that uses
the dissociation of carbon dioxide in water
to form hydrogen ions to measure partial
pressure of carbon dioxide
●● Two electrodes sit on either side of hydrogen
ion-sensitive glass and in contact with a
sodium bicarbonate solution
●● Sample is separated from the sodium bicar-
bonate by a carbon dioxide permeable (H+
impermeable) plastic membrane
●● Carbon dioxide diffuses through membrane
in about 2–3 minutes, as predicted by Henry’s
law, the concentration of dissolved gas is pro-
portional to the partial pressure
53
●● It then dissociates according to the equation
CO2 + H2O ↔ H2CO− + −
3 ↔ H + HCO 3
●● The change in concentration of hydrogen
ions is measured by the glass electrode (as
in the pH electrode)
●● Electrode must be calibrated regularly and
maintained carefully to ensure accuracy. For
example, a hole in the semipermeable mem-
brane would make it inaccurate
●● Temperature control is also important,
because dissociation increases with increas-
ing temperature; the temperature of the
apparatus is maintained at 37°C
●● Excess heparin may cause dilution and a
falsely low reading of pCO2
Measurement of PO2
Clark electrode = oxygen electrode = polaro-
graphic cell
●● measures oxygen tension within gases or
liquids
●● platinum cathode and a silver/silver chlo-
ride anode linked by a buffered potassium
chloride solution
●● oxygen in sample diffuses across semiperme-
able plastic membrane (prevents protein
build-up) into potassium chloride solution
●● membrane is impermeable to halothane
(falsely high reading)
●● potential difference of 0.6 V is applied across
the electrodes
●● current flow depends on the supply of oxy-
gen and is proportional to the oxygen
concentration
●● at the cathode: O2 + 4e− + 2 H2O → 4OH −
●● in the electrolyte: KCl + OH − → KOH + Cl−
●● at the anode: Ag + Cl− → AgCl + e−
●● must be kept clean and the plastic mem-
brane kept free of holes or protein deposits
●● blood sample must be taken anaerobically
and heparinized and analysed rapidly, as
metabolism in blood cells will reduce the PO2
value
●● temperature kept constant because the
­solubility of the oxygen is affected by temper-
ature and will give a higher measured PO2
than is actually present in vivo in a hypother-
mic patient. The analyser will correct for this
●● Other methods
■■ Intravascular probes give continuous
measurement but are difficult to calibrate
■■ Transcutaneous electrodes use a heat-
ing coil to induce vasodilation and
increase the rate of oxygen diffusion. They
are inaccurate and may cause burns
■■ Intravascular fibre-optic sensors work by
measuring the intensity or wavelength of
reflected light but are difficult to calibrate
 Physics
Clincal Monitoring and Measurement
Derived measurements – bicarbonate and base excess
Actual bicarbonate
●● This is the concentration of the bicarbonate in
the plasma
●● It is derived by the blood gas machine on
the basis of pH and pCO2 via the Henderson-
Hasselbalch equation
●● A simplified version HCO−3 = 0.03 × pCO2 × 10(pH-6.1)
(6.1 = pKa for carbonic acid; 0.03 is Henry’s solubil-
ity constant for CO2)
●● The lab sample measures the bicarbonate using
an enzymatic reaction. There is close concor-
dance between derived and measured bicarbon-
ate values (>98% have error of <1.3%)
Standard bicarbonate
●● This is what the bicarbonate should be if all
non-metabolic (i.e. respiratory) influences are
controlled
●● The value is derived for a normal pCO2 (5.3 kPa),
normal PO2 (13.3 kPa) and normal temperature
(37oC)
●● The level is derived by the Henderson-Hasselbalch
equation using the measured pH and pCO2 5.3 kPa
●● Clinically it addresses the question of what would
be the bicarbonate if ventilation was normal
54
Actual base excess
●● This is the concentration of titrable base when
the blood is titrated back to a normal pH at a nor-
mal pCO2 and temperature
●● The oxygen concentration is not controlled for; the
derivation uses the actual oxygen saturation
●● This represents the metabolic contribution to the
change in base excess
●● Although it controls for the respiratory contribution
to acid/base disturbance it does not control for the
buffering effect of haemoglobin on the extracellular
fluid (ECF)
Standard base excess
●● The standard base excess controls for the buffer-
ing of haemoglobin by applying the titration as
per the actual base excess but at a haemoglo-
bin of 50 g/L
●● This is generally a valid correction factor for buffering
unless there is an abnormal amount of ECF of low
albumin and phosphate (e.g. ITU patients)
●● For practical reasons it was easier to derive this
from the Siggaard-Andersen nomogram or
from an equation
●● The nomograms are now mostly replaced by a
computer calculation using the Van Slyke equation
Oxygen consumption, carbon dioxide production and respiratory quotient
Measurement of oxygen ­consumption; ●● Rebreathing technique (Campbell and Howard)
method 1 ■■ patient rebreathes from a 2 litre bag contain-
ing 50% oxygen for 90 seconds
●● Measurement of the volume of oxygen taken up
■■ patient rests for 3 minutes
from a sealed spirometer that contains a carbon
■■ patient rebreathes for a further 30 seconds
dioxide absorber
■■ bag pCO2 approximates to mixed venous
●● After conversion to standard temperature and
pCO2
pressure, the basal metabolic rate may be cal-
■■ arterial pCO2 is normally 0.8 kPa lower than
culated by multiplying by the average energy
mixed venous pCO2
produced per litre of oxygen

Oxygen delivery to an organ (i.e. the Respiratory quotient

●● Ratio of the volume of CO2 produced by tissues to
body) minus oxygen return; method 2
the volume of O2 consumed per unit time
●● Oxygen delivery is calculated by multiplying
●● Depends on the type of substrate being used
arterial oxygen content by cardiac output
●● Respiratory exchange ratio is the estimation of
●● Similarly, oxygen return is calculated by multiplying
respiratory quotient
mixed venous oxygen content by cardiac output
●● Derived from expired CO2/inspired O2 measurements
●● Thus dependent on ventilation
Measurement of carbon dioxide
production
●● End-tidal gas sampling (ETCO2 approximates
pACO2, which approximates arterial paCO2)
 Physics

Equipment 55
Classification of vaporizers
Vaporizers are devices used to deliver accurate and safe concentrations of volatile inhalational
agents to patients

Plenum vaporizers
●● Positive upstream pressure drives the gas
●● High internal resistance, so are used outside circle systems (vaporizer outside circle, VOC)
●● Gas passes through under pressure at the back bar
●● At low flows, large changes in the dialled concentration are reflected very slowly. By increasing the
fresh gas flow, changes in concentration can be effected more quickly
●● Examples include temperature-compensated (TEC) vaporizers

Drawover vaporizers
●● Gas is drawn into the vaporizing chamber by the patient’s inspiratory effort
●● Low internal resistance
●● Suitable for use within circle systems (vaporizer in circle, VIC) and for drawover techniques
●● At low flows, the concentration rises more quickly as the inhalational agent is added to each
inspiration
●● Examples include the Epstein Macintosh Oxford (EMO) vaporizer, Goldman vaporizer, Oxford
Miniature Vaporizer (OMV) and Boyle’s bottle
Factors that affect delivered concentration of anaesthetic agent
Saturated vapour ●● Inhalational agents with high SVP are more volatile
pressure (SVP) ●● Desired concentration at the common gas outlet will be adjusted by
means of the splitting ratio
Splitting ratio ●● The ratio of the gas passing through the vaporizing chamber compared
with the gas bypassing the chamber
Fresh gas flow ●● Modern vaporizers function independently of flow rates between 0.5 and
15 L/minute
Temperature of liquid ●● SVP is dependent on temperature, so delivered concentration of agent
falls with temperature drop that occurs with vaporisation
●● Temperature compensation mechanisms include bimetallic strip, heat
sinks, water bath and ‘copper kettle’ (secondary flow meter)
Surface area ●● Surface area of the gas/liquid interface is maximised to ensure full
saturation of gas by wicks and baffles
Pumping effect ●● Ventilators may produce cyclical pumping of gas that may be forced
back into the vaporizing chamber
●● As the ventilator cycles forward, this may lead to an increased anaes-
thetic concentration being delivered
Pressurizing effect ●● If the overall vaporizer pressure is raised (at high flows), then the gas
reaching the common gas outlet will expand to atmospheric pressure and
reduce the effective concentration
Physics

Equipment 56
Types of vaporizers
Temperature compensated (TEC) vaporizers
Control dial
– divides the FGF into 2 streams (splitting ratio)

Fresh gas flow Common gas outlet

Metal case
Allows heat from the
Wick environment to enter
the vaporizer
Anaesthetic agent Temp. control
valve (e.g.
bimetallic strip)
Heat sink Metal/water
heat sink
Types of vaporizers (cont.)
Desflurane vaporizer
●● Desflurane is extremely volatile, with a boiling point of 22.8°C
●● The Tec 6 vaporizer heats desflurane liquid to 39°C to a saturated vapour pressure (SVP) of 200 kPa
●● The pure vapour is then added to the carrier gas
●● The carrier gas is restricted by an orifice, so the pressure of the carrier gas is proportional to the
gas flow
●● A differential pressure transducer (P) senses this pressure and adjusts a resistor (R1) so that the flow
of desflurane out of the vaporizing chamber is proportional to the carrier gas flow
●● The control dial adjusts a second resistor (R2), which controls the output of desflurane gas and thus
the output concentration
●● Requires a mains electricity supply

Control dial

R1 R2
Gas

Liquid P
To
patient
H
Carrier Fixed resistor
gas
 Physics
Methods of killing contaminating organisms
Decontamination
The removal of infected material
●● Involves cleaning using detergent
●● Performed before disinfection or sterilization
Disinfection
The killing of infective organisms (not spores)
●● Pasteurization involves maintaining the
temperature of a hot water bath for a known
period of time in order to achieve a log
reduction in the number of viable organisms,
so that they are in numbers unlikely to cause
disease
●● Pasteurization times: 70°C for 20 minutes,
80°C for 10 minutes, 100°C for 5 minutes
●● Chemical disinfection (CEFGH), which must
be followed by washing/drying: chlorhexi-
dine (0.1%–0.5%), 70% ethanol, formaldehyde,
­glutaraldehyde, hypochlorite solution (bleach)
Equipment 57
Sterilization
Sterilization is the killing of all infective organ-
isms (including spores)
●● Dry heat sterilization – 160°C for 1 hour
●● Moist heat
■■ Autoclaving (effectively a pressure
cooker) using steam and indicator tape.
Rubber and plastic items may be dis-
torted: 30 minutes at 122°C and 1 atm, 10
minutes at 126°C and 1.5 atm, 3 minutes at
134°C and 2 atm
■■ Low temperature steam and formaldehyde
●● Chemical sterilization – ethylene oxide
(toxic and flammable)
●● g-irradiation – most disposable equipment is
irradiated during manufacture
●● Increasing use of disposable equipment
due to convenience, economy, risk of dis-
ease caused by prions (e.g. Creutzfeldt-Jakob
disease)
Classification of ventilators
●● Negative (e.g. cuirass, iron lung) tube for microlaryngeal surgery. This is attached to a
●● Positive pressure ventilation 400 kPa wall outlet. High frequency jet ventilators are
available for longer-term use, for example in ITU for
Classification of positive pressure lung protection ventilation strategies
ventilators ●● Minute volume dividers – open-system ventilators
where all of the driving gas is delivered to the patient,
By power for example Manley MP3 where the driving gas fills a
●● Electrical series of bellows and a sliding weight provides con-
●● Pneumatic stant pressure. The Servo 900 series is (was) a pneu-
●● Pneumatic and electrical matically driven, electronically controlled minute
volume divider
By cycling method ●● ‘Intermittent blowers’ are driven by a high pressure
●● Inspiratory cycling – the ventilator switches to expi- (400 kPa) continuous flow of gas which can be deliv-
ratory mode once a certain value has been reached ered to the patient but is more normally attached to
on one of four parameters anaesthetic gases flowing through a closed or semi-
■■ Volume cycling closed system. The Penlon-Nuffield has settings for
■■ Time cycling, using mechanical, pneumatic or flow rate and timing controls for cycling. The Newton
electronic timers valve attachment allows it to be used as a paediatric
■■ Pressure cycling, this depends on the resistance ventilator
and compliance of the patient
■■ Flow cycling – rarely used Additional features
●● Expiratory cycling – the ventilator can control cycling ●● Positive end-expiratory pressure (PEEP)/continuous
from expiration to inspiration using one of the aforemen- positive airway pressure (CPAP)
tioned methods. Time cycling using an electronic timer ●● BiPAP (bilevel positive airway pressure)
can allow for expiratory pause ●● IMV (intermittent mandatory ventilation) – the ventila-
tor allows breaths from the patient and may synchro-
By function nise them with the mandatory breaths. Spontaneous
●● Jet ventilation; for example jetting with entrained breaths can be augmented with pressure support
air down a rigid bronchoscope or using a Carden’s (SIMV-PS)
 Physics

Equipment 58
Breathing systems
Classification Mapleson A
APL valve
●● Open – room air, e.g. the original Schimmelbusch
mask
FGF
●● Semi-open – room air with some augmenta-
tion, e.g. tube and cupped hand or face mask Reservoir bag P Patient
●● Closed – completely closed circle system
Mapleson B Mapleson C
●● Semi-closed – no air intake but escape of
FGF
excess gas allowed FGF

Mapleson classification of semi-

closed breathing systems P
Mapleson D
●● Classified according to the position of the FGF
face mask, flexible hosing, reservoir bag and
adjustable pressure-limiting (APL) valve
●● Fresh gas flow (FGF) needed to prevent
P
rebreathing indicates efficiency
Mapleson E Mapleson F
FGF FGF

P P
Breathing systems (cont.)
Mapleson classification (cont.)
Mapleson A ●● Efficient for spontaneous ventilation – required FGF of alveolar minute volume (70 mL/kg/min)
●● Inefficient for intermittent positive pressure ventilation (IPPV) as exhaled gas retained in system and
some fresh gas lost through APL valve when bag squeezed – FGF 2–4 times minute volume required
●● Difficult to scavenge as APL valve next to patient
Mapleson B ●● Rarely used but has similar properties to Mapleson C
Mapleson C ●● Used mainly for resuscitation
●● Low pressure oxygen supply needed
●● Low dead space
●● Inefficient – FGF 2–3 times minute volume needed
Mapleson D ●● Inefficient for spontaneous ventilation as exhaled gas goes into reservoir bag and may be
rebreathed – FGF 2–4 times minute volume required
●● Efficient for IPPV as exhaled dead space gas goes into the bag and is rebreathed, but exhaled
alveolar gas vents through the APL valve – FGF of alveolar minute volume (70 mL/kg/min)
Mapleson E or ●● Low dead space
Ayre’s T-piece ●● Low resistance, so suitable for children
●● Reservoir limb volume must exceed tidal volume to prevent inhalation of room air
●● IPPV with intermittent occlusion of reservoir limb
●● FGF of 2–3 times minute volume needed
Mapleson F or ●● Bag movement indicator of spontaneous ventilation and for easier IPPV
Jackson Rees ●● FGF of 2–3 times minute volume needed
modification ●● FGF of 200 mL/kg for IPPV

Coaxial versions
●● More practical, with longer and lighter tubing and an accessible APL valve
●● Lack is coaxial Mapleson A
●● Bain is coaxial Mapleson D
●● Any holes or damage to inner hose may be dangerously overlooked
 Physics
Scavenging
Scavenging systems are used to transfer waste
gases from the expiratory port of anaesthetic
breathing systems to a safe remote location
●● They may be passive or active and consist of
■■ a collecting system, e.g. a shroud around
the exhaust valve or various connectors or
funnels or a canopy over a patient
■■ plastic tubing with 30 mm connections
to avoid inadvertent connection to the
breathing system
■■ a receiving system with a reservoir
and pressure relief valve to prevent
barotrauma
■■ a disposal system to safely remove waste
gases away from where personnel are
working
Equipment 59
Passive scavenging
●● No external energy supply and may be a sim-
ple wide-bore tube that leads to the roof of
the building
●● The least efficient system, as it depends
upon the direction of the wind
●● Maximal resistance should be 0.5 cmH2O at
30 L/minute
●● Disadvantages include: Increased resis-
tance to expiration and a risk of complete
obstruction
●● Water trap is needed
●● Cardiff Aldasorber has been used to remove
volatile anaesthetic agents but does not
remove N2O
●● Assisted passive scavenging uses the air-
conditioning’s extractor ducts
Scavenging (cont.)
Active scavenging
●● Usually consists of a type of fan system that
produces a continual low suction pressure for
safety reasons
●● Must be high volume and should be able
to  remove 75 L/min, with a peak flow of
130  L/­m in
●● Alternatively, an ejector flow meter uses the
Venturi principle to drive the scavenging
Difficulties
●● In paediatrics with semi-closed breathing
systems
●● In recovery with open or semi-open breath-
ing systems
●● In obstetrics with 50:50 O2:N2O
Control of Substances Hazardous to
Health (COSHH) regulations
●● Employers must identify and control any sub-
stances that may be hazardous to health
●● Health and Safety Commission has set
maximal limits of 100 ppm N2O and 50 ppm
isoflurane over 8 hours
Possible adverse effects
●● Chronic exposure to anaesthetic agents may
cause increased incidence of
■■ spontaneous abortion
■■ congenital abnormalities
■■ leukaemia and lymphoma
■■ female births
■■ infertility
 Physics

Equipment 60
Carbon dioxide absorbers
Carbon dioxide absorbers are used in anaesthetic breathing systems to allow rebreathing of
exhaled gases

Soda lime
●● Composed of 75% Ca(OH)2, 20% H2O, 3% NaOH, 1% KOH and <1% silicates (binding)
●● Carbon dioxide initially reacts with NaOH and KOH to produce the respective carbonates, which
then react with calcium hydroxide to replenish the hydroxides. The reaction is exothermic and
overall can be written as:
■■ CO2 + Ca(OH)2 → CaCO3 + H2O
●● Under ideal conditions, 1 kg of soda lime can absorb 250 L of CO2
●● Canisters are packed tightly with up to 2 kg of granules to avoid channelling, but the total volume
of space between granules should equal the volume
●● Granules are size 4–8 mesh (mesh is the number of openings per inch in a uniform metal strainer)
●● Exhaustion of soda lime is indicated by dyes:
■■ colour change is pink to white when phenolphthalein is used (most often)
■■ colour change is white to purple when ethyl violet is used
Carbon dioxide absorbers (cont.)
Baralyme
●● Composed of 80% calcium hydroxide and 20% barium octahydrate
●● Less efficient than soda lime, but its reaction with CO2 is less exothermic and it is more stable in dry
atmospheres

Dangers of CO2 absorbers

●● Potentially dangerous reactions may occur with CO2 absorbers and anaesthetic agents
●● Carbon monoxide (CO) may be formed when volatile agents containing a (CHF2) group (isoflu-
rane or desflurane) are passed over warm, dry Baralyme or soda lime
●● Sevoflurane may react with CO2 absorbents to produce degradation products (compounds A, B,
D, E and G). Compound A has been shown to cause dose-dependent nephrotoxicity in rats (this
has not been reproduced in studies in humans)
●● Trichloroethylene and soda lime produce a neurotoxin that particularly affects the trigeminal and
facial nerves
●● Soda lime dust is caustic and causes respiratory tract burns if inhaled; a problem with the to-and-
fro Waters canister
●● Granules that are too small can provide too high a resistance to gas flow; too large and the gran-
ules provide inadequate surface area to work efficiently
 Physics
Suction
Suction apparatus can be small and individual or
large to supply a whole establishment. The essential
components are nevertheless the same.
●● Vacuum
■■ Driven by an electrical pump which can be
piston-type, rotary vane or diaphragm
■■ The pump should be capable of maintain-
ing a vacuum of 0.67 bar below 1 atmo-
sphere and unrestricted air flow of 25 L min −1
(displacement)
■■ Can also be driven by foot pumps or hand-
powered devices
■■ An injector suction unit is driven by the
Venturi principle from compressed gases
■■ Most hospitals will have a high-displacement
piped vacuum source which will have a non-
interchangeable valve at the theatre/ward
end of the pipeline. This central setup will have
two central pumps to allow for maintenance
■■ There must be a vacuum indicator and regula-
tor in the system so that low vacuum and flow can
be applied (e.g. when draining a closed cavity)
●● The collection vessel (reservoir)
■■ Needs to be an appropriate size; too small
and it will need constant changing and if too
Equipment 61
large it will mean the vacuum will take too
long to build up
■■ Leak around the collection vessel is a com-
mon cause for suction failure
■■ Filters aid in preventing contamination. Float
valves are designed to protect the suction
unit as they are designed to close off if the
collection vessel gets full
●● Delivery tubing
■■ Disposable
■■ Attached to rigid catheter (e.g. Yankauer)
or flexible catheters (e.g. for bronchial
suctioning)
■■ Round-tipped catheters should be used for
suctioning areas which might be damaged
(e.g. after pharyngeal surgery)
■■ Tracheobronchial suctioning should be done
with a catheter size double the ETT size (e.g.
a size 4 ETT should accommodate a size 8
suction catheter). Pre-oxygenation is neces-
sary prior and recruitment manoeuvre after
suctioning to prevent hypoxaemia
■■ Enclosed suction catheters which can be
used without detachment of the ETT are avail-
able to use on ITU
CO2 removal systems
I. To-and-fro – Waters II. Circle systems
FGF

FGF
CO2 absorber
Rebreathing (1–2 kg)
APL
bag Valve

Rebreathing APL
Patient
bag
CO2 absorber
(approx. 500 g) Valve Valve

Patient

N.B. The soda lime cannister is larger (c.f. the to-and-

fro) and can be placed vertically. The unidirectional
valves are usually flip valves mounted on the absorp-
tion cannister.
 Physiology

General Principles 62
Effects of old age on anaesthesia
Increased incidence of coexisting disease
●● COPD, atherosclerosis, ischaemic heart disease, high blood pressure, arthritis, diabetes mellitus,
dementia, Parkinson’s disease, frailty, malnutrition and sensory impairment
●● Polypharmacy
●● ↓ physiological reserve

Airway ● Edentulous, ↓ oropharyngeal muscle tone, osteoporotic mandible and cervical

spondylosis
Respiratory ● ↓ PaO2  ● ↓ sensitivity to hypoxia and hypercapnia  ● ↓ compliance  ● ↓ vital
capacity  ● ↑ closing capacity  ● ↑ V/Q mismatch leads to ↑ alveolar–arterial oxygen
gradient  ● ↑ atelectasis and pneumonia postoperatively
Cardiovascular ● ↓ heart rate, stroke volume and contractility  ● ↓ cardiac output (20% at age 60 years)
system ● ↓ left ventricular compliance  ● ↓ sensitivity to inotropes  ● ↑ risk of pulmonary
thromboembolism
CNS ● Cerebral atrophy (10% reduction in brain weight)  ● ↓ cerebral blood flow (CBF) and
oxygen consumption  ● ↓ MAC  ● ↓ short term memory  ● ↓ neurotransmitter
concentrations  ● ↑ sensitivity to benzodiazepines and opiates  ● ↑ risk of confusion
Autonomic ● Orthostatic hypotension (25% at age 60 years)  ● ↓ basal metabolic rate (BMR) and
nervous system temperature control
Gastrointestinal ● ↑ hiatus hernia  ● Slower gastric emptying  ● ↓ hepatic drug metabolism
Renal ● ↓ renal blood flow  ● ↓ GFR (by 30%–45%)  ● ↓ urine concentrating ability
● ↓ drug clearance
Paediatric anatomy and physiology
●● Neonate is up to one month of age
● Infant is up to one year of age

Surface area to ● Smaller child = ↑ ratio  ● ↑ heat loss and risk of hypothermia  ● ↑ BMR, so:
mass ratio ■ ↑ oxygen consumption  ■ ↑ risk of desaturation  ■ ↑ heart rate
■ ↑ respiratory rate
Airway ● ↑ relative head size
● Narrow upper airway:  ■ Large tongue  ■ Lymphoid tissue  ■ Narrow
pharynx  ● Longer, bigger, U-shaped epiglottis  ● More anterior and cephalad
larynx (C3–4)  ● Neonates are obligate nasal breathers  ● Cricoid is narrowest
point (compared with glottis in adults)
Respiratory ● Trachea short and narrow  ● Main bronchi branch at equal angles  ● 50%
airway resistance by distal airways  ● Horizontal ribs  ● Diaphragmatic
respiration  ● Tidal volume relatively fixed; compensation by increasing rate
● Closing capacity grater than FRC until age 6 years  ● Infants generate CPAP
through expiratory cord adduction
Cardiovascular ● Cardiac output 30%–50% more than in adults  ● Stroke volume fixed;
system compensation by increasing rate  ● Relatively small limbs, so less blood volume
to mobilize and therefore smaller reserve
Renal ● ↓ GFR  ● ↓ tubular function  ● ↓ urinary concentrating ability
Nervous system ● Myelination completed at six months  ● Spinal cord ends at L3–4 at birth;
reaches adult level by age 2 years  ● Immature sympathetic nervous system
 Physiology
The cell
The cell is the basic structural, functional and
biological unit of all known living organisms.
All cells are produced by division of pre-exist-
ing cells
Modern cell theory adds that:
●● Cells contain hereditary information DNA
which is passed on during division
●● In similar species, all cells have the
same  basic  chemical and physiological
function
●● The activity of an organism depends on
the total activity of independent cells which
depends on the activities of subcellular struc-
tures (metabolism)
Eukaryotic
●● Cells may be eukaryotic (containing a
nucleus,  multicellular organs in general) or
prokaryotic (without a nucleus, single-celled
organisms)
●● Humans contain more than 10 trillion (1012)
cells. Most cells are 1–100 µm diameter
General Principles 63
●● Eukaryotic DNA is organised into linear mole-
cules called chromosomes contained within
the nucleus
●● Many eukaryotic cells are ciliated and play
important roles in chemosensation, mecha-
nosensation and thermosensation
Cells consist of:
●● Cell membrane
●● Cytoplasm – the intracellular contents outside
the nucleus containing organelles and including:
■■ Cytosol – the intracellular fluid containing
proteins and electrolytes
■■ Cytoskeleton – network of protein fibres
within the cytoplasm responsible for organ-
isation of organelles, cell division and cell
movement
●● The nucleus
■■ Surrounded by a double envelope which is
relatively impermeable to maintain genetic
integrity
■■ Contains the nucleolus (site of transcrip-
tion and ribosome assembly) and nucleic
acids (DNA, RNA)
The cell (cont.)
●● Organelles – parts of the cell adapted for ■■ Centrosomes – organises the cytoskel-
specific functions eton and produces the cell microtubules
■■ Mitochondria – self replicating, primary ● Composed of two centrioles which
function is energy conversion via oxidative separate during cell division and help
phosphorylation to release ATP in the formation of the mitotic spindle
■■ Ribosomes – large complex of RNA and ● A single centrosome is present in mam-
protein, and two subunits which act as an malian cells
assembly line for the translation of mRNA
Cytoplasm
into amino acid chains
■■ Endoplasmic reticulum (ER) – transport
Cell membrane
network for molecules targeted for specific Ribosomes
destinations. Two forms: Rough ER
● Rough ER – ribosomes on the surface Nucleolus
which synthesise and folds proteins Nucleus
● Smooth ER – participates in lipid and
steroid hormone synthesis, as well as Smooth ER
Vesicles
calcium sequestration and release
■■ Golgi body – modifies, processes and
Golgi apparatus
packages proteins synthesised by rough ER Lysosome
■■ Lysosomes – store inactive hydrolases which
when activated digest worn-out organelles
and engulfed bacteria and viruses
Mitochondria
■■ Peroxisomes – membrane-bound enzymes
to rid the cell of toxic peroxidases
 Physiology

General Principles 64
Cell membrane characteristics
●● Separates and protects the cell interior from the Transport across the membrane can occur by:
external environment ●● Diffusion
●● Classically described as fluid mosaic model ●● Osmosis
●● Other functions: ●● Active transport
■■ maintains the membrane potential ●● Endocytosis
■■ selectively permeable to control movement in/ ●● Exocytosis
out of cell
■■ maintains the cell shape (with cell wall/cytoskeleton) Cell signalling
■■ cell adhesion and signalling ●● Cells communicate via the release of molecules
which trigger intracellular signalling → up/down-
Structure regulation of genes in the target cell
●● Phospholipid (hydrophilic, polar head and hydropho- ●● Via extracellular or intracellular receptors
bic non-polar tail) bilayer with embedded proteins ●● Examples include steroid and thyroid hormones
●● Low permeability to ions and polar molecules
Outside cell
●● Cholesterol accounts for 20% of lipids in mammalian Peripheral
Glycocalyx protein
cell membranes
Hydrophilic
●● Proteins account for 50% of the membrane mass: Regions of
integral protein
■■ Integral – span the membrane and have both Hydrophobic

hydrophilic and hydrophobic domains (e.g.

G-protein coupled receptors, ion channels)
■■ Peripheral proteins – do not significantly pene-
Phospholipid
trate hydrophobic core; tend to have temporary bilayer

interactions (e.g. some enzymes/hormones)

■■ Glycocalyx is a carbohydrate coat on the extra-
cellular surface; involved in cell recognition, hor-
Cytoskeleton
mone receptors, cell adhesion
●● Other membrane protein functions include pumps Inside cell

for active transport, carrier molecules, ion chan-

nels and enzymes
Genes and their expression
A gene is the molecular unit of heredity. It is a region of
DNA made up of nucleotides
●● DNA has three structures:
■■ backbone spiral structure (deoxyribose linked
with phosphate bonds)
■■ nucleotides – purine (adenine/guanine) or
pyrimidine (cytosine/thymine) base combined
with a deoxyribose and a phosphate group
■■ double helix structure is via complementary
base pairing via hydrogen bonds – adenine
forms two bonds with thymine, guanine forms
three bonds with cytosine
●● Each triplet of bases codes for a specific amino acid
●● DNA ‘clumps’ with proteins in the nucleus to form
chromatin. During cell division, chromatin forms
pairs of chromosomes
●● The human genome has 46 chromosomes (23
pairs) containing 3 billion base pairs
Transcription is the process by which sequences of DNA
produce specific messenger ribonucleic acid (mRNA)
sequences
●● RNA is a single-stranded polynucleotide, synthesised
in the nucleus
●● Contains ribose and a phosphate group with a
purine/pyrimidine base but thymine is replaced by
uracil
●● RNA polymerase ‘unzips’ the DNA double helix by
breaking the hydrogen bonds
●● mRNA is created by complementary base pairing of
the ‘anti-sense’ DNA strand; transfers the amino acid
sequence to the ribosome
●● Ribosomal (rRNA) – where the mRNA sequence is
translated into the amino acid sequence
●● Transfer (tRNA) carries amino acids to the ribosome
for complementary linkage to mRNA codons
●● Transcription factors regulate expression by bind-
ing to specific DNA sequences
●● Polypeptides leave the ribosome → golgi apparatus
for processing → secretory granules for exocytosis
 Physiology
Acid–base balance
●● An acid is
■■ a substance that can donate a hydro-
gen (H+) ion to another substance
(Brønsted-Lowry definition)
■■ a compound that is a potential electron
pair acceptor (Lewis definition)
●● A base accepts H+ ions or donates an elec-
tron pair
●● Normal body pH is 7.35−7.45 (H+ ion concen-
tration 35−45 nmol/L)
●● Maintenance of a stable pH in body fluids is
imperative for normal enzyme activity, protein
structure and ion distribution
●● Stable pH is maintained by
1. Lungs
●● Excrete 15,000–20,000 mmol/L H+ per
day and can compensate for non-
respiratory acidosis or alkalosis by
hyperventilation or hypoventilation
Biochemistry 65
●● Carbon dioxide can be excreted rap-
idly by the lungs, with effects on pH
balance via the reaction catalyzed by
carbonic anhydrase:
CO2 + H2 O ↔ H2 CO 3 ↔ H+ + HCO−3
2. Kidneys
●● Excrete 60–80 mmol/L H+ per day from:
■■ lactic acid (blood cells, muscle
and brain)
■■ acetoacetic acid (fatty acid
metabolism)
■■ sulphuric acid (metabolism of sul-
phur-containing proteins)
3. Buffers
Acid–base balance (cont.)
Henderson-Hasselbalch equation ●● If the level of bicarbonate increases or
●● The Henderson-Hasselbalch equation describes the level of CO2 decreases, the pH will rise
the relation between concentrations of disso- (alkalosis)
ciated and undissociated acid or base, disso- ●● If the level of bicarbonate decreases or the
ciation constant (Ka) and pH level of CO2 increases, the pH will fall (acidosis)
●● It is often specifically applied to the bicarbon-
Anion gap
ate buffer system
■■ K a [H2 CO3 ] ↔ [H+ ][HCO−3 ] and ●● The difference between anions (e.g. phos-
phate, ketones, lactate) and cations:
[H+ ] [HCO−3 ]
Ka = +
[H2 CO3 ] Anion gap = [Na+ + K ] − [HCO−3 + Cl−]
●● Taking logs
+ [HCO−3 ]
■■ log K a = log [H ] + log
[H2CO3 ]
●● Hence if: [HCO−3 ] = [H2CO3 ]

then pH = pKa
[HCO−3 ]
therefore pH = pK a + log
[H2CO3 ]
[HCO−3 ]
simplified to pH = pK a + log
0.2 PCO2

where 0.2 is the solubility coefficient of CO2

in mmol/L/kPa
 Physiology
Buffers
●● A buffer is a solution that contains a weak
acid and its conjugate base
■■ Minimises changes in pH when an acid
or base is added to the solution
■■ Maintains homeostasis for enzymatic
reactions
■■ The buffering capacity is maximal at the
pKa of the weak acid
Extracellular fluid (ECF)
●● HCO−3 is the major ECF buffer
■■ It has a pKa of 6.1 and is an open buffer
system, as both CO2 and HCO−3 can be
altered
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO−3
●● Haemoglobin (Hb) is the major buffer for
CO2 and thus H+ ions in red blood cells. Each
Biochemistry 66
molecule has more histidine residues than
plasma proteins to buffer the excess H+ ions
●● Deoxyhaemoglobin is a more powerful buf-
fer than oxyhaemoglobin (Haldane effect)
●● Plasma proteins – not important extracellu-
larly as they are in a low concentration
●● Calcium and phosphate salts in bone –
long-term acid–base balance
●● Urinary buffers – phosphate (titratable acid-
ity of urine) and ammonia through the forma-
tion of NH+4
Intracellular buffers
●● Proteins and phosphates have a pKa of 6.8;
they are effective buffers as the intracellular
pH is lower than the extracellular pH
Buffers (cont.)
Phases of buffering
1. Immediate chemical buffering
2. Respiratory compensation by expiration or
retention of CO2
■ Rapid, high capacity buffering system
■ Ventilation increases by 2 L/min for every
mmHg increase in CO2 production
■ Regulated by central chemoreceptors
(80%) and peripheral chemoreceptors
(20%)
3. Renal buffering
■ Reabsorption of filtered HCO−3
■ Net excretion of H+
● Secretion of H+ in the proximal con-
voluted tubule
■ High capacity, low gradient (limited
to a urinary pH of ∼7.0)
■ Driven by active transport of Na+
ions out of the basolateral mem-
brane, which drives the resorption
of Na+ in exchange for H+ excretion
at the luminal membrane
● Secretion of H+ ions into the distal
convoluted tubule
■ Low capacity, high gradient (to a
urinary pH of ∼4.4)
■ Mostly buffered by phosphate and
ammonium salts
● Secretion of NH+4 ions into the PCT/
DCT
■ Because HCO−3 is reabsorbed, it
cannot buffer urinary H+
■ Glutamine is deaminated to yield
HCO−3 and NH3 (lipid soluble,
crosses cell membrane easily)
■ Ammonium is formed in urine:
NH3 + H+ → NH+4
■ NH+4 less permeable as it is charged,
so it remains in the urine as a buffer
(ion trapping)
 Physiology
Sodium
●● Main cation in extracellular fluid (ECF)
●● Important for membrane and action
potentials
●● Constitutes 90% of osmotically active sol-
ute in ECF and determines ECF volume
●● Normal plasma concentration 135–145
mmol/L
●● Requirement is 1–1.4  mmol/kg/day (100
mmol/day)
Hyponatraemia
Hypovolaemic hyponatraemia (loss of Na +
and H2O, proportionately >Na+)
●● Renal (urinary Na+ >30 mmol/L)
■ Diuretics
■ Salt-losing nephritis
■ Proximal renal tubular acidosis
■ Hypoadrenalism
■ Osmotic diuresis
■ Ketonuria
Biochemistry 67
●● About 150–450 mmol lost in urine and 10 mmol
each in faeces, sweat and skin per day
Regulation
●● Concentration of sodium ions in ECF and
osmolality by osmoreceptors and the renin–
angiotensin–aldosterone system
●● Changes in volume of ECF through barore-
ceptors and atrial natriuretic peptide
Hypernatraemia
Hypovolaemic hypernatraemia (loss of Na+
and H2O, proportionately >H2O)
●● Renal (urinary Na+ >30 mmol/L)
■ Loop or osmotic diuretics (mannitol, etc.)
■ Post-obstructive
●● Extrarenal (urinary Na+ <30 mmol/L)
■ Vomiting, diarrhoea
■ Sweating
■ Burns
■ Fistulae
■ Inadequate intake
Sodium (cont.)
Hyponatraemia (cont.) Hypernatraemia (cont.)

Hypovolaemic hyponatraemia continued Euvolaemic hypernatraemia

●● Extrarenal (urinary Na+ <30 mmol/L)
■ Vomiting, diarrhoea
■ Burns
■ Trauma
■ Pancreatitis
Euvolaemic hyponatraemia (no oedema)
●● Inappropriate administration hypotonic fluid
(e.g. polydipsia, TURP, IV fluids)
●● Drugs via ADH (e.g. oxytocin)
●● Glucocorticoid deficiency
●● Hypothyroidism
●● SIADH
●● Insensible losses
●● Diabetes insipidus (cranial or renal)
Hypervolaemic hypernatraemia (Na+
retention unmatched by increasing fluid
intake)
●● Hyperaldosteronism
●● Cushing’s syndrome
●● Iatrogenic (hypertonic NaCl, NaHCO3)

Hypervolaemic hyponatraemia (Na+ and H2O

retention, proportionately >H2O)
●● Acute or chronic renal failure
●● CCF (congestive cardiac failure)
●● Cirrhosis
●● Nephrotic syndrome
 Physiology

Biochemistry 68
Potassium
●● Main intracellular cation (90% of total body ●● Normal plasma concentration 3.5–5 mmol/L
potassium) ●● Requirement is 0.7–0.9 mmol/kg/day or about
●● Important for protein synthesis, acid-base 60 mmol/day
balance and osmolality
●● Extracellular levels important because of
effect on membrane potentials, action poten-
tials and plasma acid–base balance

Hypokalaemia Hyperkalaemia

Reduced intake Increased intake

●● Hypotonic IV fluids ●● Iatrogenic − IV fluids or blood
●● Dietary insufficiency or malabsorption (e.g. ●● Haemolysis
alcoholism) Decreased renal excretion
Increased losses ●● Renal failure
●● Renal ●● Adrenocortical failure
■ Hyperaldosteronism ●● Drugs − K+-sparing diuretics, ACE inhibitors,
■ Cushing’s syndrome ATII-receptor antagonists
■ Diuresis (DKA, hypertonic saline, mannitol) Extracellular potassium shifts
■ Renal tubular acidosis (type I and II) ●● Acidosis
■ Diuretics ●● DKA (but total body K+ low)
■ Ureterosigmoidostomy ●● Digoxin toxicity
Potassium (cont.)
Hypokalaemia (cont.) Hyperkalaemia (cont.)

Increased losses continued Extracellular potassium shifts continued

●● Extrarenal ●● Rhabdomyolysis
■ Chronic diarrhoea ●● Trauma, vigorous exercise
■ Vomiting (loss of H+ → metabolic alkalosis ●● Malignant hyperthermia
and ↑ aldosterone) ●● Suxamethonium
■ GI fistulae Pseudohyperkalaemia
●● Intracellular shift of K+ ●● In vitro haemolysis, extended tourniquet time
■ Alkalosis when sampling blood
■ Insulin ●● Very elevated white cell count (WCC) or
■ β-adrenoceptor agonists (catechol- platelets (secrete K+)
amines, salbutamol)
■ Theophylline toxicity
 Physiology

Biochemistry 69
Causes of acid-base disturbances
Acidosis Alkalosis

Hypoventilation Central causes

●● Drugs – anaesthetics, sedatives or muscle
relaxants
●● CNS trauma, infarct, etc
●● Cervical spinal cord trauma or lesions
●● Poliomyelitis ⚫ Tetanus ⚫ Guillain-Barré syndrome
●● Myasthenia gravis
Defects of lung or chest wall
Respiratory
●● Head injury ⚫ Stroke ⚫ Anxiety
●● Drugs – analeptics and salicylates
Hypoxaemia
●● Respiratory stimulation via
peripheral chemoreceptors
●● Altitude

●● Trauma ⚫ Pneumothorax ⚫ Pulmonary oedema Pulmonary

●● Acute respiratory distress syndrome ⚫ Aspiration ●● Pulmonary embolism (PE)
●● Pneumonia ⚫ Asthma
Disorders of the airways ●● Pulmonary oedema
●● Obstruction ⚫ Bronchospasm ⚫ Laryngospasm
Intermittent positive pressure
Inadequate mechanical ventilation ventilation (IPPV)
Hypercatabolic disorders (e.g. malignant
hyperthermia)

High intake of CO2

●  Rebreathing ⚫ Insufflation of CO2 (laparoscopic
surgery)
Causes of acid-base disturbances (cont.)
Acidosis (cont.) Alkalosis (cont.)

Metabolic acidosis with a normal anion gap Loss of H+ from the ECF
●● GI tract causes ●● Diuretics
■ Diarrhoea (HCO−3 loss) ●● NG aspirates
■ Utero-enterostomy ●● Vomiting
■ Pancreatic/small bowel fistulae ●● Metabolic – Cushings, Conns,
●● Renal causes Secondary hyperaldosteronism
■ Renal tubular acidosis (↓K+ ions)
■ Carbonic anhydrase inhibitors
●● Other Gain of alkali in the ECF
●● Exogenous (sodium bicarbonate,
Metabolic

■ Ammonium chloride intoxication

■ Recovery from ketoacidosis citrate [blood transfusion])
●● Endogenous (metabolism of
Metabolic acidosis with an elevated anion gap ketoanions → HCO−3 )
●● Ketoacidosis
■ Diabetes Drugs
■ Alcoholic ●● Laxatives
■ Starvation ●● Corticosteroids
●● Lactic acidosis (Type A or B)
●● Renal causes
■ Acute renal failure
■ Uraemic acidosis
●● Toxins – ethylene glycol, methanol, salicylates
 Physiology

Biochemistry 70
Bicarbonate and phosphate
Bicarbonate
An anion important for acid-base balance because it is part of the main buffer system and its
reabsorption by the kidney may be varied to normalize blood pH
●● Normal plasma concentration 24–33 mmol/L
●● Carbonic anhydrase catalyzes CO2 + H2O ⇌ H+ + HCO−3
●● Also regulates pH in the small intestine, released under the influence of secretin from the pancreas
into the duodenum
■■ Therapeutic use as 8.4% solution (1 mmol NaHCO3 per mL) to:
● Reverse acidosis (Dose = Weight (kg) × Base deficit × 0.3) although primary cause should
be corrected
● Emergency management of hyperkalaemia
● Promote alkaline diuresis (e.g. increase salicylate excretion)
−
■■ Adverse effects of HCO3 administration
● Alkalosis
● Hypokalaemia
● Hypernatraemia
● Hypocalcaemia
● Hypercapnia (increase mechanical ventilation)
● Impaired oxygen unloading (left shift of oxygen dissociation curve) so caution in tissue
hypoxia
● May worsen lactic acidosis (removes acidotic inhibition of glycolysis)
Bicarbonate and phosphate (cont.)
Phosphate
●● Constituent of cell membrane phospholipids
●● Important for energy storage in adenosine triphosphate (ATP), enzyme regulation, oxygen
transport (2,3-diphosphoglycerate [2,3-DPG]) and buffering
●● Normal plasma phosphate concentration 0.8–1.45 mmol/L but only 0.1% is in ECF
●● 80% of phosphate in bone and 15% in soft tissues
●● Hyperphosphataemia → ↓ Ca2+ and ↓ Mg2

Hyperphosphataemia causes Hypophosphataemia causes

●● Impaired renal phosphate excretion ●● Shift from ECF to ICF:

■■ Renal failure ■■ Respiratory alkalosis
■■ Hypoparathyroidism ■■ Treatment of DKA
■■ Pseudohypoparathyroidism ■■ Refeeding syndrome
■■ Acromegaly ●● Alcohol abuse
■■ Heparin therapy ●● Malabsorption
●● Massive ECF phosphate load ●● Liver failure
■■ Iatrogenic administration ●● Malignancy (lymphoma, leukaemia,
■■ Cellular injury (crush injuries, tumour-induced osteomalacia)
rhabdomyolysis)
■■ Transcellular phosphate shifts in acidosis
 Physiology
Calcium
●● Normal plasma ionized calcium 2.12–2.65
mmol/L
●● Levels of ionized calcium decrease with
acidosis, increase with alkalosis and are
affected by the concentrations of protein
in plasma (for every g/L albumin <40 g/L,
add 0.02 mmol/L calcium; for every g/L
>40 g/L, subtract 0.02 mmol/L)
●● Only 1% of calcium in plasma, 99% in bone
Functions
●● Second messenger in many systems, for
example muscle contraction, neuromuscular
blockade and oxidative pathways
●● Coagulation factor (acts via calmodulin to
activate enzymes and promote conforma-
tional changes)
●● Positive inotrope
Calcium homeostasis
1. Vitamin D
■■ Action of ultraviolet light on skin forms cho-
lecalciferol from pre-vitamin D3
Biochemistry 71
■■ Converted in liver to 25-hydroxycholecal-
ciferol and in kidney to 1,25-dihydroxyc-
holecalciferol, which has the following
actions:
●● mobilizes bone Ca2+ and PO42+
●● ↑ intestinal absorption of Ca2+
●● ↑ renal reabsorption of Ca2+
2. Parathyroid hormone (PTH)
■■ Produced by parathyroid glands
■■ Production increased by ↓ Ca2+ and ↓ Mg2+
■■ Actions
●● ↑ osteoclast activity to mobilize bone
Ca2+
●● ↑ renal reabsorption of Ca2+
●● ↑ renal excretion of PO42+
●● ↑ formation of vitamin D
3. Calcitonin
■■ Produced by C-cells in the thyroid gland
■■ Inhibits osteoclasts in bone, ↑ bone depo-
sition of Ca2+ and PO42+
Calcium (cont.)
Hypercalcaemia
Causes ● Hyperparathyroidism  ● Malignancy  ● Hyperthyroidism
● Sarcoidosis  ● Hypoadrenalism  ● thiazides
Features (‘bones, ●  Muscle pains and weakness  ●  Psychiatric disturbances
moans and stones’) ●  Renal calculi, renal failure, dehydration, polyuria and polydipsia
●  Nausea, vomiting and constipation

Treatment ● Cause  ●  Rehydration and forced diuresis (occasionally dialysis)

●  Bisphosphonates (e.g. disodium pamidronate 15–60 mg over 2–4
days)  ● Corticosteroids  ● Calcitonin

Hypocalcaemia
Causes ●  Decreased parathyroid activity  ●  Decreased levels of vitamin D
●  Increased loss of calcium (e.g. chelating agents, pancreatitis, rhabdomyolysis)

Features ●  Muscle cramps/spasm/tetany (Chvostek’s and Trousseau’s sign)

● Stridor  ● Paraesthesiae  ●  Prolonged QT interval

Treatment ●  ABC and treat the cause  ●  Intravenous calcium gluconate

(10–20 mL) or calcium chloride (5–10 mL)
 Physiology

Biochemistry 72
Magnesium
●● Fourth most common cation, second most com- ■■ Musculoskeletal
mon intracellular cation ● Involved in terminating contraction – skeletal
●● Normal serum concentration 0.7–1mmol/L muscle relaxation and weakness
●● Total body Mg2+ ■■ Genitourinary
■■ ∼50% in bone, 49% in muscle, soft tissue and ● Tocolysis
small amount in erythrocytes; 1% in ECF ■■ Haematology
●● Role of Mg2+ ● Reduction in platelet activity
■■ Involved in Na+/K+/ATPase to maintain electro-
chemical gradients
■■ Regulation of calcium metabolism (acts as a
Clinical nugget
physiological antagonist) Causes of hypomagnesaemia
■■ DNA, RNA, ATP and protein synthesis ●● ↓ intake
●● Actions of magnesium ■■ Inappropriate IV fluids
■■ Cardiovascular system ■■ Dietary deficiency
● Myocardial depression – ↓ CO ●● ↑ loss
● Slows SA node conduction and AV node ■■ Diuretics
refractory period – anti-arrhythmic ■■ Nephrotoxic drugs (aminoglycosides)
● Vasodilation – hypotension, ↓ pulmonary ■■ Alcohol abuse
vascular resistance ■■ Diarrhoea, GI fistulae
● Inhibits catecholamine release ●● Redistribution
■■ Respiratory ■■ Citrated blood transfusion
● Bronchodilator ■■ Insulin administration
● Muscle weakness may cause respiratory ■■ Hyperparathyroidism
failure
■■ Central nervous system Causes of hypermagnesaemia
● Ca2+ antagonist at NMJ – ↓ acetylcholine ●● Iatrogenic fluid administration
release ●● Excessive intake antacids or purgatives
● Anticonvulsant ●● DKA
●● Tumour lysis syndrome
Magnesium (cont.)
Clinical features
Hypomagnesaemia Hypermagnesaemia
Early Early
●● Anorexia ●● Headache
●● Nausea ●● Vomiting and diarrhoea
●● Muscle weakness ●● Hypotonia
●● Cramps ●● Muscle weakness (4–5 mmol/L)
●● Lethargy Late
●● Weight loss ●● Respiratory depression (5–7.5 mmol/L)
Late ●● Respiratory arrest
●● Hyperexcitability – Convulsions ●● Hypotension
●● Muscle spasms ●● Bradycardia
●● Stridor ●● Widened QRS (prolonged AV conduction)
●● Tetany ●● Arrhythmias
●● HTN ●● Cardiac arrest (10–12.5 mmol/L)
●● Pulmonary oedema Treatment
●● Prolonged PR and QT, ST depression, flat T ●● IV calcium gluconate (2.5–5 mmol/L)
waves ●● Induced diuresis or dialysis
●● SVT, VT
●● Trousseau’s sign
●● Chvostek’s sign
●● Hypocalcaemia (↑ urinary losses)
●● Hypocalcaemia (↓ PTH secretion)
 Physiology

Biochemistry 73
Chloride (Cl ) −

●● Main ECF anion Chloride shift

●● Normal blood levels are 98–106 mmol ⋅ L−1 ●● Movement of Cl − into red blood cells (RBCs) as
●● Important to maintain oxygen is given up and exchanged for CO2 in tissues
■■ Acid–base state ●● CO2 enters cells, is converted to carbonic acid by
■■ Normal renal tubular function carbonic anhydrase before dissociating into H+ and
■■ Formation of gastric acid HCO3
−

●● Regulation is passive, inversely related to plasma
−
HCO3
●● In the renal proximal tubule Cl − is excreted with NH4+
to eliminate H+ ions in exchange for Na+
●● H+ buffered by the reduced haemoglobin, HCO3
−
moves into the plasma
●● Cl− enters the cells to maintain electrical equilibrium
●● Reverse happens in the lungs

Causes of Causes of Hyperchloraemic metabolic acidosis

hyperchloraemia hypochloraemia ●● Excessive administration of normal saline
■■ Due to the large sodium load, renal excretion of
●● Dehydration ●● Overhydration Na+ occurs in preference to Cl− and H+
●● Renal tubular acidosis ●● Chronic respiratory ■■ This causes metabolic acidosis (may be attrib-
●● Acute renal failure acidosis uted to tissue hypoxia leading to treatment with
●● Metabolic acidosis ●● Salt-losing
fluid resuscitation, worsening the situation)
associated with nephropathy
●● Severe diarrhoea
prolonged diarrhoea ●● Metabolic alkalosis
■■ Acute infective diarrhoea (small bowel origin
and NaHCO3 loss ●● Congestive cardiac
●● Diabetes insipidus failure (CCF) such as cholera) leads to a normal anion gap
●● Adrenocortical excess ●● Addisonian crisis (hyperchloraemic) metabolic acidosis due to
−
●● Salicylate intoxication ●● Prolonged vomiting loss of HCO3
●● Excess NaCl infusions ●● Bromide intoxication
●● SIADH
Enzymes
Macromolecular biological catalysts that accel-
erate chemical reactions whilst remaining them-
selves unchanged
●● Almost all metabolic processes need enzymes
to occur at rates fast enough to sustain life
●● Most are globular proteins, much larger than
their substrates. A few are catalytic RNA mol-
ecules (ribozymes)
●● May be highly specific for a given substrate –
specificity comes from their unique three-
dimensional structures
●● Sensitive to pH and temperature change
Classification (International Union of
Biochemistry and Molecular Biology)
●● Oxidoreductases – oxidation/reduction (e.g.
drug metabolism)
●● Transferases – transfer of a functional group
(e.g. transaminases)
●● Hydrolases – catalyse hydrolysis of bonds (e.g.
acetylcholinesterase)
●● Lyases – cleavage of C-C, C-N etc. without
oxidation or hydrolysis (e.g. decarboxylases)
●● Isomerases – isomerisation changes within a
single molecule (e.g. mutases)
●● Ligases – join two molecules with covalent
(high energy) bonds (e.g. ATP, formation of
C-C, C-N etc.)
Substrate binding
●● ‘Lock and key model’ (Fischer, 1894) – enzyme
and substrate possess complementary geo-
metric shapes; explains specificity
●● ‘Induced fit model’ (Koshland 1958) – the
active site is continually remodelled by inter-
actions with the substrate until the substrate is
completely bound. May enhance the fidelity
of molecular recognition in the presence of
competition
Catalysis
●● All enzymatic reactions lower the activation
energy of the reaction:
■■ By stabilising the transition state
■■ By providing an alternative reaction
pathway
■■ By destabilising the substrate ground state
(to reduce the energy required to reach
the transition state)
 Physiology

Body Fluids 74
Body fluid compartments
Total body water (TBW) ●● 45%–75% of body weight in an adult depending on the amount of
adipose tissue (contains less water)
●● About 60% in a man (42 L) and 50% in a woman
Intracellular fluid (ICF) ●● Total content of all cells of the body
●● Similar in most cells, so considered a single fluid compartment
●● About 40% of total body weight (28 L) in an adult male
Extracellular fluid (ECF) ●● Sum of plasma and interstitial fluid
●● About 20% of total body weight (14 L) in an adult male
Plasma (intravascular) ●● Volume of fluid excluding cells in the vascular compartment
volume ●● About 5% of total body weight (3.5 L) in an adult male
Interstitial fluid ●● Interstitial fluid = ECF – plasma volume
●● About 15% total body weight (10 L) in an adult male
Transcellular fluid ●● Composed of secreted fluid that is separated from the plasma by a
layer of epithelium (e.g. cerebrospinal fluid [CSF] and intraocular
fluid)
●● May or may not be considered part of extracellular fluid because it is
not readily exchangeable with other body fluids
Measurement of fluid compartment volumes
●● Most fluid compartment volumes in the body are measured using a tracer chemical by the dilution principle
Amount of tracer
■■ Compartment volume =
Concentration of tracer
●● Tracer must be non-toxic, must not undergo metabolism or excretion, must be rapidly and evenly distributed
through the compartment to be measured and easy to measure, and must not interfere with body fluid distribution

Total body water (TBW) ●● Estimated by the volume of distribution (VD) of isotopes of H2O (e.g. deuterium) oxide.
This is accurate and reproducible

Extracellular fluid (ECF) ●● Measured by

■ Ionic tracers (e.g. 82Br, 35SO4)
● Small molecules that distribute evenly
● ECF volume is overestimated as some enters cells
■ Crystalloids (inulin and mannitol)
● Large molecules but do not distribute evenly and so ECF volume is
under-estimated

Intracellular fluid ●● TBW – ECF

Plasma (intravascular) ●● Evan’s blue dye

volume ●● Radioactively labelled serum albumin
●● These tracers remain in the intravascular space and their VD is the plasma volume

Blood volume 100

●● Blood volume = plasma volume ×
100 − haematocrit
51
●● Alternatively, Cr labelled red cells are used by the dilution method, but the
distribution is uneven because haematocrit varies throughout the circulation

Interstitial fluid ●● ECF – Plasma volume

 Physiology

Body Fluids 75
Osmolality and osmolarity
Osmole ●● Amount of solute that exerts an osmotic pressure of one atmosphere when placed in 22.4 L
of solution at 0°C

Osmolarity ●● Number of osmoles per litre of solution

Osmolality ●● Number of osmoles per kilogram of solvent

●● Measured directly by the depression of freezing point
●● Normal plasma osmolality 280–300 mosmol/kg
●● Osmolality and osmolarity often used interchangeably, although plasma proteins and fats
give rise to a small difference (osmolality > osmolarity)
●● Osmolality (mosomol/kg) can be estimated by
■ Osmolality = 2[Na+ + K+] + [urea] + [glucose] (mmol/L)

Osmotic pressure ●● Pressure needed to prevent movement of solvent molecules by osmosis across a
semipermeable membrane
●● Calculated by the van’t Hoff equation:
p = RTC
where p = osmotic pressure (Pa), R = universal gas constant (8.32 J/K), T = absolute
temperature (K) and C = osmolality (mosmol/kg H2O)
●● Normal plasma osmotic pressure is approximately 7.3 atmospheres

Osmolar gap ●● Difference between measured and calculated plasma osmolality

●● Increased by osmotically active particles (e.g. alcohol, mannitol, glycine [TURP syndrome])

Tonicity ●● The relative osmolality between two fluid compartments (hypotonic, isotonic and hypertonic)

Osmoreceptors ●● Cells within the anterior hypothalamus which respond to changes in plasma osmolality and
hence control thirst and secretion of antidiuretic hormone (ADH)
●● Outside the blood–brain-barrier
Starling’s forces
●● Starling’s forces (Ernest Starling 1866−1927 – London
Physiologist) are factors determining the movement of i Pi
fluid across the capillary endothelium
Arterial Venous
●● Factors pushing fluid out of the capillary into the interstitial 30 mmHg Pc Capillary c 15 mmHg
fluid are Net Net
■■ Pc, or capillary hydrostatic pressure filtration absorption
■■ πi, or interstitial fluid colloid osmotic pressure
●● Factors pulling fluid into the capillary from the interstitium are
■■ Pi, or interstitial fluid hydrostatic pressure
■■ πc, or capillary colloid osmotic pressure
●● The net flow of fluid for a given surface area (Q) is given by: Q = κ[(Pc − Pi) − σ(πc − πi)] where κ =
­filtration coefficient (flow rate per unit pressure gradient across the endothelium), which is a mea-
sure of how ‘leaky’ the capillaries are to water (e.g. in histamine release), and σ = reflection coef-
ficient, which is a measure of the permeability of the capillaries to proteins
●● The following table shows typical values of Starling’s forces in systemic capillaries

Pressure Arteriolar end Venous end

Pc 30 15
πi 5 5
Pi 6 to –6 6 to –6
πc 25 25

●● The net driving pressure is outward at the arteriolar end and inward at the venous end because of
the decrease in the capillary hydrostatic pressure along the length of the capillary
●● Normally, fluid leaving the capillary exceeds that entering by 10% and is reabsorbed as lymph
●● In oedema due to hypoalbuminaemia, pc is decreased and more interstitial fluid accumulates
 Physiology

Body Fluids 76
Cerebrospinal fluid (CSF)
●● Clear, colourless fluid that bathes the brain and the spinal Circulation of CSF
cord
Lateral
●● Contained within ventricles and subarachnoid space ventricles
●● Total volume approximately 150 mL (about one-third is spinal)
Foramina
●● Secreted by choroid plexus (two-thirds) and directly by epen-
of Monro
dyma of the ventricle walls (one-third) at the rate of 0.3 mL/min
●● Formed by filtration of plasma Third
ventricle
●● Largely independent of intracranial pressure but removal
increases with increasing pressure Aqueduct
●● Reabsorption of the CSF via the arachnoid villi (90%) into the dural of Sylvius
venous sinuses and via cerebral venules (10%) Fourth
ventricle
Functions of the CSF Magendie foramen
●● Protects brain and spinal cord against impact to bony sur- Lushka foramen
rounds through a buoyancy effect. The brain weight is reduced
from 1400 g to an effective weight of 52 g (1⁄30 the actual weight) Spinal Cerebral
cord hemispheres
●● Buffers any increase in intracranial pressure by translocation of
CSF into the spinal subarachnoid space

Composition
An ultrafiltrate with the following differences relative to plasma
●● Higher pCO2 and thus lower pH of 7.33
●● Protein <0.3 g/L, hence low acid-base buffering capacity
■■ Higher level of Cl− and lower level of K+
■■ Glucose 2–5 mmol/L
Blood–brain barrier (BBB)
●● Physiological barrier between the CNS and
the bloodstream
●● Functions to regulate or prevent the transmis-
sion of ions, toxins, drugs, glucose and neu-
rotransmitters from the plasma to the brain
●● Consists of ultrafiltration barrier in choroid
plexus and tight junctions between the cap-
illary endothelial cells
●● Chemical barrier also exists in form of enzymes
(e.g. monoamine oxidase) in the endothelial
cells
●● Water, carbon dioxide, oxygen and lipid-
soluble molecules are freely diffusible across
the BBB, whereas larger molecules and
charged ions cross with difficulty
●● Sodium and glucose cross by active transport
Substance
Plasma
Cerebrospinal fluid
0.5% bupivacaine
0.5% bupivacaine with 4% glucose
●● All substances eventually cross the BBB, but the
rate of brain penetration may be important
clinically (e.g. atropine versus glycopyrrolate)
●● The BBB is deficient at some sites including the
hypothalamus and the chemoreceptor trig-
ger zone. The efficacy of the BBB is reduced in
neonates and in meningitis
Specific gravity (SG)
●● Density of a substance divided by that of
water (which has a specific gravity of 0.997)
●● Depends on the amount and type of solute
particles
●● The following table shows some relative spe-
cific gravities
Relative specific gravity
1.010
1.004−1.007
1.004
1.026
 Physiology

Body Fluids 77
Other body fluids
Pleural fluid
●● Serous fluid produced by the pleural mem- Clinical nugget
brane covering the two pleurae Pleural effusions are pathological collec-
●● Colourless, pH 7.62 and with a low protein tions of pleural fluid
content (<1.5 g ⋅ dL−1)
●● Mechanisms
●● Outer pleura (parietal)
■■ Lymphatic obstruction
■■ Attached to the chest wall but separated
■■ ↑ capillary permeability
from it by endothoracic fascia
■■ ↓ plasma colloid oncotic pressure
■■ Blood supply – intercostal arteries
■■ ↑ capillary venous pressure
●● Inner pleura (visceral)
■■ ↑ negative intrapleural pressure
■■ Covers the lungs and surrounding tissues
■■ Blood supply – bronchial circulation
●● Functions Exudative (high Transudative
■■ Allows the pleurae to glide over each protein) (low protein)
other in respiration Infections Congestive
■■ Surface tension allows close apposition of Pneumonia cardiac
the lung surfaces with the chest wall Malignancy failure (CCF)
●● 90% venous drainage, 10% via lymphatics Granulomatous disease Cirrhosis
(e.g. TB) Nephrotic
Collagen vascular syndrome
disease
Other body fluids (cont.)
Pericardial fluid
Clinical nugget
●● 15–50 mL of serous lubricating fluid produced
by visceral mesothelial cells Tamponade
●● Separates parietal pericardium from inner vis- Acute causes Chronic causes
ceral layer (continuous with the epicardium)
●● Buffers heart from external impact, reduces Trauma Pericarditis
resistance during heart motion, provides bar- Aortic dissection Malignancy
rier to infection Infection
●● Rapid increase in fluid volume (e.g. penetrat- Bleeding post-surgery
ing trauma) does not allow pericardial mem-
branes to stretch resulting in tamponade ●● Signs
■■ Beck’s triad (hypotension, muffled
heart sounds, ↑ JVP)
■■ Dyspnoea
■■ Pulsus paradoxus >10 mmHg
●● Treatment – pericardiocentesis
 Physiology

Body Fluids 78
Other body fluids (cont.)
Lymph
Lymph is interstitial fluid that enters the lymphatic system

Lymphatic capillaries
●● Present throughout the body except in CNS and bone
●● Blind-ending tubules with no basement membrane
●● One-way flap valves permit entry of interstitial fluid
●● Low-pressure system (1 mmHg at rest)
●● Forward flow aided by regular one-way valves and increased interstitial fluid pressure (arterial pul-
sation/muscular contraction/positive intrathoracic pressure)
●● Capillaries → venules → lymph veins → lymph nodes → thoracic duct (left) or lymphatic duct
(right) → subclavian veins

Functions of lymph
●● Returns protein and fluid to the circulation to maintain low interstitial fluid protein concentration
and maintain the oncotic gradient across the capillary membrane
●● Fat absorption and transport from the small intestine (here lymph is known as chyle due to large
numbers of chylomicrons)
●● Immunological role – large numbers of lymphocytes and antibodies
Other body fluids (cont.)
Intraocular fluid
●● Consists of aqueous and vitreous humour
●● Aqueous
■■ Plasma diasylate actively secreted by choroidal plexus (small amount in the anterior chamber)
at 0.08 mL/hr
■■ Passes through the pupil to the anterior chamber, drains into the venous circulation via the
canal of Schlemm
■■ Provides metabolic and respiratory substrate for the anterior chamber
■■ Reduced by acetazolamide, glycerol and meiosis
●● Vitreous
■■ Contains gelatin-like protein – gives eye its spherical shape
■■ Contains phagocytes to remove unwanted debris in the visual field and hyalocytes
■■ Helps to keep the retina in place
■■ Reduced by mannitol

Peritoneal fluid
●● Serous fluid secreted by peritoneal cells
●● Reduces resistance to peristaltic movement of intestine
●● Increased fluid (RHF, cirrhosis, malignancy) causes ascites
 Physiology

Haematology and Immunology 79

Blood groups
ABO system
●● Naturally occurring immunoglobulin (Ig) M antibodies to groups A and B are present in people
who lack these antigens and can cause haemolytic transfusion reactions in ABO incompatibility
●● Exposure to foreign antigens in infancy is thought to account for their production – they are not
present at birth
●● 80% of the population can secrete ABO antigens in saliva and sweat

Blood Antigens present Naturally occurring Can donate Can receive Proportion of
group on red blood cells antibodies blood to blood from population in UK (%)

O None Anti-A, Anti-B All (universal O 47

donor)
A A Anti-B A, AB A, O 42
B B Anti-A B, AB B, O 8
AB A, B None AB All groups 3
(universal
recipient)
Blood groups (cont.)
Rhesus (Rh) system Complications of blood transfusion
●● Second most important blood group system Immuno­ ●● Immediate ●● Febrile
●● Rh antibodies (IgG) are found only on the logical haemolytic non-haemolytic
surface of red blood cells; presence ‘+’ (84% reactions transfusion transfusion
of European population) and absence by ‘–’ reactions (ABO reactions
incompatibility) ●● Transfusion-
(16%) ●● Delayed haemolysis related lung
●● Rh system consists of two closely related loci (minor groups) at injury (TRALI)
(‘D’ and ‘CcEe’) on chromosome 1, so each 7–10 days ●● HDN
person has up to four Rh genes Infective ●● Donors are routinely excluded if risk of
●● Antibodies are formed when blood from a hepatitis, HIV, malaria, syphilis, brucellosis
●● Bacterial contamination by gram-­
donor who is Rh D-positive is infused into a
negative organisms, which can lead to
recipient who is Rh D-negative septic shock
●● If a mother who is Rh D-negative bears an ●● Creutzfeldt-Jakob disease (blood is now
infant who is Rh D-positive, antibodies can routinely leucodepleted)
cross the placenta causing haemolytic dis- Metabolic ●● Hyperkalaemia ●● Iron overload
ease of the newborn (HDN) in subsequent ●● Hypocalcaemia (chronic
●● Acidosis transfusion)
pregnancies
●● Citrate toxicity ●● Hypothermia
Cardiovas­ ●● Cardiac failure ●● Microag­
Minor groups cular (especially in gregates
elderly patients) ●● Air embolism
●● Includes Kell, Duffy, Lewis and Kidd ●● Impaired oxygen ●● Throm­
●● May be important following type-specific delivery to tissues bophlebitis
but not cross-matched or multiple transfu- (left shift of ODC)
●● Impaired
sions, leading to the production of atypical coagulation
antibodies
 Physiology

Haematology and Immunology 80

Immune responses
The major role of the immune system is host
defence
●● All WBC’s produced from haemopoetic stem cells in
the bone marrow
●● WBCs may be classified as myeloid (neutrophils,
monocytes, eosinophils and basophils) or lymphoid
(lymphocytes) by cell division lineage
●● Neutrophils target bacteria and fungi
●● Eosinophils target parasites and modulate hypersen-
sitvity responses
●● Monocytes migrate to tissues and differentiate into
resident macrophages (e.g. Kupffer cells)
●● Humoral immunity: B lymphocytes produce specific
antibodies against antigens to which they have been
previously exposed, B lymphocytes differentiate into
plasma cells. Some B lymphocytes become memory
cells
●● Cellular immunity
■■ T lymphocytes kill infected or foreign cells
and produce lymphokines, which amplify the
immune response
■■ Natural killer cells: attack and kill invading organ-
isms, malignant cells and antibody-coated viruses
Type of T cell Function

Non-specific immunity (innate) Cytotoxic ●● Kill cells via binding of the T cell
(CD8+) receptor (TCR) to MHC class I-bound
●● Not dependent on prior exposure to the foreign antigen in infected cell membranes
agent
●● Barrier functions: skin and mucosal epithelial barriers, Helper (CD4+) ●● T cell receptor recognizes specific
peptide antigen bound to MHC
low gastric pH, lysozyme in lacrimal secretions
class II proteins on antigen-
●● Local inflammatory responses: macrophages,
­presenting cells
natural killer cells
●● Involved in regulation of immune
●● Complement system response
●● Secreted immunoglobulins
Suppressor ●● Provide negative feedback control
Memory ●● Proliferate on repeat antigen
Specific immunity (acquired) exposure to produce large numbers
●● Powerful and specific but delayed in onset of cytotoxic T cells
Hypersensitivity
●● Hypersensitivity occurs when an otherwise beneficial immune response is inappropriate or
exaggerated resulting in tissue damage
●● Originally a four-group classification but now five (Gell and Coombes, 1968)

Type Descriptive name Mechanism Examples

I IgE-mediated ●● Antigen induces cross-linking of IgE ●● Anaphylaxis
hypersensitivity bound to mast cells with release of ●● Hay fever, asthma, eczema
vasoactive mediators
II Antibody- ●● Antibody (IgG and/or IgM) directed ●● Blood transfusion reactions
mediated against cell-surface antigens mediates ●● Haemolytic disease of the
cytotoxic cell destruction via antibody-dependent newborn
hypersensitivity cellular cytotoxicity or complement ●● Autoimmune haemolytic
anaemia
III Immune-complex ●● Antigen–antibody complexes (IgG and ●● Arthus reaction (localized)
mediated complement) deposited at various sites ●● Disseminated rash
hypersensitivity induce mast cell degranulation ●● Rheumatoid arthritis, SLE
●● Neutrophil degranulation damages tissue (systemic lupus erythematosus)
●● Glomerulonephritis
IV Cell-mediated ●● Memory Th1 cells release cytokines that ●● Contact dermatitis
hypersensitivity recruit and activate macrophages ●● Tubercular lesions
V Autoimmune ●● Antibodies (IgG, IgM) recognize and ●● Graves’ disease
hypersensitivity bind to the cell surface receptors, thus ●● Myasthenia gravis
impairing cell signalling
 Physiology
Haematology and Immunology
Inflammation
Inflammation is the first response of the
immune system to irritation and is charac-
terized by the following quintet (Celsus, then
Virchow)
●● Redness (rubor)
●● Heat (calor)
●● Swelling (tumor)
●● Pain (dolor)
●● Dysfunction of the organs involved (func-tio
laesa)
Inflammation has three main
components
●● Hyperaemia – increased blood supply to the
site from arteriolar dilatation
●● Exudation – increased capillary perme-
ability from endothelial cell retraction causes
oedema and pain
●● Emigration of leucocytes – phagocytes ini-
tially migrate between endothelial cells fol-
lowed by lymphocytes along chemotactic
gradients
81
Mediators of inflammation
●● The kinin system mediates the immediate
vasoactive response, which causes vasodi-
lation, increased capillary per-meability and
pain
●● Histamine and leukotrienes
■■ Released by mast cells and basophils
■■ Increase vascular permeability
■■ Stimulate granulocyte migration to sites of
injury
●● Neutrophils
■■ Stimulation by inflammatory mediators
causes neutrophils to express adhesion
molecules
■■ Attracted by chemotactic agents, neu-
trophils migrate along the subendothelial
matrix
■■ At the site of injury, neutrophils release
platelet activating factor (PAF), which
stimulates the release of mediators from
platelets and activates other neutrophils
Inflammation (cont.)
Mediators of inflammation (cont.)
●● Tumour necrosis factor Lectin pathway/
Classical pathway
■■ Released by macrophages and lympho- alternative pathway
cytes Antigen–antibody Pathogen
■■ Activates endothelial cells which become complex surface
adhesive and more permeable
■■ Leads to production of nitric oxide and
subsequent vasodilation C3
■■ Important mediator in septic shock
●● Complement
■■ A series of plasma proteins synthesized in Opsonisation Membrane attack
of pathogens Phagocyte complex
the liver C3b recruitment C5b C9
■■ When activated and combined with anti- C4a
C3a
body, forms a cascade resulting in lysis of C5a
bacteria
■■ Three pathways: classic, alternative and lytic Removal of
antigen–antibody
■■ IgM and IgG bind complement and are complexes Chemoattraction
involved in hypersensitivity reactions

Direct cell lysis

Systemic inflammatory response
syndrome (SIRS) and sepsis
●● SIRS is defined as two or more of
■■ Hypothermia (<36°C) or hyperthermia
(>38°C)
■■ Heart rate >90 beats per minute
■■ Tachypnoea (>20 breaths per minute)
Phagocytosis
■■ White cell count <4000/mm3 or >12,000 mm3
●● Sepsis is SIRS that results from infection
■■ Vasodilation and organ dysfunction may
lead to septic shock and death
 Physiology
Haematology and Immunology
Haemostasis
Termination of blood loss after damage to a
vessel, which leads to formation of an organ-
ised clot
Development of platelet plug
●● Platelets are formed from bone marrow
megakaryocytes
●● Platelet cell membranes contain glycopro-
teins (GPIa, GPIb and GPIIb/IIIa, which are
adhesion molecules)
●● Cytoplasm contains
■■ α-granules (which contain fibrinogen,
von Willebrand factor [vWF], PF4 [a
heparin antagonist] and platelet growth
factor)
■■ dense granules (which contain ADP and
serotonin [5-HT])
●● Damage to vessels exposes tissue collagen
(binds GPIa) and tissue myofibrils (bind GPIb)
●● Bound GPIa and GPIb expose GPIIb/IIIa,
which binds vWF and fibrinogen to activate
the platelet
82
●● Activated platelets become rounded and
spiky, which increases aggregation, and
release 5-HT, which causes vasoconstriction
●● Membrane phospholipid releases arachi-
donic acid, which is converted to thromboxane
A2 within the platelet; this causes vasoconstric-
tion and, together with released ADP, increases
platelet activation and aggregation
●● Normal endothelium produces prostacyclin
(PGI2), which strongly inhibits platelet aggre-
gation and prevents spread of the plug
Blood clot formation
●● Thrombin causes the formation of a blood
clot of insoluble fibrin polymers from soluble
plasma fibrinogen (also under the influence
of activated factor VIII)
Fibrinolysis
●● Plasminogen is converted to active plasmin
by tissue-type plasminogen activator (t-PA),
which is released from endothelium
Peripheral circulation
Closed system of arteries and arterioles (muscu-
lar and elastic), capillaries (site of exchange),
venules and veins (capacitance vessels)
Functions
●● Exchange O2 and CO2
●● Deliver nutrients and remove metabolic
waste products
●● Carry hormones to target sites
●● Influence blood pressure and blood flow
distribution
●● Immune function
●● Thermoregulation
●● Prevent bleeding or thrombosis
Arteries and veins have three layers:
●● Tunica intima – single layer of squamous
endothelial cells and connective tissue
●● Tunica media – elastic fibres and smooth
muscle which control the diameter
●● Tunica adventitia – connective tissue, nerve
supply and vasa vasorum (larger vessels)
Endothelial functions
●● Regulate vasomotor tone and hence blood
pressure by controlled release of vasodilators
(nitric oxide, prostacyclin) and vasoconstric-
tors (endothelins, platelet activating factor)
●● Non-thrombogenic surface (expresses pro-
teins C, S and heparin sulphate
●● Encourages laminar flow (smooth)
●● Regulate growth of surrounding connective
tissue
Capillaries
●● Contain 5% of circulating blood volume
●● 5–10 µm diameter
●● Semi-permeable membrane to transport
substances by diffusion
●● Three types dependent on endothelial cell
arrangement
■■ Continuous (e.g. brain) – diffusion only of
ions and water through tight junctions
■■ Fenestrated – pores allow small mole-
cules to diffuse
■■ Sinusoidal – e.g. liver – larger proteins,
white blood cells and red blood cells may
cross
●● Permeability increases in disease (e.g. sepsis)
Vessel diameter is determined by vascular tone:
●● Autonomic control (sympathetic via α and β
receptors)
●● Metabolic – ↓ O2, ↑ K+, ↑ H+, ↑ lactic acid, ade-
nosine, prostaglandin and histamine
●● Myogenic – passive stretch of arteriolar smooth
muscle → vasoconstriction (negative feed-
back) or vasodilation (positive feedback)
 Physiology

Haematology and Immunology 83

Clotting cascade
●● The sequential activation of proenzyme clotting factors
●● The two pathways are the contact activation pathway (formerly intrinsic pathway) which interacts
with the tissue factor pathway (formerly extrinsic pathway)
●● The primary pathway is the tissue factor pathway that functions to form a ‘thrombin burst’
●● Thrombin primarily converts fibrinogen to fibrin but also causes positive feedback throughout the
cascade and activates clotting factors and inhibitors
●● The contact activation pathway is activated by collagen when tissue is cut but has a relatively
minor role in initial clot formation
●● Cofactors are required for correct functioning of the cascade including calcium and vitamin K
●● Protein C (cofactor inhibitor), antithrombin (serum protease inhibitor) and tissue factor pathway inhib-
itor all regulate the coagulation cascade. Abnormalities lead to an increased thrombotic tendency

Measures of haemostasis
Activated partial
­thromboplastin time (APTT)
Prothrombin time
Thrombin time
Antithrombin III
Thrombodulin
Vitamin K
●● Measures the intrinsic pathway
●● Used to monitor heparin therapy
●● Measure of the extrinsic pathway
●● International normalized ratio (INR) used to monitor treatment
with warfarin
●● Measures fibrinogen deficiency or thrombin inhibition
●● Anticoagulant that inhibits factors IX, X, XI and XII and thrombin
●● Heparin facilitates antithrombin III
●● Forms a complex with thrombin that activates protein C which, with
the cofactor protein S, inactivates factors V and VIII
●● Necessary for the formation of several clotting factors
Coagulation – cell-based model
●● Cascade model fails to reflect observed hae-
mostatic effects in vivo
●● Cell-based model highlights importance of
(tissue factor VIIa) TF-VIIa complex at the
centre of the theory
●● Highlights the importance of thrombin in pro-
moting and inhibiting coagulation
●● Five stages
■■ Initiation
● TF binds to VIIa and in the presence of
factor V, converts IX to IXa and X to Xa.
Xa binds to prothrombin to generate a
small amount of thrombin
■■ Amplification
● The small amount of thrombin gener-
ated is insufficient to convert fibrinogen
to fibrin. Thrombin mediated feedback
on the activated platelet surface
amplify the system
■■ Propagation
● TF-VIIa complex ensures a supply of
IXa. IXa with VIIIa activates X to ensure
adequate supply of Xa and maintains
thrombin burst
■■ Stabilisation
● High thrombin levels stimulate XIII to
cross-link soluble monomers and pro-
tection of the clot by thrombin-activat-
able fibrinolysis inhibitor
■■ Inhibition
● Thrombosis controlled by thrombin-
activated protein C (aPC), which
cleaves Va and Xa. TFPI inhibits TF-VIIa
and Xa by binding them and AT inhibits
thrombin, IXa and Xa
●● Conventional laboratory tests are unlikely
to adequately reflect the complexity of the
coagulation system. Other testing modalities
include:
■■ Activated clotting time (normal 120–
140s), >480 considered safe for cardiopul-
monary bypass (CPB)
■■ Platelet functioning analysers – can also
distinguish the effects of aspirin from other
abnormalities of platelet function
■■ Thromboelastography (TEG/ROTEM) –
quantifies clot formation kinetics from ini-
tial fibrin formation through to clot lysis
 Physiology
Haematology and Immunology
Haemoglobin
●● Haemoglobin is a complex polypeptide
found in red blood cells, which contains four
haem rings and an iron atom
●● Its functions are oxygen transport and car-
bon dioxide transport (as carbamino com-
pounds) and to act as a buffer
Structure
●● Normal adult haemoglobin has 2α and 2β
chains
●● Fetal haemoglobin (HbF) has γ instead of
β chains and a higher affinity for oxygen,
which improves oxygen transport to the fetus
●● Deoxyhaemoglobin exists in the tense state
(salt bridges between the globin chains)
●● Each haem moiety can bind one molecule of
oxygen and displays ‘co-operative binding’
■■ Binding of oxygen results in a conforma-
tional change, which converts the hae-
moglobin to the relaxed state
■■ This increases the affinity of the remain-
ing haem moieties for oxygen and results
in the sigmoid shape of the oxygen dis-
sociation curve
84
Sickle cell disease
●● Sickle haemoglobin (HbS) has an amino acid
substitution on the β chain
●● Decreased PO2, decreased pH, infection
or dehydration causes crystallization and
polymerization of HbS into ‘tactoids’, which
causes painful crises in homozygotes
●● In sickle cell trait (heterozygotes), sickling
does not usually occur, as the red blood cells
have <45% HbS
Thalassaemia
●● Gene deletions occur and cause reduced
production of α or β chains
●● Three α gene deletions (HbH disease) cause
chronic anaemia
●● Four α gene deletions (Hb Bart’s) usually
result in intrauterine death
●● β thalassaemia major (homozygotes) results
in severe anaemias
●● β thalassaemia trait (heterozygotes) causes
mild or no anaemia
Red blood cells
●● Red blood cells (RBCs) constitute 45% of total blood volume; this is the haematocrit or packed
cell volume
●● The structure of the RBC is a biconcave disc
■■ This enables it to have a large surface area:volume ratio and flexibility to navigate capillaries
■■ The average diameter is 7.2 µm and thickness 2 µm at the edges
●● RBCs have no organelles, so they obtain energy anaerobically
●● Lifespan of 120 days
●● The rate of erythropoiesis is controlled by the renal hormone erythropoietin
■■ Erythropoietin secretion is stimulated by decreased oxygen delivery to the kidney
■■ This may be due to decreased oxygenation of the blood, anaemia or abnormal haemoglobin
●● RBCs contain haemoglobin and the enzyme carbonic anhydrase
−
■■ Carbonic anhydrase catalyzes the formation of H+ and HCO3 from carbon dioxide produced
in the tissues
■■ The bicarbonate formed diffuses into the plasma in exchange for chloride (chloride shift)
■■ In the lungs, the opposite occurs to release carbon dioxide
●● Removal of RBCs is by macrophages of the reticuloendothelial system, mainly in the bone mar-
row but also in the liver and spleen
■■ Haemoglobin is broken down into haem and globin
■■ Haem is then broken down into iron, which is reused, and biliverdin, which is catabolized to
bilirubin and excreted in the bile
■■ Globin is metabolized to amino acids and recycled
 Physiology

Nervous System 85
Resting membrane potential (RMP)
●● The RMP is the potential difference across the cell membrane when no stimulation is occur-
ring and is due to the differential distribution of charged ions inside and outside the cell
●● The RMP is approximately −85 mV in muscles and −70 mV in nerves and can be calculated for a
given ion at equilibrium (where the net ion movement is zero) with the Nernst equation:

RT [C o ]
E= loge
zF [Ci ]

where E = equilibrium potential of the ion, R = universal gas constant, T = absolute temperature, Z =
valency of the ion, F = Faraday’s constant and Co/Ci = extracellular/intracellular ion concentration
●● The RMP is affected by
■■ permeability of the membrane to ions (100 times more permeable to K+ than Na+)
■■ active transport mechanisms (e.g. Na+/K+ pump)
■■ other particles (Gibbs-Donnan effect)
■■ proteins remain intracellularly and have a negative charge
●● The Goldman constant-field equation takes into account other ions and their differing perme-
abilities to give an overall membrane potential
Neurones and nerve fibres
●● Neurones are the basic unit of the nervous system comprising a cell body (containing the nucleus)
with two extensions:
■■ Dendrite – transmits incoming information to the cell body
■■ Axon – transmits information from the cell body
●● Speed of conduction increases with diameter of the nerve fibre
●● The axon divides into terminal branches ending in a demyelinated terminal button containing
neurotransmitters which transmit the impulse across the synapse to other neurones
●● Myelin insulation (produced by Schwann cells) increases transmission speeds by up to 50 times
through saltatory conduction where depolarization ‘jumps’ from one non-myelinated area (node
of Ranvier) to the next

Characteristics of nerve fibres

Fibre Type Function Diameter (mm) Velocity (m/s)

Aa Somatic motor 12–20 70–120

Ab Touch, proprioception 5–12 30–70
Ag Muscle spindle afferents 3–6 15–30
Ad Sharp pain, temperature 2–5 12–30
B Preganglionic autonomic <3 3–15
C Dull pain (non-myelinated) 0.4–1.2 0.5–2
 Physiology

Nervous System 86
Action potentials
The sequential, electrochemical polarization and depolarisation across the membrane of an
excitable cell resulting in the propagation of electrical impulses

Mammalian nerve fibre action potential

S low depolarization of the membrane

A 
35 above the RMP caused by a slow
ingress of Na+ ions into the cell
B
potential (mV)

C  s threshold potential is reached, Na+

B A
Membrane

0 channels open and there is rapid

depolarisation of the cell membrane
to approximately +35 mV
Threshold C Sodium permeability then falls and
Threshold potential there is rapid repolarization due to
55 the efflux of K+ ions.
ARP
E
RRP
70 D Hyperpolarization
Resting membrane
A potential (RMP) E N
 ormal ion distribution is restored
D due to the action of the Na+/K+ ATPase
pump
0 4
Time (ms)
Action potentials (cont.)
●● After the action potential is the two-phase refractory period, in which the neurone is insensitive
to further stimulation
■■ In the absolute refractory period (ARP); no stimulus may excite the neurone
■■ In the relative refractory period (RRP); a stimulus stronger than normal may excite the neu-
rone; corresponds to increased Na+ conductance during repolarisation
●● The all or none law states that the action potential fails to occur with a subthreshold stimulus and
occurs with constant amplitude despite the magnitude of the threshold stimulus

How is an action potential propagated?

●● As the action potential reaches threshold, voltage-gated sodium channels open
●● Na+ enters the neurone and a ‘slow wave’ of local current spreads through the cytoplasm
●● Charge is displaced along the outer surface of the membrane and, if this depolarisation is suf-
ficient, a ‘new’ action potential will be generated further down the membrane
●● Previously stimulated areas will be refractory to further stimulation, which results in unidirectional
transmission of the action potential
 Physiology

Nervous System 87
Organisation of the nervous system
Nervous system

Central nervous system

Peripheral nervous system

Spinal cord Brain

Somatic nervous Autonomic nervous
Conducts signals to system system
and from brain,
controls reflex Sensory Motor
activities afferents efferents SNS PNS
‘Fight or flight’ ‘Rest or digest’

Forebrain Midbrain Hindbrain

Telencephalon Diencephalon
Mesencephalon Metencephalon Myelencephalon
Cerebral cortex
Memory, perception,
thought, language, GCS Thalamus Tectum Pons Medulla

Basal ganglia Regulation of Auditory/visual Relay centre Cardiac,

consciousness + reflexes sleep, respiration, respiratory,
Control of voluntary
motor movements Sleep Swallowing vomiting +
bladder control Vasomotor
Hippocampus centres.
Hypothalamus Tegmentum Cerebellum
Memory (short, long-term CN IX, X, + XII
and spatial) Metabolic homeostasis, Controls movement Motor control + nuclei
hunger, attachment CN V, VI, VII, VIII nuclei Co-ordination
Amygdala
behaviours, circadian
Memory, decision-making, rhythms
emotion
Motor pathways
Pyramidal pathways
●● Upper motor neurons that descend directly
from the cerebral cortex to the spinal cord
●● Fibres arise from the motor cortex of the pre-
central gyrus (legs represented uppermost,
head in lower part) and premotor area
●● Regions of greater importance have dispro-
portionately larger representation (e.g. hands)
●● Pass via the internal capsule and cerebral
peduncle to pons and medulla (forming the
pyramids)
●● 80% fibres decussate in the lower medulla,
and pass within the lateral corticospinal
tracts (white matter) of the spinal cord
●● 10% do not cross and join the tract
●● 10% travel in the anterior corticospinal tract
●● Some pass to cranial nerve nuclei (corticobul-
bar tract)
●● Most synapse with intermediate neurones
●● Function
■■ Lateral corticospinal tracts: controls fine
movement
■■ Anterior corticospinal tracts: controls
movements of axial (trunk) muscles
Extrapyramidal pathways
●● Consists of motor-modulation systems caus-
ing involuntary movements
●● Fibres arise from the premotor area and cor-
pus striatum
●● Pass via the basal ganglia, substantia nigra
and nuclear masses of the mid and hind brain
●● This system includes:
■■ Rubrospinal
■■ Vestibulospinal
■■ Reticulospinal
■■ Tectospinal tracts
●● Other pathways pass from the tectum of the
midbrain and olives of the medulla
●● Regulate:
■■ Axial muscles maintaining balance and
posture
■■ Muscles controlling coarse movements
of the proximal portions of limbs
■■ Head, neck and eye movements
Cerebellar pathways
●● Involve the thalamus, red nucleus, pons,
medulla and cerebral cortex
 Physiology
Special senses
●● Sight
■■ The cornea and iris refract light → retinal
photoreceptors (rods and cones) which
create electrical impulses transmitted via
the optic nerve
■■ Medial fibres of the optic nerve decussate
at the optic chiasm
■■ Optic nerve → lateral geniculate nucleus
→ visual cortex for processing
■■ The inferior temporal gyrus recognises
complex shapes and faces, and with the
hippocampus creates new memories
●● Taste
■■ Substances in the mouth react chemically
with chemoreceptor taste cells, mostly on
the tongue
■■ Five types – salt, sweet, bitter, sour and
umami (savoury)
■■ Food flavour is determined by taste, olfac-
tion and trigeminal nerve stimulation
(texture, pain and temperature)
■■ Facial nerve (CN VII) carries taste from
the anterior two-thirds of the tongue,
glossopharyngeal nerve (IX) from the
Nervous System 88
posterior one-third and taste from the
back of the oral cavity via the vagus
■■ Multiple nuclei project → gustatory cortex
●● Smell
■■ Receptors are the olfactory neurones
in the olfactory epithelium → olfactory
nerve (CN I – unmyelinated) → through
the cribriform plate → olfactory bulb
●● Hearing
■■ The pinna focuses sound waves to the
eardrum which vibrates
■■ Vibrations are transmitted via the ossicles
(which overcome impedance mismatch-
ing between air and water) → cochlear
■■ The cochlear is a fluid filled spiral tube,
the main organ of mechanical to ­n eural
transduction. Motion causes depo-
larisation of the hair cells in the organ
of Corti, which divides the cochlear
longitudinally
■■ Action potentials transmitted via the audi-
tory nerve → cochlear nucleus (brain-
stem) → midbrain tectum → thalamus →
primary auditory cortex (temporal lobe)
Somatic sensation
●● Divided into:
■■ Exteroceptive – touch, pressure, temper-
ature and pain
■■ Proprioceptive – body position and
movement
●● Enter the spinal cord through the dorsal root.
Cell bodies lie in the dorsal root ganglia
●● Proprioception, vibration and touch (fine touch,
vibration, two-point discrimination) sensation
■■ Mechanoreceptors in the skin are
stimulated
■■ First-order neurones ascend ipsilaterally
in the posterior columns
■■ Synapse with cells in the cuneate or grac-
ile nuclei in the lower medulla
■■ Second-order neurones – cross the con-
tralateral side of the medulla, ascend in
medial leminiscus → ventral posterolateral
thalamic nucleus
■■ Third-order neurones → sensory cortex
(postcentral gyrus)
■■ This pathway is tested with Romberg’s
test (standing patient is asked to close
their eyes, a loss of balance is a positive
Romberg’s test)
●● Pain, temperature and half of touch
■■ First-order neurones – synapse in lami-
nae VI and VII of the dorsal horn
■■ Second-order neurones – cross at every
segmental level to the spinothalamic
tracts which form the spinal lemniscus in
the medulla → thalamus
■■ Lateral spinothalamic tract – pain and temp
■■ Anterior spinothalamic tract – crude
touch, firm pressure
■■ Third-order neurones → postcentral gyrus
●● Sensory pathway lesions
■■ Sensory cortex – paraesthesia with or
without disturbed appreciation of sensa-
tion (e.g. confusing heat and pain)
■■ Brainstem/thalamic – complete loss of
hemisensation
■■ Pure thalamic – central pain (diffuse,
continuous burning pain)
■■ Spinothalamic – contralateral loss of
pain and temperature
■■ Posterior column – ipsilateral loss of posi-
tion and vibration sensation
■■ Posterior root – pain and paraesthesia in
the dermatomal distribution
■■ Peripheral nerve lesion – loss of sensa-
tion in that distribution
 Physiology

Intracranial pressure (ICP) and cerebral blood flow (CBF)
●● ICP is the pressure in the lateral ventricles
of the brain relative to atmospheric pressure
●● It is normally 10–15 cmH2O (7–11 mmHg)
when supine
●● Intracranial contents: 50–75  mL blood,
75–150 mL CSF and 1.4 kg brain tissue
●● The Monro–Kellie doctrine states that as
the skull is rigid with a constant volume, any
increase in the volume of one of the con-
tents must be compensated for by a reduc-
tion in volume of another if raised ICP is to be
avoided
Nervous System 89
●● Gradual increases in intracranial tissue vol-
ume caused by a SOL will be compensated
for by increased outflow into the spinal cord
and absorption of CSF and ↓ cerebral blood
volume
●● Rapid increase of intracranial volume because
of acute haematoma cannot be rapidly
compensated
Intracranial volume – pressure
relationship
60

Intracranial pressure (mmHg)

Increased ●● ↑ CBF Global
blood volume ●● ↓ venous drainage (head down, 50 ischaemia
kinked jugular veins, ↑ CVP or
40
↑ intrathoracic pressure
Focal
(coughing/straining) 30 ischaemia
Increased ●● Space-occupying lesion (SOL)
20
brain volume ●● Cerebral oedema
Compensation
Increased ●● Congenital (Dandy-Walker 10
volume of CSF syndrome, Arnold-Chiari syndrome)
0
(i.e. ●● Acquired (meningitis, surgery,
hydrocephalus) head injury, tumour) Intracranial volume
Intracranial pressure (ICP) and cerebral blood flow (CBF) (cont.)
Intracranial volume–pressure
Autoregulatory
relationship range
●● CBF is the amount of blood flow per unit time and is 100
normally 14% of cardiac output (50 mL/100 g/min) Normal Chronic

(mL · 100g–1 · min–1)

hypertension

Cerebral blood flow

●● Cerebral oxygen consumption (cerebral meta- 75
bolic rate for oxygen, CMRO2) is 3.5 mL/100 g/min
●● Cerebral perfusion pressure (CPP) is the pressure
50
that perfuses the brain:
CPP  = MAP - (ICP + CVP)
●● Autoregulation of CBF occurs between mean arterial 25
pressures of 50 and 150 mmHg, but these limits are
higher in patients with hypertension 0
●● Autoregulation is impaired by hypoxia, hypercap- 0 50 100 150 200
nia, trauma and volatile anaesthetics Mean arterial pressure (mmHg)

Factors affecting CBF Effects of PaCO2 on cerebral blood flow

Increase CBF Decrease CBF
100
●● ↑ CPP (outside the limits of ●● ↓ CMRO2 Normal
autoregulation) ●● All intravenous

Cerebral blood flow

(mL · 100g–1 · min–1)
●● ↑ PaCO2 (through induction agents
vasodilatation) except ketamine (by Chronic
●● ↓ PaO2 (but the effect is reducing CMRO2) hypercapnia
minimal unless PaO2 falls ●● Hypothermia 50
below 50 mmHg [6.7 kPa]) ●● ↑ plasma viscosity
●● ↓ pH (vasodilatation) (haematocrit >50%)
●● ↑ levels of adenosine and ●● ↑ venous pressure
potassium cause local ●● Cerebral steal
vasodilatation where injury causes
●● Volatile anaesthetics loss of local 0
0 5 10 15
●● Ketamine autoregulation
PaCO2 (kPa)
 Physiology

Nervous System 90
The vasomotor centre
The vasomotor centre is a group of neurones in the ventrolateral medulla involved in the control
of arterial blood pressure
●● Normal continuous discharge maintains vasomotor tone and resting heart rate

Carotid sinus baroreceptors

Aortic arch
baroreceptors
(via IX)
Lung stretch
(via X) Cardioinhibitory centre Pain, emotion
receptors
Nucleus ambiguus, dorsal (N.B. prolonged pain/emotion →
motor nucleus and nucleus ↓ vasomotor discharge)
tractus solitarius

↓ PO2 (initial direct

stimulation, then
Chemoreceptor depression)
Vasomotor centre
discharge

Sympathetic preganglionic
neurones (spinal cord)

Adrenal
↑ Inotropy Blood vessels medulla

↑ Chronotropy Vaso/venoconstriction Catecholamines

Autonomic nervous system
●● The autonomic nervous system (ANS) regulates non-voluntary bodily functions by means of
reflex pathways
●● The ANS comprises two nerves between the CNS and the relevant organ, and the nerve cell bodies
for the second nerve are organized into ganglia:

CNS → preganglionic nerve (myelinated) → ganglion → postganglionic nerve

(non–myelinated) → organ

●● The ANS is divided anatomically and functionally into parasympathetic (PNS) and sympathetic
(SNS) nervous systems
●● Most organs are under dual control, although one system usually predominates
●● Sensory input may affect autonomic activity
 Physiology
Sympathetic nervous system (SNS)
●● The SNS is a division of the ANS that func-
tions as a mass unit to cause increased
arousal and cardiovascular activity while
reducing visceral activity for the ‘fight-or-
flight’ response
●● Thoracolumbar outflow (T1–L2) of fibres
passes via white rami communicantes (WRCs)
to the ganglia
●● The preganglionic fibres can do one of four
things on reaching the ganglia
■■ synapse at that level in the sympathetic
chain
■■ move to another level to synapse
■■ pass through the sympathetic chain to syn-
apse in special ganglia (coeliac, superior
mesenteric and inferior mesenteric)
■■ pass through (but not synapse in) the coe-
liac ganglion until they reach the adrenal
medulla (which is seen as a primitive sym-
pathetic ganglion and secretes catechol-
amines into the bloodstream)
●● Ganglia form the sympathetic trunk – a
nerve chain that extends from base of skull
Nervous System 91
to coccyx and lies 2–3 cm lateral to the
vertebrae
■■ Cervical ganglia – superior, middle and
inferior
■■ Thoracic ganglia – usually 12 to splanch-
nic and intercostal nerves
■■ Lumbar ganglia – usually 4
■■ Sacral ganglia – usually 4
●● Short preganglionic and long postgangli-
onic fibres
●● Preganglionic synapses – nicotinic recep-
tors with acetylcholine as neurotransmitter
●● Postganglionic synapse – adrenoceptors
with noradrenaline/adrenaline as neu-
rotransmitter (except in sweat glands, pilo-
erector muscles and a few blood vessels,
which are nicotinic receptors with acetylcho-
line as neurotransmitter)
●● Sympathetic innervation of viscera is via car-
diac, coeliac and hypogastric plexi
●● Juxtaglomerular apparatus, piloerector
muscles and adipose tissue are organs
under sole sympathetic control
Parasympathetic nervous system (PNS)
●● The PNS is the division of the ANS that
opposes the SNS to cause decreased arousal
and cardiovascular activity and increased GI
tract activity
●● Craniosacral outflow
■■ CN III to the eye via the ciliary ganglion
■■ CN VII to the submandibular, lacrimal
and sublingual glands (pterygopalatine
and submandibular ganglia)
■■ CN IX to the lungs, larynx and tracheo-
bronchial tree via the otic ganglion
■■ CN X to heart, parotid gland and proximal
gut
■■ Sacral nerves S2–S4 to the distal gut, blad-
der and genitalia
●● 75% of all fibres of the PNS are carried by the
vagus nerve, which innervates the heart,
lungs, larynx, tracheobronchial tree and
proximal gastrointestinal tract to the splenic
flexure, liver, pancreas and other viscera
●● Long preganglionic and short postgangli-
onic fibres
●● Preganglionic synapses – nicotinic (ACh)
●● Postganglionic synapse – muscarinic recep-
tors (ACh); a few may release vasoactive
intestinal peptide (VIP)
●● Subtypes of muscarinic receptors
■■ M1 – CNS (pupillary constriction), stimu-
lates gastric acid secretion
■■ M2 – heart (decreased cardiac excitabil-
ity, contractility, conductivity and rate)
■■ M3 – vascular endothelium (visceral vaso-
dilation and coronary artery constriction)
and increased salivary, lacrimal and pan-
creatic secretions
■■ M4 – brain and adrenal medulla
■■ M5 – brain
●● More organ-specific stimulation (although
may be coordinated, e.g. salivary secretion
and gastric secretion)
●● Lacrimal glands are under sole PNS control
 Physiology

Nervous System 92
Spinal cord
Anatomy
●● Cylindrical structure 45 cm long, which runs within the vertebral canal from the foramen magnum
to L1–2 in the adult (L3 at birth)
●● Flat anteroposteriorly
●● Surrounded by the meninges, which consists of three layers:
■■ pia mater – the innermost covering, which forms the dentate ligament which pierces the dura
at intervals
■■ arachnoid
■■ dura – the outermost layer, which ends at S2 by fusion with the arachnoid. It consists of an inner
layer continuous with the arachnoid and an outer layer which is adherent to the periosteum of
the vertebral column. The potential space in between these layers is the epidural space
●● Relations:
■■ superiorly – medulla oblongata
■■ inferiorly – tapers to form the conus medullaris and then the filum terminale (an extension of
the pia mater) which is attached to coccyx
●● Central H-shaped mass of nerve cells (grey matter) that consists of two anterior columns, two pos-
terior columns and two lateral columns in the thoracic region, which convey sympathetic impulses
●● Nerve fibres surrounding the nerve cells make up the white matter and are arranged posteriorly,
laterally and anteriorly according to their relation to the grey matter
Spinal cord (cont.)
Blood supply
●● Anterior spinal artery (branch of the vertebral artery) runs in the anterior median fissure and sup-
plies the anterior two-thirds of the spinal cord
●● Two posterior spinal arteries from the vertebral artery supply anteriorly and posteriorly to the
nerve roots
●● Local radicular arteries (from intercostal or lumbar arteries)
■■ Most important at T1 and T12/L1
■■ Spinal cord most vulnerable to ischaemia at T3–5 and T12–L1
●● Venous drainage via anterior and posterior spinal veins, which form a plexus that drains into seg-
mental vessels and thus into azygous/lumbar and sacral veins

Anterior spinal artery syndrome

●● Insufficient anterior spinal artery blood supply leads to spinal cord infarction, which usually results
from profound hypotension
●● Leads to
■■ paralysis (LMN impairment) at the level of the infarction
■■ spastic paraplegia below the infarction
■■ reduced pain and temperature sensation below the infarction
■■ preserved proprioception and vibration (supplied by posterior spinal arteries)
 Physiology

Spinal cord anatomy
Fasciculus cuneatus
ipsilateral touch/proprioception
from upper body
Nervous System 93
Fasciculus gracilis
ipsilateral touch/proprioception
from lower body
Posterior median sulcus

Lateral corticospinal tract

Spinocerebellar tracts:
Motor innervation from the cerebral
Posterior cortex via crossed (pyramidal) fibres.
Anterior Descends via contralateral side
Proprioception Cerebellum to the anterior horn and UMN/LMN

Central Rubrospinal
canal
Lateral spinothalamic tract Brainstem nucles
contralateral pain + temperature Tectospinal LMN’s

Spinotectal tract Vestibulospinal

spinovisual reflexes posture + balance

Anterior spinothalamic tract

contralateral touch + pressure

Anterior median fissure

Anterior corticospinal tract
motor innervation via uncrossed
(extrapyramidal) fibres

Ascending tracts Descending tracts

Spinal cord injury
●● Commonly males 15–35 involved in road traf-
fic accidents
●● C5-6 and T12-L1 most common injuries
●● Acute injury:
■■ Hypertension, vasoconstriction
■■ Arrhythmias
■■ Cervical lesions – neurogenic pulmonary
oedema
■■ Above T1 – bradycardia
■■ Above T6 – hypotension
■■ Autonomic hyperreflexia may occur
after 4–6 weeks above T5-6
■■ Initial flaccid paralysis → spastic paralysis
(after 2–3 weeks)
■■ Paralytic ileus
●● Incomplete injury
■■ Hemisection (Brown-Séquard) – ipsilat-
eral paralysis and loss of proprioception,
touch and vibration. Contralateral loss of
pain, temperature
■■ Anterior cord – paralysis below the lesion.
Preserved proprioception, touch and
vibration
■■ Central cord – paralysis, arms more than
legs, bladder dysfunction, variable sen-
sory loss
■■ Posterior cord – loss of touch and
temperature
●● Primary injury – direct cord compression,
haemorrhage, traction forces
●● Secondary injury – ischaemia, compression,
oedema, release of free radicals, leakage of
Ca2+ into cells and K+ out of cells
Clinical nugget
Management
●● ABC with cervical spine control
●● Rapid sequence intubation (RSI) with
manual in-line stabilisation (MILS) if
required (potential difficult intubation)
●● Hyperkalaemic response to suxametho-
nium 72 hours to 6 months post-injury
●● Low threshold for IPPV especially C3-C5 injuries
●● Hypotension may be fluid-resistant and
require vasopressors
●● Suspect polytrauma and early CT/MRI – neu-
rogenic shock may mask normal physi-
ological response to haemorrhage
●● NASCIS II study recommended the use of
high-dose steroids but concerns over sepsis
means they are not routinely used in the UK
or USA
●● May have impaired temperature regulation
●● Prevention of stress ulcers, deep vein throm-
bosis (DVT), pressure sores
 Physiology

Nervous System 94
Pain pathways
●● Unmyelinated C fibres are Thalamus
Somatosensory Periaqueductal
polymodal nociceptors that cortex (venteroposterior
grey
(3rd order nucleus)
respond to heat, chemical, neurone)
mechanical stimuli and endog-
enous stimuli and are respon- Spinothalamic
tract Supraspinal
sible for slow pain sensation structures
(2nd order
●● Myelinated A fibres respond to
Dorsal root neurone)
touch (pinprick) and mechani- Painful Nociceptors ganglion
stimulus Decussation
cal stimulation Descending
Heat Aδ inhibitory
■■ Aδ fibres responsible for Laminae I V
pathways
H C
rapid pain sensation and ATP
Laminae II III
(1st order
reflex withdrawal neurone) Dorsal horn of
■■ Aβ fibres responsible for (cell bodies) spinal cord
Touch
touch and proprioception proprioception
Aβ
Laminae III IV

Pain An unpleasant sensory and emotional experience resulting from actual or potential tissue
damage
Allodynia Pain due to a stimulus that does not normally provoke pain
Analgesia Absence of pain in response to a normally painful stimulus
Hyperalgesia Increased response to a normally painful stimulus
Neuralgia Pain in the distribution of a nerve or nerves
Neuropathic pain Initiated or caused by a primary lesion or dysfunction in the nervous system
Nociception The sensation of noxious stimuli occurring via specialised nociceptors
Gate control theory of pain
●● Proposed in 1965 by Melzack and Wall Supraspinal structures
●● Theory states that pain is a function of the bal-
ance between information travelling to the
spinal cord in large (Aβ) fibres and small (C)
Aβ
fibres
●● More activity in small fibres (‘opening the GABA
gate’) causes pain; more activity in large C
SG
ENK
fibres (‘closing the gate’) prevents pain Substance P 5HT
●● ‘Gate’ thought to be located in substantia
gelatinosa (SG) and laminae II and III of Descending
pathways
the dorsal horn, which subsequently projects
to higher centres Aδ
●● Transcutaneous electrical nerve stimulation
(TENS) activates Aβ fibres Inhibitory synapse
●● Aδ fibres from superficial receptors (e.g. tem-
perature, pinprick, acupuncture) project via Excitatory synapse
spinothalamic fibres to CNS, which causes
serotonin (5HT)-mediated descending path-
ways (also affected by mood and emo-
tion) to close gate via enkephalin-secreting
interneurons
 Physiology
Intraocular pressure (IOP)
●● IOP is a measurement of the fluid pressure
inside the eye
●● Normal intraocular pressure is 1.3–2 Kpa
(10–15 mmHg) and can be estimated by
tonometry
●● Control of IOP is important during open oph-
thalmic surgery, when there is a risk of haem-
orrhage into the globe or expulsion of the
contents leading to a loss of vision
Factors that affect IOP
1. External pressure on the eye, such as by a
facemask, extraocular muscles, retrobulbar
haemorrhage or venous congestion
4. Anaesthetic drugs
2. Skeletal muscle rigidity (e.g. with age or
myopia)
3. Intraocular contents
■■ Choroidal blood volume
●● Increases with ↑ PCO2 (vasodilatation)
●● Decreases with ↓ PO2
●● Increases with acutely ↑ BP
●● Increases with ↑ CVP (head-down,
vomiting, etc.)
Nervous System 95
■■ Aqueous humour
●● Secreted by choroid plexus of posterior
chamber at rate of 0.08 mL/hour
●● Circulates through pupil into anterior
chamber and then to the canal of
Schlemm, where it is reabsorbed into
venous system
●● Production reduced by acetazol-
amide, timolol, glycerol and meiosis
■■ Vitreous humour
●● Jellylike substance behind the lens
●● Gives rigidity to eye and allows light to
pass through to retina
●● Reduced with mannitol
■■ atropine – ↑ IOP in glaucoma
■■ intravenous induction agents – ↓ IOP
with propofol, etomidate, thiopentone but
↑ IOP with ketamine
■■ benzodiazepines ↓ IOP
■■ volatile anaesthetics ↓ IOP
■■ suxamethonium ↑ IOP (possibly through
choroidal vasodilatation and extrinsic eye
muscle contraction)
Pupillary responses
●● The pupil is the central orifice of the iris; it measures
Pupillary light reflex
1–8 mm in diameter
Direct/contralateral
illumination
Causes of constriction Causes of dilation
(meiosis) (mydriasis)
Optic nerve
●● PNS stimulation ●● SNS stimulation
●● Opioids ●● Drugs Optic tract

●● general anaesthesia (GA) ■ anticholinergics

●● Pontine lesions ■ cocaine Pretectal nucleus
of high midbrain
■ tricyclics
■ ganglion blockers Edinger–Westphal
●● Awareness under GA nucleus (of CN III)

Abnormal pupillary reflexes Ciliary ganglion

●● Cranial nerve (CN) III palsy causes an ipsilateral fixed

dilated pupil with reduced extraocular motility; there may be Short ciliary CN III occulomotor
nerve nerve
sudden ptosis, diplopia, and pain
●● Midbrain lesions cause loss of light reflex with mid-point pupils Iris sphincter
●● Pontine lesions cause meiosis but normal light response Afferent pathway
●● Brainstem herniation (e.g. due to head injury) causes fixed Pupil constriction Efferent pathway

dilated pupils because of ‘stretching’ of CN III

●● Horner’s syndrome – interruption of SNS supply which leads to ipsilateral ptosis, meiosis, enoph-
thalmos, anhydrosis and nasal congestion
●● Argyll Robertson pupil (small, irregular pupil) is a light-accommodation dissociative response
associated with neurosyphilis, diabetes mellitus and brainstem encephalitis
●● Holmes-Adie pupil (large, regular pupil with sluggish reflexes) associated with viral infections,
neuropathies or trauma
 Physiology

Nervous System 96
Nausea and vomiting
Nausea ●● Unpleasant sensation that often relates to pharynx and abdomen, and is
associated with desire to vomit
Vomiting ●● Forceful expulsion of contents of upper gastrointestinal tract from mouth
Regurgitation ●● Passive reflux of stomach contents into oesophagus
Vomiting centre ●● Discrete set of nuclei within brainstem
●● Includes nucleus tractus solitarius, dorsal and ventral respiratory groups and
dorsal motor nucleus of vagus
●● Afferents to vomiting centre are via sympathetic nerves and vagi from viscera,
vestibular nuclei (in motion sickness), diencephalons and limbic system
Chemoreceptor ●● In medulla on lateral walls of fourth ventricle outside blood–brain barrier
trigger zone ●● Directly responds to chemicals within blood
(CTZ) ●● Various receptors including serotonin (5HT3), dopamine (D2), histamine (H1) and
opioids (m)
Mechanism of ●● Increased sympathetic activity causes sweating and anxiety, while parasympa-
vomiting thetic stimulation causes salivation (pre-ejection phase)
●● Reverse peristalsis empties upper small intestinal contents into stomach
●● Glottis closes and breath held in mid-inspiration, which fixes chest
●● Abdominal wall muscles contract, which increases intra-abdominal pressure
●● Lower oesophageal sphincter and oesophagus relax, which results in ejection
of stomach contents
Nausea and vomiting (cont.)
High intracranial ↓pO2 Migraine Toxins pH change Stretch Obstruction
pressure

Chemoreceptors Mechanoreceptors
Visual Olfactory
Pain Fear Anxiety

Cardiac Gastrointestinal Peritoneal

Organic pain tract irritation
Psychiatric Senses disturbances

Visceral afferents
Cortical afferents
Vestibular
apparatus Vomiting
Chemoreceptor centre
trigger zone

Pre-ejection
Drugs
Opioids
Cytotoxic Ejection
Cardiac glycosides
Volatile anaesthetic agents

Retching Vomiting
 Physiology

Muscle 97
Neuromuscular junction
The neuromuscular junction (NMJ) is the junc- There are two stores of ACh:
tion between the presynaptic motor neurone ●● ‘Active zones’ opposite the ACh receptors for
and the postsynaptic muscle membrane immediate release
●● As the axon approaches the NMJ, it becomes ●● ‘Deep stores’ within the nerve terminal acting
demyelinated and divides into terminal but- as an ACh reserve
tons that fit into the depressions of the motor
end plate
●● Only one nerve fibre converges on each end
Myelin
plate, with no convergence of inputs sheath
●● The synaptic cleft is about 50 nm wide and is
filled with extracellular fluid Axon
●● The neurotransmitter at the junction is ace- terminal

tylcholine (ACh), which is stored in vesicles in Terminal Vesicles containing

the terminal buttons button acetylcholine

Formation of Ach in the motor

neurone
Diet Synaptic
cleft
Choline Acetylcholine
Choline-O-transferase
Liver synthesis +
Coenzyme A Postsynaptic Motor end plate
acetylcholine Acetylcholinesterase
Mitochondria Acetyl CoA receptors
Neuromuscular junction (cont.)
Generation of the muscle action potential
●● The action potential is propagated to the terminal button
●● Depolarization of the motor neurone increases the permeability of the nerve ending to Ca2+ by the
opening of voltage-gated Ca2+ channels
●● The inward flux of Ca2+ stimulates the exocytosis of about 60 ACh vesicles, releasing 10,000 mol-
ecules of ACh into the junctional cleft. Only 1,000 molecules are needed to stimulate a postjunc-
tional action potential and so represents a high safety margin
●● ACh binds to the funnel-shaped postjunctional nicotinic receptor. The ACh receptor has a
molecular weight of 250,000 and five glycoprotein subunits (2 × α, 1 × β, δ and ε [γ in the fetus])
surrounding a central ion pore. Binding of one molecule of ACh to the α subunit facilitates binding
of the second to the other α subunit, which induces a conformational change and increases the
conductance of the membrane to Na+ and K+
●● The resulting influx of Na+ causes depolarization of the membrane and an end-plate potential (EPP)
●● If the EPP is large enough, it will lead to propagation of the action potential across the muscle surface
●● ACh is metabolized to choline and acetate by acetylcholinesterase, which is present in the junc-
tional folds of the muscle membrane

Types of ACh receptor at the neuromuscular junction

●● Postjunctional receptors that are responsible for traditional NMJ transmission
●● Prejunctional receptors that control specific Na+ channels and modulate further ACh mobiliza-
tion and release by a positive feedback mechanism (thought to be important in fade of non-
depolarizing neuromuscular blocking [NDNB] drugs)
●● Extrajunctional receptors that are normally present in small numbers but proliferate in denerva-
tion injuries, hypersensitivity reactions and burns
 Physiology

Muscle 98
Muscle types and contraction
Type of muscle

Characteristic Skeletal Cardiac Smooth

Structure ●● Elongated cylindrical fibres ●● Branched cylindrical ●● Sheets of interconnecting
surrounded by a sarcolemma fibres cells
●● Visible striations (regular ●● Joined end to end by ●● Random arrangement of
arrangement of actin and myosin intercalated discs actin and myosin
filaments) ●● Gap junctions – ●● Functional syncytium
●● T-tubule system connects all functional syncytium ●● Few mitochondria
myofibrils with extracellular space ●● Many mitochondria
●● Few mitochondria
Depolarization ●● Nervous innervation necessary ●● Fast pacemaker ●● Slow pacemaker function
●● No pacemaker function function ●● Autonomic nervous
●● Nerve action potential spreads to ●● Action potential system innervates
each muscle cell – no connec- spreads from cell to cell ●● Action potential spreads
tion between individual fibres ●● All or none from cell to cell
●● All or none ●● Graded response
Involvement of ●● Source – sarcoplasmic reticulum ●● Source – SR (well ●● Source – extracellular fluid
Ca2+ (SR) (extensively developed) developed) (poorly developed SR)
●● Ca2+ binds to troponin ●● Ca2+ binds to troponin ●● Ca2+ binds to calmodulin
Contraction ●● 7.5–100 ms ●● 300 ms ●● Capable of prolonged
●● Voluntary ●● Involuntary contraction
●● Can exhibit tetany ●● No tetanic contraction ●● Involuntary
due to prolonged ●● Can exhibit tetany
refractory period
Muscle types and contraction (cont.)
Types of skeletal muscle fibre
●● Type I
■■ Red muscle suitable for prolonged contraction (e.g. postural muscles)
■■ High oxidative capacity, slow metabolism, many mitochondria
●● Type II
■■ White muscle suitable for rapid skilled movements (e.g. eye movements)
■■ Glycolytic and fatigable

Excitation–contraction coupling
The sequential series of steps from the action potential arriving at the motor endplate until the
skeletal muscle contracts
●● The postsynaptic membrane of the motor endplate is depolarized by the action potential and an
end-plate potential (EPP) is created, which depolarizes the adjacent muscle membrane
●● The muscle membrane threshold potential is reached, and a muscle action potential is created,
which spreads over the whole muscle membrane (via increased Na+ and K+ conductance) and
into the muscle bulk (via the T-tubule system)
●● As the depolarization spreads down the T tubules, L-type Ca2+ channels are activated, which
causes an increase in cytoplasmic Ca2+ and the release of Ca2+ from the sarcoplasmic reticulum
via the ryanodine receptor
●● Calcium ions bind to troponin C on the thin actin filament, which then interacts with troponin I and
tropomyosin. This complex is then displaced to expose the myosin binding site
●● Myosin binds to the actin with the hydrolysis of adenosine triphosphate and shortening of the
muscle fibre. This is known as the sliding filament hypothesis
 Physiology

Muscle 99
Muscle components
Motor neurones ●● Two types of muscle spindle transmit impulses
●● Lower motor neurones (LMNs) directly inner- when stretched
■■ β-efferent fibres (slow fibres from the cere-
vate muscle
●● Lesions of LMNs cause flaccid paralysis, fas- bral cortex)
■■ Iα primary afferent fibres (i.e. Aα fibres to
ciculations, absent reflexes, muscular atrophy
the spinal cord)
and denervation hypersensitivity
■■ γ–efferent fibres (Aγ fibres)
●● Upper motor neurones (UMNs) are all other
●● Nuclear chain fibres provide static control
motor neurones including motor cortex, extra-
of muscle length innervated by
pyramidal and cerebellar pathways
■■ Ia primary afferent fibres (fibres that spiral
●● UMN lesions cause increased tone, spastic
around the central portion)
paralysis, increased reflexes, upgoing plan-
■■ II secondary afferent fibres (‘flower spray’
tars, increased hyperkalaemic response to
endings near the ends)
suxamethonium
■■ γ–efferent fibres
●● A motor unit is one LMN and the muscle fibres
it innervates. All muscle fibres in a single motor
Extrafusal
unit are of the same type (fast or slow). fibre
γ-efferent
Muscle spindles Iα afferent

●● Specialized muscle fibres that lie in parallel

with the rest of the muscle fibres enclosed Bag
Connective
in a connective tissue capsule ain tissue capsule
Ch
●● Involved in the reflex control of muscle -motor-
neurone
length; respond to change in length and
Extrafusal
rate of change fibre
Muscle components (cont.)
Reflex arc consists of: ■■ Activation of the reflex inhibits reciprocal
●● Sensory organ – e.g. patellar tendon tap innervation (contraction of antagonistic
causes stretch of the quadriceps muscle muscle groups) via an inhibitory spinal
●● Afferent neurone – spindle fibres are interneurone
stretched which causes increased sensory
output via 1a and II afferents entering the spi- Monosynaptic reflex
nal cord via the dorsal roots
DRG
●● One or more synapses Input
Afferent (sensory) neurone White
■■ Monosynaptic (e.g. knee jerk – Ia sen-
sory axons directly synapse with α-motor mu Grey

neurones) Muscle

■■ Polysynaptic reflexes (two or more syn- Efferent (motor) neurone

apses, e.g. withdrawal reflex) Output
●● Efferent neurone – quadriceps innervated by
α-efferents
Polysynaptic reflex
●● Effector – reflex contraction of quadriceps Interneurone
muscle to maintain muscle length. Spindle is DRG
no longer stimulated and Ia sensory output Input
Afferent (sensory) neurone White
decreases.
mu Grey
●● Notes:
Muscle
■■ Fibre discharge is proportional to the
degree of stretch (static response) or the Efferent (motor) neurone
speed of stretch (dynamic response) Output
 Physiology

Muscle 100
Sarcomere
●● Tropomyosin (protein complex formed by
Myosin Myosin troponin C, I and T) wraps around the actin
filament and covers the binding sites for the
Myosin Myosin myosin; important in excitation–contraction
coupling
Myosin Myosin ●● A-band (anisotropic) is the dark band formed
by the thick filaments
●● I-band (isotropic) is uniform in all directions
M-line Z-line formed by thin filaments not overlapped by
thick filaments
A-band ●● H-band – thick filaments not overlapped by
thin filaments
I-band H-band
●● M-line – cross-linkage of myosin filaments
●● Z-lines – cross-linkage of actin filaments, also
●● Basic contractile unit of skeletal muscle the boundary between adjacent sarcomeres
●● Consists of multiple thick myosin and thin ●● During skeletal muscle contraction the Z-lines
actin filaments in a parallel arrangement move closer together as thick and thin fila-
●● Thick filaments contain cross bridges which ments overlap
when activated bind to the thin actin filaments
Disorders of neuromuscular function
Disorders of presynaptic release of ACh ■■ Increased sensitivity to NMBDs and relative
●● Eaton-Lambert syndrome (myasthenic syndrome) resistance to suxamethonium
■■ Acquired autoimmune disorder (IgG mediated)
of the voltage-gated calcium channels causing Muscle contraction disorders
less ACh to be released into the synapse Malignant hyperthermia
■■ Improves with exercise
●● Autosomal dominant disorder causing dysfunc-
■■ Affects proximal limb muscles
tion in the ryanodine/dihydropyridine receptor
■■ Increased sensitivity to depolarising and neuro-
which controls calcium flux in and out of the sar-
muscular blocking drugs (NMBDs)
coplasmic reticulum
●● Neuromyotonia
●● Follows exposure to triggers, particularly suxametho-
■■ Autoimmune attack on voltage-gated calcium
nium and volatile agents
channels causing hyperpolarisation of the pre-
●● Leads to
synaptic membrane
■■ Sustained muscle contraction
●● Botulism (Toxin inhibits ACh release)
■■ Muscle breakdown, hyperkalaemia
Disorders in postsynaptic receptors ■■ Hyperthermia
■■ Increased oxygen consumption/hypoxia
●● Myasthenia gravis
■■ Hypercapnia
■■ Immune mediated, neonatal, congenital or drug
●● Treatment
induced
■■ Dantrolene 1 mg/kg to 10 mg/kg
■■ Most are due to immune-mediated IgG attack
■■ Supportive
on post-synaptic receptors (may involve presyn-
aptic receptors) causing reduction in receptor
Burns
density
■■ Muscle weakness – especially ocular, bulbar ●● Increased (immature) extrajunctional ACh receptors
(high risk of aspiration), respiratory and limb leads to increased potassium release with suxame-
■■ Treament – anticholinesterase inhibitors (e.g. thonium approximately 2 weeks to 2 months post-burn
pyridostigmine), immunosuppression, IvIG and ●● Resistance to NMBDs – may involve altered pharma-
plasmapheresis in severe cases cokinetics or receptor function
 Physiology
Myopathies
●● Myopathies are a group of disorders in which the
muscle fibres do not function properly resulting in
muscular weakness
●● Many different causes include endocrine, inflamma-
tion, paraneoplastic, infection, drug-induced, criti-
cal illness myopathy, metabolic or collagen-related
●● Inherited causes include:
■■ Myotonic disorders – myotonic dystrophy, myo-
tonic congenital and paramyotonica
■■ Muscular dystrophies
■■ Metabolic and mitochondrial myopathies
Myotonic dystrophy
●● Disorder of chloride conductance characterised by
incomplete muscle relaxation
●● Extramuscular features include:
■■ Cardiomyopathy
■■ Conduction abnormalities
■■ Restrictive lung disease
■■ Obstructive sleep apnoea (OSA)
■■ Delayed gastric emptying
■■ Hypothyroidism
■■ Diabetes
Muscular dystrophies
●● Group of progressive disorders – genetically deter-
mined degeneration of muscle
Muscle 101
●● Dystrophin is a protein that conducts the force of
muscle contraction by anchoring the cytoskeleton to
the extracellular matrix
●● Muscular dystrophy characterised by dystrophin gene
abnormality (Becker muscular dystrophy [BMD]) or
absence of (Duchenne muscular dystrophy [DMD])
●● Functional assessment vital as respiratory and car-
diovascular system (CVS) symptoms correlate poorly
■■ 90% have abnormal ECG (some may require peri-
operative pacing)
■■ Cardiomyopathy common
■■ Respiratory weakness compounded by hyper-
sensitivity to respiratory depressants
■■ Stomach and oesophageal motility problems ↑
aspiration risk
■■ Overexpression of extrajunctional ACh recep-
tors → hyperkalaemia and rhabdomyolysis with
suxamethonium/anticholinesterases
■■ Volatile anaesthetics may → MH-like crises/
rhabdomyolysis
Metabolic/mitochondrial myopathies
●● Multiple pathophysiologies – aggressive metabolic
monitoring perioperatively vital
●● Most anaesthetic drugs depress mitochondria
●● Avoid suxamethonium, atracurium seems safe
●● Risk of third-degree heart block may require pacing
●● Some association with seizures requiring anticonvulsants
Sphincters
Circular muscle that surrounds the opening from an organ and, by maintaining a constant state
of moderate contraction, prevents escape of contents from the organ
●● They can be classified into:
■■ Anatomical – have a localised and often circular muscle thickening to facilitate their action
■■ Functional – do not have this localised muscle thickening and achieve their action through
muscle contraction around (extrinsic) or within (intrinsic) the structure
●● Sphincters may be under voluntary (somatic) or involuntary (autonomic) control

Important sphincters
Gastrointestinal ●● Lower oesophageal sphincter prevents reflux of gastric contents into
tract oesophagus
●● Pyloric sphincter – thickening of circular muscle of stomach around its
opening into duodenum
●● Internal (involuntary) and external (voluntary) anal sphincters
●● Sphincter of Oddi invests associated bile and pancreatic passages as
they traverse wall of duodenum
Genitourinary tract ●● External (voluntary) and internal (involuntary) urethral sphincters
Cardiovascular ●● Precapillary sphincters encircle true capillaries where they originate
from arterioles and regulate blood flow through capillary bed
Eyes ●● Pupillary sphincter controls light entry through the iris
 Physiology

Heart and Circulation 102

Cardiac action potentials
There are two types of cardiac cells: pacemaker Pacemaker action potential
cells and cardiac muscle cells
Depolarisation
caused by transient
Pacemaker cells (T-type) Ca2
●● Cardiac muscle cells that initiate cardiac mV channels opening
muscle contraction by spontaneously depo- 20 Influx of Ca2
larising (demonstrating automaticity) at a Repolarisation – K efflux

regular rate (rhythmicity) due to changes in 0 Time (ms)

0 3
K+ permeability
Restoration of
●● Found in the SA node (70–80 bpm), AV node ionic gradient
(60 bpm), Bundle of His (50 bpm) and ventric- 40
– Na /K ATPase
ular cells (40 bpm) 4 4
60 – Ca2 efflux
Rate of discharge depends on: RMP
●● slope of phase 4 depolarization (varied by the
400 420 440 460 480 500 ms
ANS)
●● RMP (more negative (e.g. ↑ acetylcholine or Slow leak of Na inwards
↓  K+) means longer to reach threshold and until threshold potential reached
thus a slower rate)
●● threshold potential (less negative  means
slower rate, e.g. ↑ Ca2+ or class Ia
antiarrhythmics)
Cardiac action potentials (cont.)
Cardiac muscle action potential
Early rapid repolarisation – K+ efflux
mV Plateau phase – Ca2+ influx
20 1 2 balanced by K+ efflux
0 Time (ms)
100 200 Rapid repolarisation
0 3 K+ efflux
ARP
Initial rapid RRP ARP = Absolute Refractory Period
depolarisation RRP = Relative Refractory Period
Na+ influx 4
90
RMP
Restoration of resting
membrane potential
Na+ /Ca2+ efflux
K+ influx
 Physiology

Heart and Circulation 103

Cardiac definitions
Excitability ●● Ability of cardiac tissue to depolarize to a given electrical stimulus
Cardiac output ●● Volume pumped by the left ventricle per minute
(CO) ●● Normally 5 L/min
Cardiac index ●● Cardiac index = CO/Body surface area (BSA) = 3–3.5 L/min/m2
Stroke volume (SV) ●● Volume of blood ejected from the ventricle in a single contraction
●● Normally 70–80 mL for a 70 kg man at rest
●● SV = End-diastolic volume (EDV) - End-systolic volume (ESV)
●● As CO = SV × HR, SV = CO/HR
Stroke index ●● Stroke index = SV/BSA = 30–50 mL/m2
Mean arterial ●● Average arterial blood pressure throughout the cardiac cycle
pressure (MAP) (2 × Diastolic) + Systolic
●● MAP ≈
3
Preload ●● End-diastolic ventricular wall tension
Afterload ●● Tension per unit cross-section developed in the ventricular wall during systole
Systemic vascular ●● All the forces that oppose blood flow through the systemic vascular bed
resistance (SVR) MAP −CVP
●● SVR = × 80 dynes ⋅ s/cm5 = 900−1400 dynes ⋅ s/cm5
CO
Cardiac definitions (cont.)
Ejection fraction ●● Ejection fraction = (SV/EDV) × 100
●● Normally 60%–65%
●● An index of contractility
Contractility ●● Intrinsic ability of a cardiac muscle fibre to do mechanical work
when it contracts with a predefined load and an initial degree of
stretch
●● Increased by
■■ intrinsic mechanisms (Starling’s law, Anrep effect, Bowditch
phenomenon)
■■ extrinsic mechanisms (sympathetic nervous system (SNS), catechol-
amines and inotropes)
●● Decreased by
■  reduced filling (Starling’s law) – related to ventricular compliance
and heart rate  ■  parasympathetic nervous system (PNS)
■  increased CO2, decreased O2 (direct effects and SNS)
■  ­acidosis or alkalosis  ■  cardiac disease  ■  ↑ K+, ↓ Ca2+
■  drugs (anaesthetic agents, antiarrhythmics)
Venous return ●● The blood entering the right atrium per minute
●● An important determinant of cardiac output as described by
Starling’s law
●● Depends on:
■  venous tone  ■  intrathoracic or intra-abdominal pressure
■  blood volume  ■  right and left ventricular function  ■  skeletal
muscle pump  ■  posture  ■  vasodilator or vasopressor function
 Physiology
Control of blood pressure
●● Blood pressure (BP) is defined as the pulsa-
tile ejection of the stroke volume that gives
rise to the arterial waveform
●● Mean arterial pressure (MAP) =  CO × SVR
= (HR × SV)
× SVR
Short-term control
Intrinsic regulatory properties of the
heart
●● Starling’s Law of the heart
●● Anrep effect – describes the response to
acute increases in afterload. Initially ↓ SV and
↑LVEDP then return to normal
●● Bowditch phenomenon – describes the
response to increased rate of stimulation. As
rate increases, contractility increases
Baroreceptors
●● Baroreceptors are stretch receptors in the
walls of blood vessels, which respond to
Heart and Circulation 104
increased pressure. They may be classified
into high and low pressure receptors
■■ High pressure baroreceptors are found
within the carotid sinus and aortic arch
●● Their rate of discharge is increased by
increasing BP and by increasing rate
of rise of BP
●● Afferent impulses travel to the vasomo-
tor centre and the cardioinhibitory
centre in the medulla via the glosso-
pharyngeal nerve (from the carotid
sinus) and vagus (from the aortic
arch) resulting in a reduction in BP
■■ Low pressure baroreceptors are found in
the right atrium
●● They discharge either during atrial sys-
tole (Bainbridge reflex) or during dias-
tole in response to distension
●● This results in a decrease in sympa-
thetic activity, venodilation and an
inhibition of ADH release
Control of blood pressure (cont.)
Intermediate and long-term control of blood pressure
●● Renin–aldosterone–angiotensin system (RAAS)-see Renal
●● Antidiuretic hormone (ADH)
■■ Polypeptide containing nine amino acids, synthesized in the supraoptic nucleus of the hypo-
thalamus and released by the posterior pituitary
■■ Increases permeability of the collecting ducts of the kidney to water, thus conserving fluid and
producing more concentrated urine
■■ Achieves increases in permeability through G protein-coupled receptors using cyclic adenos-
ine monophosphate (cAMP) as a second messenger
●● Adrenaline and noradrenaline as part of the sympathetic response
●● Atrial natriuretic peptide (ANP)
■■ Hormone isolated from the right atrium and produced in response to atrial stretch
■■ Relaxes vascular smooth muscle
■■ Inhibits renin activity and aldosterone release
■■ Increases sodium and water excretion and increases glomerular filtration rate (GFR)
 Physiology

Heart and Circulation 105

Cardiac cycle
●● The cardiac cycle describes the relation between the electrical and mechanical events
within the heart over time
●● Systole refers to contraction (atrial and ventricular), while diastole refers to relaxation
●● Isovolumetric changes refer to changes in intraventricular pressure that occur without a change
in the length of the muscle fibres
●● The cardiac cycle is usually divided into five phases
■■ Atrial contraction resulting from depolarization at the sinoatrial node, which accounts for 30%
of ventricular filling
■■ Isovolumetric contraction (IVC), which starts at the tricuspid and mitral valve closure (first
heart sound) until the pressure in the ventricles exceeds the pressure in the aorta and pulmo-
nary artery. The aortic valve (AV) and pulmonary valve (PV) then open
■■ Ventricular ejection, which is most rapid initially. Lasts until the pressure in the ventricle is lower
than that in the aorta and pulmonary artery, at which point the AV and PV close (second heart
sound)
■■ Isovolumetric relaxation (IVR) lasts until the mitral and tricuspid valves open
■■ Passive ventricular filling, which is most rapid initially
Cardiac cycle (cont.) 120
Phase 1 – Atrial systole

Pressure
Phase 2 – Isovolumetric contraction,

(mmHg)
80 Aortic pressure
starts with the closure of mitral
and tricuspid valves. C wave of 40
CVP trace represents TV bulging
a c v LA pressure
into RA 0 LV pressure
Phase 3 – Aortic and Pulmonary LVEDV
120

LV volume
valves open, ejection
Phase 4 – Isovolumetric relaxation at

(mL)
closure of aortic and pulmonary
valves
Phase 5 – Ventricular filling, initially 40 LVESV
R
rapid then slows (diastasis) before T
P
atrial contraction and the cycle ECG
restarts Q S
IV I II III
Heart
sounds Systole

0.4 0.8 Time (s)

Phases 1 2 3 4 5

LVEDV = LV end diastolic volume

LVESV = LV end systolic volume
 Physiology

Heart and Circulation 106

Pressure–volume loop for the left ventricle

Ventricular ejection
A Mitral valve opens
120
D
B Mitral valve closes
Pressure (mmHg) C Aortic valve opens
End systolic C
80 D Aortic valve closes
volume

IVR IVC
Stroke volume
40
le
Ventricular diasto End diastolic
and filling volume
A B
0
70 140
Volume (mL)

The area inside the loop represents the work performed by the left ventricle for that cycle
(Work = Pressure × Volume)
 Autoregulation
Autoregulation is the intrinsic ability of an organ to maintain a constant blood flow despite changes in perfu-
sion pressure
●● It occurs in the kidney, heart and brain
●● When perfusion pressure (arterial pressure minus venous pressure, PA − PV) initially decreases, blood flow (F) falls because
of the following relation between pressure, flow and resistance (R):

(PA − PV )
F=
R
●● Autoregulation occurs at a mean arterial pressure of 60–140 mmHg in normotensive people. Below this perfusion
pressure, blood flow decreases passively in response to further reductions in perfusion pressure
●● Autoregulation is impaired by
■■ disease states (such as the effect of head injury on cerebral blood flow)
■■ volatile anaesthetics
Organ blood flow (mL/min)

■■ vasodilator drugs

Theories of the mechanism of autoregulation

●● Myogenic theory
■■ The muscle in the wall of the vessel contracts to reduce the radius as the
intraluminal pressure rises. This maintains wall tension by Laplace’s law
●● Metabolic theory
■■ At low blood flow there is an accumulation of vasodilator substances (e.g.
60 140 nitric oxide, CO2, H+), which increase the flow through the vessel and are
Mean arterial pressure (mmHg) subsequently washed away
●● Tissue theory
■■ As blood flow increases, interstitial fluid volume rises (Starling’s forces)
and the blood vessels are compressed
 Physiology

Heart and Circulation 107

Cardiovascular response to haemorrhage
Immediate ●● Decreased CVP and decreased RAP → decreased RVEDP → decreased LVEDP → decreased LVSV
responses ●● ↓ blood pressure, which is sensed by the baroreceptors (carotid sinus) and the volume receptors
(seconds) (right atrium)
●● Resulting vasomotor stimulation → increased sympathetic stimulation to maintain arterial blood
pressure including
■■ ↑ heart rate and contractility
■■ redistribution of the cardiac output by peripheral vasoconstriction and venoconstriction
(increased SVR) and renal vasoconstriction (↓ GFR)
■■ mobilization of blood reservoirs (lungs or liver)
■■ preferential maintenance of cerebral blood flow
Intermediate ●● Net reabsorption of interstitial fluid across the capillaries by Starling’s forces
responses ●● ↑ levels of renin, angiotensin and aldosterone
(minutes) ●● ↓ ANP
●● ↑ ADH release of (>10% loss of plasma volume stimulates volume receptors) and ↑ thirst
Long-term ●● Plasma volume returns to normal in 12–72 hours
responses ●● ↑ plasma protein synthesis by the liver
(hours) ●● ↑ production of erythropoetin and RBCs (reticulocytes peak at 10 days, red blood cell count
restored within 4–8 weeks)
ANP ●● Polypeptide hormone secreted by atrial myocytes in response to atrial distension, β-adrenoceptor
stimulation, ↑ levels of Na+ and angiotensin II
●● Actions
■■ Vasodilation of glomerular afferent arteriole, vasoconstriction of the efferent hence ↑ GFR and
↑ excretion of Na+ and water
■■ ↓ production of aldosterone (from adrenal cortex) and ↓ renin
■■ ↓ renal reabsorption of Na+
Response to the rapid infusion of 1000 mL saline
Immediate ●● Initial expansion of intravascular fluid (IVF) compartment with one litre of fluid
responses ●● Increased CVP and increased RAP → increased RVEDP → increased LVEDP →
(seconds) increased LVSV
●● Increased blood pressure → carotid sinus baroreceptor stimulation
●● Vasomotor and cardioinhibitory reflexes → decreased heart rate
Intermediate ●● Physiological saline remains in the extracellular fluid (ECF) compartment
responses ■ Saline can freely cross the vascular endothelium and will distribute by
(minutes) diffusion across the plasma (3.5 L) and interstitial compartments (10 L)
according to their relative volumes (i.e. 750 mL interstitial fluid [ISF] and
250 mL plasma)
■ If 250 mL remains in the intravascular fluid (IVF), then the overall increase in
plasma volume is (250/5000) × 100 = 5%
●● Physiological saline is isotonic, so there is no change in osmolality, no net
movement of fluid in or out of cells and no osmoreceptor stimulation
●● Secretion of ANP does not alter, as the 5% increase in plasma volume is not
enough to stimulate the atrial stretch receptors (10% volume change required)
Long-term ●● Two factors contribute to excretion of the fluid by increasing the filtration
responses fraction in the renal glomerulus
(hours) ■ Excess saline leads to a slight drop in plasma oncotic pressure
■ ↑ intravascular volume increases blood pressure
 Physiology

Heart and Circulation 108

Frank–Starling law of the heart
●● The energy of contraction of the cardiac muscle is proportional to the initial length of the
muscle fibre up to a point
●● It is an intrinsic regulatory mechanism of the heart
●● Neither contraction nor muscle fibre length are measured easily, so the law is extrapolated:
■■ Myocardial contraction approximates CO, SV, SW and SI
■■ Fibre length approximates LVEDV, LVEDP and PCWP
●● The curve is shifted upwards and to the left with exercise and inotropes
●● Reduced contractility shifts the curve downwards (e.g. heart failure or cardiogenic shock), which
implies that the heart generates a smaller stroke volume for the same end-diastolic volume
●● Initial compensation in dilatation of the heart (increased preload) manifests as a shift to the right

Normal during
exercise/inotropes
Cardiac output (L/min)

Normal at rest
Contractility

Heart failure

Cardiogenic shock

With ↑ preload
LVEDP (mmHg) (preload)
Heart failure
Failure of the heart to maintain a cardiac out-
put sufficient to meet the metabolic demands
of the body
Causes
●● Volume overload (high output failure)
■■ Mitral regurgitation
■■ Cardiac shunts
●● Pressure overload
■■ Systemic hypertension
■■ Outflow obstruction (aortic stenosis or
hypertrophic obstructive cardiomyopathy
[HOCM])
●● Myocardial disease
■■ Altered contractility (e.g. ischaemic heart
disease, toxins or myocarditis)
Pathophysiology
●● Initially, the failing myocardium compen-
sates to improve cardiac output by the follow-
ing mechanisms, which later contribute to the
progression of the disease
■■ Cardiac dilatation (Frank–Starling law)
■■ Sympathetic effects
●● Direct increase in contractility
●● Indirect increase in preload (constric-
tion of capacitance vessels) and after-
load (PVR)
●● Diversion of blood from the viscera to
the brain
■■ Activation of the renin–angiotensin–
aldosterone system
●● Aldosterone causes retention of Na+
and increases preload
●● Angiotensin increases systemic vascu-
lar resistance (SVR) through peripheral
vasoconstriction
●● Increased SVR increases cardiac work,
wall tension and oxygen requirements.
Ventricular filling pressures are increased by
raised venous tone. This, together with reten-
tion of water and Na+, leads to peripheral
oedema, pulmonary oedema and fatigue
 Physiology

Heart and Circulation 109

Valsalva manoeuvre
●● Forced expiration against a closed glottis
●● Defining feature is an increase in intrathoracic pressure with a subsequent drop in venous return

Normal Valsalva response

Phase I ●● Increased intrathoracic pressure squeezes
Intrathoracic
intrapulmonary vessels, which increases pressure
Breathe in Exhale
venous return to the left side of the heart
●● Stroke volume (SV) increases (Starling’s
law) and mean arterial pressure (MAP) MAP
rises
Phase II ●● MAP falls because of reduced venous
HR
return and reduced cardiac output, with a
subsequent increase in sympathetic Phase I II III IV
stimulation, increased heart rate and
vasoconstriction
Phase III ●● Straining is released and the MAP initially drops, with pooling of blood in the intratho-
racic vessels (reverse of phase I)

Phase IV ●● A rapid increase in MAP then occurs as vasoconstriction and increased heart rate are
still in operation
●● A reflex bradycardia occurs
●● MAP and heart rate rapidly return to normal
Valsalva manoeuvre (cont.)
Abnormal Valsalva responses
Autonomic dysfunction (e.g. neuropathy
or drugs)
●● Diminished baroreceptor reflex leads to
●● Excessive drop in blood pressure (BP) with no
overshoot in phase 4
●● No bradycardia in phase 4
Congestive cardiac failure ‘square
wave response’
●● No increase in BP or alteration in heart rate
when intrathoracic pressure is released
●● Characterized by a rise in BP in phase 2
●● This is thought to be caused by pulmonary
congestion maintaining left ventricular filling
after the onset of straining
Cardiovascular response to
standing
●● Blood immediately pools in the lower
extremities
●● Venous return and cardiac output (thus BP)
drops
●● Baroreceptors decrease firing, sensed by the
vasomotor centre in the medulla
●● Sympathetic stimulation causes
■■ vasoconstriction (increased systemic vas-
cular resistance) and
■■ venoconstriction (increased venous
return and cardiac output)
■■ increased heart rate
●● These changes tend to restore blood pressure
and maintain cerebral perfusion
Notes
●● Muscle pumps in the lower limbs will increase
venous return to minimise decreases in blood
pressure
●● In elderly people, the sympathetic response is
slower and less effective
 Physiology

Heart and Circulation 110

Exercise
Exercise leads to physiological changes that increase oxygen flux to and remove waste prod-
ucts from active tissues

CNS ●● Cerebrocortical activation of sympathetic system (anticipation)

●● Global cerebral blood flow is unchanged (small local changes, e.g. motor
cortex blood flow increases)
Cardiovascular ●● ↑ cardiac output mainly from ↑ heart rate (maximum 195 bpm) and ↑ stroke
system volume (up to ×2 in athletes) in order to meet ↑ oxygen requirements of
muscle
●● Activation of the CVS reflexes from stimulation of muscle mechanoreceptors,
baroreceptors and joint receptors
●● ↑ BP (systolic > diastolic)
●● ↑ venous return (skeletal muscle pump, thoracic pump and ↑ venomotor
tone) but CVP usually remains unchanged
●● Rediversion of blood flow from the splanchnic circulation to skin and muscle
(↑ by up to ×30)
●● Arteriovenous O2 partial pressure difference in muscle increases ×3
●● Coronary blood flow ↑ ×3
●● Haematocrit often slightly ↑ because of ↑ insensible losses and ↑ net
capillary filtration
Exercise (cont.)
Respiratory ●● ↑ minute volume proportional to oxygen demand because of ↑ respiratory
system rate and ↑ tidal volume
●● Pulmonary blood flow increases ×6
●● Oxygen uptake increases to 4000 mL/minute
●● Carbon dioxide excretion increases to 8000 mL/minute
Temperature ●● ↑ temperature because of hypermetabolic muscles
regulation ●● Temperature regulation achieved by
■■ sweating
■■ expiration of warm air
■■ vasodilation
Severe exercise ●● Vasoconstriction
leads to ●● Heart rate plateaus at about 180 bpm
exhaustion ●● Stroke volume remains the same or decreases, and leads to hypotension
●● Uncontrolled hyperthermia
●● Metabolic acidosis
●● Muscle cramps, pain, weariness and a lack of desire to continue
●● Myoglobinuria
 Physiology

Heart and Circulation 111

Pressures within the normal heart and pulmonary circulation
Percentage
Pressure oxygen
Location (mmHg) saturation Measurement Notes

Right 1–4 75 ●● Direct: catheter inserted into RA

atrium ●● Indirect: central venous
(RA) cannulation (see card Central
venous pressure)
Right 25/4 75 ●● RV ejection fraction pulmonary ●● Pulmonary bed has a low pressure, therefore RV pressures
ventricle artery catheters (RVEF PAC) are lower than systemic pressures
(RV) ●● Analogous function to LV but more difficult to assess
●● RV is very compliant, so dilates and decreased ejection
fraction with increasing afterload
Pulmonary 25/12 75 ●● Right-sided cardiac ●● Typically one-fifth of systemic pressure
artery (PA) catheterization ●● Changes may indicate variation in PCWP and pulmonary
vascular resistance
Pulmonary 6–12 75–97 ●● Pulmonary artery catheter (PAC), ●● Pressure measured within the pulmonary arterial system
capillary but caution in interpretation if during PAC with the catheter’s tip ‘wedged’ in a branch of
wedge ■■ left ventricular failure one of the pulmonary arteries
pressure ■■ raised intrathoracic pressure ●● Can represent LA filling pressure and thus LVEDP, so an
(PCWP) (e.g. PEEP) indirect indicator of LVEDV
■■ non-compliant LV ●● Usually 1–4 mmHg lower than diastolic pressure in PA
■■ aortic regurgitation ●● Traditionally measured at end expiration
Left atrium 2–10 97 ●● Direct: catheter inserted into LA ●● Mean pressure approximates to LV end-diastolic pressure
(LA) ●● Indirect – PAC (measures PCWP); (LVEDP) unless mitral valve is abnormal
usually measured from midaxilla
or sternal angle
Left 120/10 97 ●● Direct: cardiac angiography ●● LVEDP (normally <12 mmHg) reflects preload of LV.
ventricle ●● Indirect: inferred via PAC ●● With constant ventricular compliance, LVEDP reflects LVEDV
(LV) ●● Increased LVEDP may reflect increased blood volume,
increased venous return and increased contractility
Aorta (AO) 120/70 97 ●● Arterial cannulation
Shock
Pathophysiological syndrome in which tissue perfusion is inadequate for the tissue’s metabolic
requirements
Type Cause Clinical features CVS Treatment
Hypovolaemic Loss of circulating volume ●● Hypotension, ↑ HR ●● ↓ Preload, ↓ CO ●● ↑ oxygen delivery
(including ●● Cool clammy skin ●● ↑ SVR ●● Control further blood loss
anaphylactic) ●● ↓ U/O (anaphylactic ●● Fluid resuscitation
leads to ↓ SVR)
Cardiogenic Myocardial dysfunction ●● Hypotension ↑ HR ●● ↓ Preload, ↓ CO ●● ↑ contractility
●● MI ●● Cool clammy skin ●● ↑ SVR (dobutamine/milrinone)
●● Valve lesions ●● ↓ U/O ●● IABP or LVAD
●● Crackles, ↑ RR ●● Cardiac transplantation
Distributive Disruption of autonomic ●● Sudden hypotension, ↓ HR ●● ↓ CO ●● Dopamine/
shock – pathways – SNS cannot be ●● Warm, flushed skin ●● Venous and Noradrenaline
neurogenic activated to compensate ●● Below C5 – diaphrag- arterial ●● Vasopressin
●● Severe brain injury matic breathing (loss of vasodilation ●● Atropine
●● Cervical or thoracic intercostals) ●● Loss of
spinal cord lesions ●● Above C3 – respiratory sympathetic tone
arrest
Distributive – Inflammatory response to ●● Hypotension, ↑ HR ●● ↓ CO ●● Fluids
septic infection causes a ●● Bounding pulse ●● ↓ SVR ●● Early antibiotics
reduction in SVR such that ●● ↑ RR ●● Early goal-directed therapy
organ perfusion cannot ●● Pink, warm, flushed skin ●● Vasopressors
be maintained despite ↑ ●● Fever ●● Rapid source
CO ●● ↓ U/O identification and control
Obstructive Physical obstruction to ●● Hypotension, ↑ HR ●● ↓ Preload ●● Relieve the obstruction
filling of the heart ●● Pulsus paradoxus ●● ↓ CO (e.g. pericardiocentesis)
●● Tamponade (tamponade) ●● ↑ SVR ●● Fluid resuscitation
●● PE ●● May be cold, clammy ●● Inotropes/vasopressors
●● Tension pneumothorax may be ineffective
Note:  Treatment depends on the cause but aims to improve oxygen delivery to the tissues.
 Physiology
Coronary artery blood supply
Arterial blood supply
●● The coronary arteries supply oxygenated blood to
the heart and are end arteries
●● Cardiac veins remove the deoxygenated blood from
the heart
Left coronary artery
●● The left coronary artery (LCA) arises from the aorta
above the left cusp of the aortic valve at the poste-
rior aortic sinus as the left main stem artery (LMS).
The LMS typically runs for 1–25 mm in the anterior
interventricular groove and then bifurcates
●● The left anterior descending (LAD) artery supplies the
anterior wall of the left ventricle and the interventricu-
lar septum and the left circumflex artery (LCX) sup-
plies the lateral wall of the left ventricle (LV)
Right coronary artery
●● The right coronary artery (RCA) originates from the
anterior aortic sinus
●● It travels down the right atrioventricular groove in
between the pulmonary trunk and right atrium on the
anterior surface of the heart. It continues inferiorly to
anastamose with the LCA
●● In addition to supplying blood to the right ventricle
(RV) and the sinoatrial node (SAN), the RCA sup-
plies the atrioventricular node (AVN) and the pos-
terior and inferior LV in 90% of the population
Heart and Circulation 112
Coronary artery dominance
●● The supply of the posterior descending artery (PDA)
determines coronary dominance
●● If the RCA supplies the PDA, the circulation is right
dominant (70% population)
●● If the LCX supplies the PDA, the circulation is left dom-
inant (10%)
●● If both the RCA and LCX supply the PDA the circula-
tion is co-dominant (20%)
Venous drainage
●● Two-thirds of venous drainage occurs via the coro-
nary sinus and anterior cardiac veins directly into
the right atrium and one-third via the Thebesian
veins and small venules into all heart chambers
●● Venous blood entering the left side of the heart will
cause a small degree of shunt
●● Tributaries of the coronary sinus include:
■■ Great cardiac vein (drains left coronary artery
supply from the apex in the anterior interventricu-
lar septum)
■■ Middle cardiac vein (drains the posterior
descending artery supply running in the poste-
rior interventricular groove)
■■ Small cardiac vein (drains blood from the RA and
RV in the posterior AV groove)
■■ Oblique vein (drains from the LA)
Coronary artery blood supply (cont.)
Coronary blood flow ●● Left ventricular blood flow is related to
●● Coronary blood flow (CBF) is about 250 mL/ ■■ difference between aortic end-diastolic
min and represents 5% of the total cardiac pressure and LVEDP
output ■■ duration of diastole and thus the heart rate
● Oxygen diffuses from the ventricular blood to ■■ blood viscosity
the inner 1 mm of the LV. The rest of the LV is ■■ the patency of the coronary arteries,
supplied by the epicardial and subendocar- which is related to
dial vessels ● autoregulation (above a mean arterial
●● During systole, the subendocardial coronary pressure of 60 mmHg)
vessels are compressed (high intraventricu- ● coronary stenosis or spasm
lar pressures) so blood flow in the subendo- ● vasodilators or vasoconstrictors
cardium stops
IVC Systole Diastole
●● Most myocardial perfusion occurs dur-

Aortic pressure
120
ing diastole, and the LV is most at risk from

(mmHg)
ischaemia
●● Myocardial metabolism is proportional to 100
CBF
●● The oxygen extraction of the myocardium 80
is about 70% and thus increased demands

Coronary blood flow

(mL/min–1.100 g–1)
must be met by increased blood flow 200
●● The heart can use a variety of substrates
to depending upon availability: it mainly 100
uses fatty acids (70%) and carbohydrates
(30%), but it can adapt to use lactate, amino
0
acids and ketone bodies 0 0.5 1.0
Time (s)
 Physiology

Heart and Circulation 113

Special circulations
Portal circulation
A portal circulation connects two capillary beds without a direct arterial supply or direct venous
drainage
●● Three portal circulations are of significance
■■ Hepatic portal vein conveys absorbed nutrients from the gut to the liver for storage or utilisa-
tion. Cirrhosis may lead to portal hypertension with distension of lower oesophagus veins form-
ing part of the circulation. These veins are a common source of upper gastrointestinal bleeding
■■ Hypothalamic–pituitary circulation conveys arterial blood from the circle of Willis to a primary
plexus on the hypothalamus and then through further capillaries to the anterior pituitary. This
is the major route for hypothalamic hormones to stimulate further hormone release from the
pituitary gland
■■ Renal circulation

Pulmonary circulation
●● Low pressure, low resistance circulation in series with the right ventricle
●● Receives the whole cardiac output
●● Contains about 10%–20% of the total body volume
●● Pulmonary arteries (left and right) have thin walls and are easily distensible, so only small rises
in pressure occur when pulmonary flow increases. They divide into a capillary network in a similar
manner to the airways
●● Total gas exchange interface is about 70 m2, with a short diffusion distance
Special circulations (cont.)
Pulmonary circulation (cont.)
●● Venous drainage (of oxygenated blood) is through venules that run close to the lung septa and
into the four pulmonary veins into the left atrium
●● The bronchial circulation arises from the aorta and drains into the pulmonary veins. It represents
an anatomical shunt and supplies
■■ the airways to the respiratory bronchioles
■■ local connective tissue
■■ visceral pleura
● Factors that affect the pulmonary circulation include
■■ Autonomic nervous system
● Vasoconstrictor fibres (sympathetic a adrenoceptor)
● Vasodilator (sympathetic b2 adrenoceptor and parasympathetic)
■■ Hypoxic pulmonary vasoconstriction
■■ Other factors that affect pulmonary vascular resistance (see card Pulmonary vascular
resistance)

Other special circulations (see relevant cards)

●● Coronary circulation
●● Cerebral circulation
●● Fetal circulation
 Physiology

Heart and Circulation 114

Pulmonary vascular resistance Lung volume and PVR

●● Pulmonary vascular resistance (PVR) is the resistance in the

­pulmonary circulation and is analogous to SVR
●● Normally 20–120 dyne ⋅ s ⋅ cm −5

PVR
●● Non-linear relationship due to effect of recruitment and distension
of vessels in the pulmonary vascular bed in response to ↑ pulmonary
blood flow
MPAP − LAP Lung volume
●● PVR (dyne ⋅ s ⋅ cm−5 ) = × 80 Residual FRC Total lung
CO volume capacity

Clinical nugget – pulmonary hypertension (PH)

●● MPAP at rest >25 mmHg (with PCWP >12 mmHg)
Classification (World Health Organization)

Pulmonary arterial hypertension (PAH) – ↑ MPAP without ↑ LAP Connective tissue disease
Left–right shunt
Idiopathic
PH with left heart disease Chronic LVF
Chronic mitral valve disease
PH with lung disease COPD
OSA
Chronic high altitude
PH due to thromboembolic disease Obstructed pulmonary artery
Miscellaneous Sarcoidosis
Pulmonary veno-occlusive
disease
Factors that affect pulmonary vascular resistance
System Increase PVR Decrease PVR

Respiratory ●● At less than the functional residual ●● PVR lowest at FRC

capacity (FRC), radial forces acting on
the extra-alveolar vessels are reduced
●● Increased airway pressure at high lung
volumes compresses blood vessels
Cardiovascular ●● Decreased vascular pressure
●● Decreased cardiac output
Haematological ●● Increased haematocrit or blood
viscosity
Metabolic ●● Decreased oxygen (hypoxic pulmo-
nary vasoconstriction)
●● Increased carbon dioxide
●● Acidosis
Hormonal ●● Vasoconstrictor drugs
●● Serotonin (5-HT)
●● Histamine
Autonomic ●● Sympathetic stimulation
nervous system (a adrenoceptors)
●● High vascular pressures recruit closed
vessels and therefore decrease PVR
●● Increased cardiac output
●● Decreased haematocrit or blood
viscosity
●● Increased oxygen
●● Decreased carbon dioxide
●● Vasodilator drugs
●● Acetylcholine
●● Parasympathetic stimulation and
sympathetic (b2 stimulation)
 Physiology

Heart and Circulation 115

Central venous pressure
Central venous pressure (CVP) is the pressure within the right atrium and great veins of the thorax
●● Estimated by the position of the jugular venous pressure (JVP)
●● Measured invasively, with the patient lying flat, using a manometer or transducer at the level of the
right atrium
●● Ranges from 0 to 8 cmH2O but is dependent on hydration status, intermittent positive pressure ven-
tilation (IPPV), position, cardiac function and chamber compliance
●● Serial readings are more important
●● Used to assess
■■ Volaemic status using fluid challenges and to guide fluid replacement
■■ Cardiac function and right ventricular preload

Increases CVP Decreases CVP

●● Increased intrathoracic pressure (e.g. IPPV) ●● Reduced intrathoracic pressure (e.g.

●● Impaired cardiac function (failure, tamponade); inspiration)
only indicates right-sided function ●● Reduced venous return (hypovolaemia
●● Obstruction of superior vena cava and venodilation)
●● Fluid overload
Venous waveform

‘C’-wave
• Transmitted pulsation from
‘A’-wave carotid arteries/bulging of
• Atrial contraction tricuspid valve into RA
• No A-wave – AF
• Enlarged A-wave ‘V’-wave
• Tricuspid stenosis • Venous return and  RAP prior
• Pulmonary HTN to tricuspid valve opening
Enlarged V-wave
10 • Tricuspid regurgitation
Pressure (mmHg)

‘x’ descent
Atrial relaxation ‘y’ descent
Passive atrial emptying
0
Systole Time (s)
Cannon A-wave
• Complete heart
block (mg)
• Junctional
arrythmias (ng)
 Physiology

Renal 116
Structure and function of the kidney
The kidney regulates body fluid and electrolyte composition by filtering plasma and then modifying the filtrate
by reabsorption and secretion
●● The functional unit is the nephron; each kidney contains 1.2 million nephrons
●● The nephron begins at the glomerulus with the invagination of glomerular capillaries into Bowman’s capsule and
continues through the proximal convoluted tubule (PCT), loop of Henle (LOH) and distal convoluted tubule
(DCT), ending at the collecting ducts
●● The glomeruli, PCT and DCT are in the cortex; ∼15%
Afferent
of the loops of Henle and collecting ducts (those of arteriole
the juxtamedullary nephrons) project down into the
medulla and allow the kidney to concentrate urine
Bowman’s
Other functions of the kidney capsule
●● Excretion of waste products of metabolism Glomerulus
■■ Urea (from protein metabolism) Efferent
arteriole
■■ Creatinine (from muscle)
PCT CD
■■ Uric acid (from nucleic acids)
■■ Bilirubin (from haemoglobin) DCT
●● Long-term control of blood volume and arterial
blood pressure
●● Excretion of chemicals including drugs Descending
limb of LOH
●● Production and secretion of hormones
■■ Renin
■■ Erythropoietin
■■ 1,25-dihydroxycholecalciferol (the active form
of vitamin D)
●● Acid–base balance via control of urinary hydrogen
ion and bicarbonate excretion Ascending limb
●● Gluconeogenesis of LOH
Renin–angiotensin–aldosterone system (RAAS)
Hormonal system that helps regulate long-term blood pressure control and blood volume
●● Reduced perfusion (e.g. hypovolaemia) of the renal juxtaglomerular apparatus causes the cells
to release the enzymatic hormone renin. Secretion also increases in cardiac failure, cirrhosis and
renal artery stenosis
●● Renin cleaves angiotensinogen (inactive peptide) to angiotensin I in the kidneys
●● Angiotensin I is cleaved to angiotensin II in the lung capillaries by angiotensin-converting
enzyme (ACE)

Actions of angiotensin II
●● Potent vasoconstrictor (half-life of a few minutes)
●● Vasoconstriction of glomerular arterioles (efferent > afferent); this increases glomerular pressure
and thus glomerular filtration rate (GFR) to maintain blood filtration despite decreased renal
blood flow (RBF)
●● Acts on the adrenal cortex to release aldosterone, which
■■ increases Na+ and H2O reabsorption in the DCT and CD
■■ increases K+ secretion in exchange for Na+
■■ acts on the hypothalamus to increase salt appetite and thirst
●● These actions aim to increase body fluid and restore circulating blood volume

Clinical implications
●● ACE inhibitors and angiotensin receptor antagonists (e.g. losartan) are useful antihypertensives
 Physiology

Renal 117
The glomerulus
The glomerulus is a cluster of capillaries that functions to produce an ultrafiltrate of the plasma
into the Bowman’s capsule of the nephron
●● The ultrafiltrate passes through the endothelial layer of the glomerular capillaries, the glomerular
basement membrane and the fenestrated epithelial cells (podocytes)
●● The basement membrane opposes filtration of negatively charged molecules
●● Molecules with a molecular weight >70 kDa are not filtered

Glomerular filtration rate (GFR)

●● GFR is the volume of plasma filtered by the kidneys per minute
●● Normally 125 mL/min or 180 L/day
●● Measured using inulin clearance (filtered but not secreted, metabolized or reabsorbed)
●● If a solute has a clearance greater than that of inulin, it also must be secreted by the tubule. If the
clearance is less than that of inulin, it is filtered less or reabsorbed
●● Clinically, creatinine clearance is used to estimate GFR. Creatinine is secreted by the kidney, but
its measurement in plasma overestimates levels of creatinine, which tends to cancel out the error.
In practice, average concentrations are calculated over 24 hours
●● Creatinine clearance (CCreat) = UCreatV/PCreat
where UCreat = urinary creatinine concentration, V = urine flow (mL/min) and PCreat = plasma creati-
nine concentration
The glomerulus (cont.)
Glomerular filtration rate (GFR) (cont.) ● leukotrienes
● histamine
●● The rate of filtration at the glomerulus is pro-
● vasopressin
portional to the forces acting to cause filtra-
● noradrenaline
tion minus the forces opposing it:
● angiotensin II contract mesangial cells
GRF = (PG + πB) − (PB + πG) ■■ Increased by
● dopamine
where PG = glomerular capillary hydro-static ● ANP
pressure, π B =  colloid osmotic pressure in ● net filtration pressure through dilata-
Bowman’s capsule, PB = Bowman’s capsule tion of the afferent arteriole and con-
hydrostatic pressure and π G = glomerular striction of efferent
capillary colloid osmotic pressure ●● Permeability of the capillary wall, basement
●● πB is effectively zero. With introduction of a fil- membrane and glomerular epithelium, which
tration coefficient (KF), the formula becomes: is dependent on substance size, protein bind-
ing and charge
GFR = KF(PG − PB − πG)
●● Hydrostatic gradient across capillary walls
Factors affecting GFR because of renal blood flow, capillary vas-
cular tone, ureteric obstruction and renal
●● Alteration of effective glomerular surface area
oedema
■■ Decreased by
● prostaglandins
 Physiology

Renal 118
Renal tubular function
The function of the tubules is to modify the ultrafiltrate by secretion (from the blood into the
tubular fluid) or reabsorption (from the tubule into the blood)

Transport mechanisms
Primary ●● Uses energy in the form of ATP to move molecules across the cell membrane
active ●● Na+K+ATPase is the most important renal primary active transport process
transport ●● Accounts for 99% of Na+ reabsorption and consumes most of the oxygen
used by the kidney
●● Other transport systems include Ca2+ATPase, H+ATPase and H+K+ATPase
Secondary ●● Uses the Na+ concentration gradient to transport other molecules
active ●● Cotransport (symport) moves the solute in the same direction as the Na+
transport ●● Countertransport (antiport) moves the solute in the opposite direction
Facilitated ●● Uniporters are cell membrane proteins that use concentration gradients to
diffusion move single substances across the membrane, for example glucose in the PCT
and urea in the collecting duct
Ion channels ●● Transport of sodium, potassium and chloride through apical channels is much
quicker than through ATPases or transporter molecules
Paracellular ●● Concentration, osmotic and electrical gradients move substances through
movement gaps between nephron cells
Proximal convoluted tubule (PCT)
●● The PCT reabsorbs
Inulin
■■ 60% of the ultrafiltrate
■■ 65% of filtered sodium, water and chloride
■■ 55% of filtered potassium
1.0
■■ 90% of filtered bicarbonate

[Tubular fluid] : [plasma]

■■ 100% of glucose, as long as plasma levels of glucose are Cl
<10 mmol/L
K
■■ 60% of filtered Ca2+ Na
■■ 80%–90% of filtered phosphate via Na+/K+ cotransporter. 1.0
Inhibited by parathyroid hormone
●● 50 g urea is filtered per day, 25–40 g is excreted. Reabsorption
leads to urea circulation between the nephron lumen and renal HCO3
–

medulla, which is important in concentration of urine 1.0

●● Active sodium absorption is by countertransport with H+ Amino acids
Glucose
secretion, which itself leads to reabsorption of chloride and
Proximal tubule length
bicarbonate
−
●● HCO3 moves across the apical cell membrane as CO2, so cellular
carbonic anhydrase is also essential
●● Water follows, which ensures osmolality is unchanged
●● Potassium, chloride and urea follow by passive diffusion because of electrical, concentration and osmotic
gradients
●● Chloride also is reabsorbed in exchange for the organic ions bicarbonate, formate (HCOO−) and oxalate, which
are secreted back into the tubule
●● The Na+/H+ antiport is essential for this process, because the H+ combines with the organic anion before diffusing
back into the cell
●● Other solutes are also transported with sodium via symports or exchanged with sodium via antiports (80% of Na+
is exchanged for H+ secretion into the tubule)
●● The PCT has transporter proteins for organic acids
●● Active and passive secretion also occurs in the proximal tubule of organic acids and bases
 Physiology

Renal 119
Loop of Henle, DCT and collecting duct
The loop of Henle
The loop of Henle functions as a countercurrent multiplier to concentrate urine by producing a
hypertonic interstitial fluid in the renal medulla and a hypotonic tubular fluid
●● Only 15% of the nephrons are juxtamedullary with long enough loops of Henle to contribute to the
production of medullary hypertonicity
●● The descending limb is permeable to water, and to a lesser extent, NaCl
●● The thick ascending limb actively extrudes sodium ions into the tubular lumen using the Na+/K+
ATPase pump
●● The thick and thin ascending segments are impermeable to water
●● Na+/K+/Cl− cotransport occurs so that accumulation of NaCl occurs in the interstitium
●● The net effect is transport of NaCl out of the ascending limb and into the descending limb
●● Gradient produced across the ascending tubular lumen and interstitium is 200 mosmol/kg H2O
●● Countercurrent multiplication results in 1400 mosmol/kg H2O gradient at the tip of the loop
●● At the end of the loop of Henle tubular fluid osmolality is 100 mosmol/kg H2O

Distal convoluted tubule

●● In the first part sodium, potassium and chloride reabsorption occurs
●● More distally potassium diffuses down its concentration gradient into the lumen – rate increased
by the decreased luminal potassium concentration and increased rate of fluid flow
●● Water is not reabsorbed – tubular fluid osmolality falls further
Loop of Henle, DCT and collecting duct (cont.)
The collecting duct
●● Impermeable to sodium, chloride and urea
●● ADH increases water permeability increasing water reabsorption (hypertonic medulla due to
countercurrent mechanism)
●● Reabsorption of sodium together with secretion of hydrogen ions and potassium is stimulated
by aldosterone
Loop of Henle

Collecting
300 100 300 duct
Cortex
Medulla

Ion Increasing
600 active transport osmotic
600 concentration
400

1000 1000
Na+ Cl– 600

1200 Free movement

of ions
Urine
Water movement
 Physiology

Renal 120
Renal glucose handling
●● The amount of glucose filtered is directly proportional to the plasma glucose concentration
●● Reabsorption increases with glucose concentration up to 11 mmol ⋅ L−1. At this point the glucose
transport maximum (Tmax) is reached (approximately 300 mg ⋅ min−1)
●● Actual Tmax varies due to nephron heterogeneity

Filtered
(mg · min–1) 600 Excreted
Glucose

300 Reabsorbed

Tmax

10 20 30 40
Plasma glucose (mmol · L–1)
Sodium and potassium handling by the kidney

Filtered potassium concentration

Filtered sodium concentration

600 100
Low flow
500
400
(mmol · L–1)

(mmol · L–1)
High flow
ADH
300 50

200

100 No ADH

0 0
PCT DL Thin Thick DCT CD PCT DL Thin Thick DCT CD
AL AL AL AL

Loop of Henle Loop of Henle

Tubular segment Tubular segment

(Adapted from P. Hutton, Fundamental Principles and Practice of Anaesthesia,

Martin Dunitz, 2002, pp. 487.)
 Physiology

Renal 121
Renal blood flow (RBF)
●● The renal arteries take 22% of cardiac output: 1.2 L/min Renal
(400 mL/100 g/min) artery
●● Autoregulation occurs if mean arterial pressure (MAP) is
70–170 mmHg even if the kidney is denervated Afferent
arterioles
Tubuloglomerular feedback
The process by which the renal tubules regulate their own blood flow Glomerular
and therefore the GFR capillaries
●● Involves flow-dependent sensing of ion delivery to the tubule via
the macula densa
Efferent
●● The macula densa is at the junction of the thick ascending LOH, arterioles
the first part of the DCT, the efferent and afferent arteriole
●● A higher concentration of sodium in the tubular fluid at this point
indicates a higher GFR Low pressure
peritubular
●● The macula densa alters tone in the adjacent afferent arteriole Vasa
capillaries Portal
(through release of mediators, e.g. ATP and/or adenosine main- recta system
(reabsorb tubular
taining a constant flow in the distal tubule) fluid)

Interlobular
veins
Renal blood flow (RBF) (cont.)
RPF
●● RBF =
(1− Haemtocrit)
RPP
●● RBF = , where RPP is renal perfusion pressure and RVR is renal vascular resistance
RVR

Clearance (Cx)
The volume of plasma that is cleared of a substance per unit time (mL ⋅ min −1)
●● Measured using inulin (freely filtered, not metabolised, secreted or reabsorbed.) Creatinine used as a surrogate
Ux V
●● C X = , where C is clearance, U is urinary concentration, V is urinary flow and P is plasma concentration
P

Renal plasma flow (RPF)

●● Measured using para-aminohippuric acid (PAH) clearance. PAH is completely excreted as long as the tubular
maximum for transport of PAH is not exceeded

Variations in RBF
Decreased Increased

●● Stimulation of SNS (directly and via increased renin and prostaglandin release) ●● Renal prostaglandins
●● Renin/angiotensin system increases angiotensin II causing vasoconstriction ●● Atrial natriuretic peptide (ANP)
and increased aldosterone secretion, which causes fluid retention ●● Dopamine
●● ↑ ADH
●● ↓ intravascular volume (for example, in haemorrhage) – MAP outside
autoregulation limits
●● Drugs (e.g. anaesthetics ↓ CO and ↓ BP)
 Physiology
Assessment of renal function
GFR
●● Gives a rough estimate of the number of functioning
nephrons
●● Can’t be measured directly so creatinine and creati-
nine clearance typically measured
Stages of chronic kidney disease
1. Damage with normal/↑ GFR (≥ 90 mL ⋅ min −1)
2. Damage with mildly ↓ GFR (60–89 mL ⋅ min −1)
3. Moderately ↓ GFR (30–59 mL ⋅ min −1)
4. Severely ↓ GFR (15–29 mL ⋅ min −1)
5. Renal failure (<15 mL ⋅ min −1)
Creatinine
●● Naturally occurring amino acid, predominantly in
skeletal muscle
●● Freely filtered and excreted
●● As plasma creatinine increases, the GFR exponen-
tially decreases
●● Limitations to estimate GFR:
■■ ↓ muscle mass, malnutrition, ↑ age may have nor-
mal creatinine despite renal disease
■■ 15%–20% creatinine is not filtered but secreted
(overestimates GFR)
■■ ↑ creatinine with trimethoprim, cimetidine
●● Creatinine clearance used to estimate GFR
Renal 122
Urea
●● Traditionally measured as an index of renal function
●● Plasma [urea] depends on the rate of formation
(hence nitrogen turnover) and rate of excretion
●● 90% excreted by the kidneys but variable quantity
is reabsorbed so excretion does not accurately
reflect GFR
●● At low urine rates (e.g. dehydration) the reabsorbed
proportion is increased leading to ↑ plasma [urea]
despite normal GFR
●● ↑ urea in:
■■ high protein diet
■■ tissue breakdown
■■ major GI haemorrhage
■■ corticosteroid therapy
●● Urea levels may be expressed as serum urea con-
centration (mmol ⋅ L−1) or just the nitrogen part of the
molecule (blood urea nitrogen [BUN])
●● BUN 10 mg  ⋅ dL−1 is equivalent to serum urea
21.4 mmol ⋅ L−1
Cystatin C
●● Protein secreted by most cells is freely filtered, reab-
sorbed and catabolised by the tubular epithelial
cells with minimal excretion
●● Serum levels are thought to be a more accurate
reflection of renal function than serum creatinine,
being less dependent on age, sex and muscle mass
Micturition
Micturition is a spinal reflex with learned ability
to control bladder emptying involving complex Cerebrum
interactions between the bladder, urethra, ure-
thral sphincter and nervous system
Pons
●● In general urinary storage is a function of the
SNS, whereas micturition is a function of the PNS S
●● The detrusor muscle is the smooth muscle of the P
I T10 (Hypogastric nerve)
bladder N – Detrusor muscle
A
●● Bladder emptying opposed by two sphincters: L L2
■■ Internal sphincter – incomplete ring of +
C
smooth muscle around urethra, under sym- O
R S1
pathetic control D –
Internal
sphincter
■■ External sphincter – complete ring of skeletal S4 (Pelvic nerve)
muscle, external sphincter, under somatic External
sphincter
Urethra
control primarily via the pudendal nerve
●● Storage phase Pudendal nerve
(L4–S4)
■■ At low bladder volumes, afferent firing from
stretch receptors in the bladder is low, increasing as the bladder volume increases which causes
a conscious sensation of urinary urge
■■ Internal sphincter remains tense and the detrusor relaxed
■■ Under sympathetic control via the hypogastric nerve
●● Voiding phase
■■ Parasympathetic stimulation via the pelvic nerve causes the detrusor muscle to contract and
the internal sphincter to relax
■■ The external urethral sphincter is consciously relaxed during micturition
 Physiology

Renal 123
Pathophysiology of acute kidney injury (AKI)
Abrupt loss of kidney function that develops within 7 days, primarily caused by ischaemia, hypoxia or
nephrotoxicity
●● 5% of all hospitalised patients develop AKI
●● Hallmarks include ↓ GFR, ↓ urine output and sudden retention of endogenous and exogenous metabolites

Pre-renal Intra-renal Post-renal

●● ↓ effective RBF and ischaemia
●● ↓ GFR → electrolyte imbalance and
metabolic acidosis
●● Renal hypoperfusion → XS
nitrogenous waste products
●● Tubular reabsorption of Na+ and H2O
Dehydration
Vascular collapse (e.g. sepsis)
↓ Cardiac output
Functional
●● ACE inhibitors
●● NSAIDs
●● Cyclosporins
●● Hepatorenal syndrome
Vascular
●● Atheroembolism
●● Dissecting arterial aneuryms
●● Malignant hypertension
●● Direct damage to epithelial structures by ●● Usually due to bilateral
nephrotoxins/inflammation/ischaemia obstruction of urine
●● Parenchymal injury and azotemia outflow
●● Fluid loss → hypotension → ischaemia →
toxic free radicals → swelling, injury and
necrosis
Specific Bladder outlet obstruction
●● Glomerulonephritis ●● ANS dysfunction
●● Interstitial nephritis ●● Infection
●● Toxins, contrast media ●● Tumours
●● Haemolytic uraemic syndrome ●● Anticholinergic drugs
Non-specific Ureteral obstruction
●● Acute tubular necrosis ●● Emboli
●● Acute cortical necrosis ●● Calculi
●● Trauma
●● Tumour
●● Retroperitoneal fibrosis
Urethral obstruction
●● Prostatic hyperplasia
●● Tumour
●● Strictures
Pathophysiology of acute kidney injury (AKI) (cont.)
Phases of acute kidney injury
●● Oliguric phase
■■ Tubular obstruction results from tubular necrosis
→ cell sloughing, cast formation and oedema
■■ Decrease in GFR and retrograde ↑ pressure → ↑
tubular permeability
■■ Intra-renal release of angiotensin II or redistribu-
tion from the cortex to medulla constricts afferent
arterioles → ↑ glomerular permeability and ↓ GFR
■■ Urine output <30 mL/hr
■■ Conservation of water and sodium
●● Diuretic phase
■■ Urine output >400 mL/24 hr
■■ GFR may be normal / ↑
■■ Excretion of dilute urine → dehydration and elec-
trolyte imbalance
■■ ↑ blood urea nitrogen (BUN) → osmotic diuresis
and further electrolyte imbalance
■■ May last days or weeks
●● Recovery phase
■■ Gradual return to normal/near normal function
■■ May last 3–12 months
Diagnosis
●● Blood
■■ ↑ BUN, ↑ Cr (≥ 26.5 µmol ⋅ L−1 in 48 hr) and ↑ K+
− ■■ Pulmonary oedema
■■ ↓ HCO3 , ↓ Hct, ↓ Hb, ↓ pH
●● Urine
■■ ↓ UO to <0.5 mL ⋅ kg ⋅ hr−! for >6 hr in adults (>8 hr
in children)
■■ Presence of casts and cellular debris
■■ ↓ specific gravity
■■ Urinary Na+ <20 meq/L if pre-renal
■■ Urinary Na+ >40 meq/L if intra-renal
●● ECG
■■ May show signs of hyperkalaemia
●● Urinary tract imaging
Management
●● In pre-renal AKI without fluid overload, give IV fluids.
CVP line monitoring/non-invasive cardiac output
monitoring may be useful to target therapy
●● Vasopressors as appropriate (not low-dose dopamine)
●● Do not routinely use loop diuretics but consider in
fluid overload whilst awaiting renal replacement
therapy (RRT)
●● RRT should be considered in patients not responding
to medical management with:
■■ Hyperkalaemia
■■ Metabolic acidosis
■■ Complications of uraemia (e.g. pericarditis or
encephalopathy)
■■ Fluid overload
 Physiology

Respiration 124
Oxygen dissociation curve
The oxygen dissociation curve describes the percentage oxygen occupancy of haemoglobin
(Hb) and other carrier molecules at different partial pressures of oxygen (PO2)
●● It has a sigmoid shape determined by the cooperativity of the oxygen binding process
●● The upper part of the curve is flat, which means that Hb is 90% saturated, even when arterial PO2
decreases
●● The steep part of the curve allows Hb to unload O2 efficiently at low PO2
●● Normally, Hb gives up less than half its oxygen, and if the PO2 falls further in times of increased
consumption, there is reserve in the system
●● The Bohr effect describes the shift in the position of the oxygen dissociation curve in relation to the
amount of CO2 within the blood. Increasing pCO2 enhances the unloading of O2 from the Hb and
shifts the curve to the right
●● Anaemia decreases the oxygen-carrying capacity of blood without independently altering the
P50 of blood
●● Polycythaemia increases the oxygen-carrying capacity of blood without altering the P50 of blood
●● Carbon monoxide has about 210 times the affinity for oxygen as haemoglobin thus reducing
oxygen-binding capacity
●● Oxidizing agents – certain drugs and chemicals (e.g. nitrates, prilocaine and sulphonamides)
can oxidize the Fe2+ in Hb to Fe3+. The resulting haemoglobin is called methaemoglobin and does
not bind O2, reducing the total oxygen-carrying capacity
Oxygen dissociation curve (cont.)
100 Arterial
Left shift (↑ affinity)
90
Myoglobin • ↓ Temp.
80 • ↓ 2,3 DPG
Mixed venous • ↓ [H+]
Haemoglobin saturation (%)

70
• CO
60 • Methemoglobinemia
• Fetal HB
50 P50
Right shift (↓ affinity)
40
• ↑ Temp.
30
• ↑ 2,3 DPG
20 • ↑ [H+]
• pCO2 (Bohr effect)
10

0
0 2 4 6 8 10 12 14
3.5 5.3 13.3
Oxygen tension (kPa)
 Physiology

Respiration 125
Work of breathing
Inspiration is active, while expiration is pas-
sive. Work is done to overcome 500
■■ Elastic forces of the lung (compliance) A
■■ Airway resistance to gas flow 400

n
Lung volume above FRC (mL)

tio
ira
■■ Tissue resistance (tissue resistive work)

p
Ex
B
●● Increasing flow rates increase the amount of 300
work done to overcome resistance
●● Work of breathing  = Pressure change × 200 C
Tidal volume
n
●● Normal work of breathing uses less than 3% tio
100 ira
of total body oxygen consumption. This may sp
In
increase substantially in patients with chronic
0
obstructive pulmonary disease (COPD) or
cardiac failure, and during exercise
●● Fibrotic lung disease increases the compli-
ance and tissue resistive work –0.5 kPa –1 –1.5
Transpulmonary pressure (kPa)
●● Obstructive airway disease increases airway
resistance work A + B = Inspiratory work to overcome elastic tissue forces
●● Work may be needed for expiration during C = Work to overcome viscous resistance and friction
forced expiration or if airway or tissue resis- B = Work done against resistance in expiration
tance is increased A = Energy lost as heat
●● In asthma or COPD, expiratory work may
exceed inspiratory work
Shunt
The fraction of mixed venous blood bypassing
oxygenation in the lungs. May be:
●● Intrapulmonary (pulmonary perfusion > ven-
tilation), for example atelectasis/pneumonia/
airway obstruction or
●● Anatomical (right to left shunt – a structural
channel bypassing alveoli), for example
Thebesian veins (in health) or congenital
heart disease
●● Normal shunt fraction is 2%–5%
Clinical nugget
●● Hypoxaemia due to shunt responds
poorly to FiO2, as O2 content of pulmonary
end-capillary blood is near maximal due
to the shape of the oxygen dissociation
curve. 100% O2 may improve dissolved
oxygen content
●● Acute respiratory distress syndrome
(ARDS) causes increased intrapulmonary
shunt through severe alveolar oedema.
PEEP may improve oxygenation in ARDS
by splinting open collapsed alveoli and
reducing intrapulmonary shunt
Shunt equation
The shunt equation is used to calculate the
percentage of shunted blood in the lung. It is
an application of the Fick principle
●● It uses a two compartment model where
■■ Ideal – perfect V/Q matching and ideal
gas exchange. Sats assumed to be 100%
■■ Shunt – pulmonary capillaries have no
exposure to the alveoli
●● The total content of oxygen leaving the lungs
is equal to the cardiac output (QT) multiplied
by the arterial oxygen content (CaO2)
●● It is also equal to the shunt flow (Q S) multi-
plied by the mixed venous oxygen content
(CvO2) (assuming no oxygen is taken up or
given to shunted blood by the lungs) plus
flow to ventilated alveoli multiplied by pul-
monary capillary oxygen content (CcO2)
(C c O 2 − C a O 2 )
Q s /Q T =
(C c O 2 − C V O 2 )
 Physiology

Respiration 126
FRC and closing capacity
Functional residual capacity (FRC) is the volume of gas remaining in the lungs at the end of a
normal expiration. It is the balance point between the tendency of the chest wall to spring outwards
and the tendency of the lung to collapse inwards

FRC = RV + ERV and is normally 30 mL/kg in a supine patient

Factors that affect FRC

Increase FRC Decrease FRC

●● Increased height ●● Obesity

●● Change from supine to erect position ●● Change from erect to supine position
●● Decreased elastic recoil (emphysema) ●● Pregnancy
●● PEEP/CPAP ●● Anaesthesia

Measurement of FRC
●● Helium dilution
■■ Breathing a known concentration of helium through a spirometer. CO2 is absorbed by soda lime
■■ At equilibrium:
Total helium = Initial concentration × Apparatus volume
= New concentration × Volume of (apparatus + lungs)
●● Nitrogen washout - (see Dead space and Fowler’s method)
●● Body plethysmography
Functions of FRC
1. Oxygen store
■■ FRC is about 2100 mL, so oxygen store is about 440 mL O2 breathing air
■■ It is the only body store that can be increased significantly and rapidly (e.g. by preoxygenation)
2. Buffers changes in arterial PO2
■■ Prevents large swings in arterial PO2 during the ventilatory cycle
3. Prevents atelectasis
■■ Maintains partial inflation and prevent collapse and impairment of gas exchange
4. Minimises work of breathing – at FRC, the lung is on the steep part of the compliance curve
5. Minimises PVR – minimum at FRC
6. Minimises V/Q mismatch – minimised by the prevention of atelectasis
7. Airways resistance decreases as lung volume decreases (not at minimum at FRC but still low)

Closing capacity (CC)

●● The lung volume at which the airways just begin to close and reflects the smaller, dependent
parts of the lung. It is the sum of the residual volume (RV) and closing volume (CV)
●● Closing capacity and closing volume increase with age (CC = FRC at 44 years in the supine posi-
tion and 66 years in the erect position)
●● Closing capacity is measured using a tracer method
■■ Person fully exhales and then inhales a single breath of oxygen to total lung capacity
■■ Nitrogen is then measured on exhalation (see Dead space and Fowler’s method)
■■ Where the dependent airways close (i.e. the closing volume), there will be an increase in the
nitrogen concentration
 Physiology

Respiration 127
Hyperbaric pressure
●● Pressure increases by one atmosphere for every 10 metres under water
●● From Boyle’s law, when pressure doubles, volume of gas halves
●● Gas is present in the lungs, gastrointestinal tract, sinuses and inner ear

Respiratory ●● Pressure of the inhaled gas must be increased to ambient pressure to overcome the
compressive effect of water on the lungs to maintain normal transthoracic pressure
●● The diver must exhale on ascent, otherwise gas expansion leads to barotrauma
(pneumothorax, mediastinal and tissue emphysema)
●● ↑ gas density leads to ↑ work of breathing and turbulent airflow
Cardiovascular ●● Submersion increases venous return (about 500 mL), which leads to improved
system ventilation–perfusion matching but ↓ secretion of ADH and ↑ secretion of ANP, which
leads to diuresis
●● Diving reflex causes ↓ heart rate and ↑ peripheral vasoconstriction
CNS ●● If Eustachian tubes are blocked, inner ear gas pressure leads to capillary or tympanic
membrane rupture
●● High pressure neurological syndrome occurs at around 200 m characterized by
tremor, nausea, inattention and poor manual dexterity
Syndromes ●● Nitrogen narcosis (below 30 m) characterized by euphoria, poor manual dexterity,
decreased mental function and irrational behaviour
●● Oxygen toxicity is related to PO2, so deeper than 50 m, divers breathe a mixture of
oxygen and helium (less soluble and less dense than nitrogen, so a reduced risk of
decompression sickness)
●● Decompression sickness is characterized by bubbles of nitrogen in tissues, which
cause joint pain, dyspnoea, neurological deficits and avascular necrosis of bone
Hypobaric pressure
1. Low PO2
■■ Atmospheric pressure at 18,000 ft (∼5500
m) is half that at sea level
■■ FiO2 is constant, so PO2 is halved; initially
offset by the sigmoid-shaped oxygen dis-
sociation curve
■■ Hypoxia initially causes hyperventila-
tion and possibly right heart strain from
hypoxic pulmonary vasoconstriction
■■ Later compensatory mechanisms include
●● ↑ erythropoietin and polycythaemia
●● ↑ blood viscosity and right heart strain
●● ↑ 2,3-DPG – shifts the oxygen dissocia-
tion curve to the right
●● Proliferation of peripheral capillaries
to facilitate perfusion
●● Renal excretion of HCO−3 to reduce
alkalosis from hyperventilation
2. High altitudes are cold (–20°C) at 18,000 ft
3. Expansion of gas-containing cavities (e.g.
inner ear and pneumothoraces)
4. Decompression sickness
5. Anaesthetic apparatus
■■ Vaporizers
●● SVP is unaffected by atmospheric
pressure, so the partial pressure of the
volatile agent delivered is the same;
delivered concentration increases
●● Action depends on alveolar partial
pressure not concentration, so the
same settings may be used
●● Cold temperatures will affect SVP
■■ Flow meters
●● Atmospheric pressure is reduced,
so a gas has reduced density and
greater volume
●● Flow meters under-read at high alti-
tude, but this does not affect their use,
as the clinical effects depend on the
number of molecules of gas not the
volume
 Physiology

Carbon dioxide stores and transport
●● Body stores of CO2 may be up to 120 L
●● PaCO2 increases by 1 kPa during the first min-
ute of apnoea and then by 0.4 kPa for each
subsequent minute
●● CO2 is 20× more soluble in blood than O2
Carbon dioxide is carried in the blood in three
forms
1. As bicarbonate in red blood cells
■■ Carbonic anhydrase rapidly converts CO2
to carbonic acid, which then dissociates
to hydrogen and bicarbonate
carbonic
anhydrase
CO2 + H2 O ← → H2 CO3 ↔ HCO−3 + H+
Respiration 128
■■ The hydrogen ions are buffered mainly by
the imidazole groups on the histidine resi-
dues of haemoglobin, but also to a small
extent by plasma proteins
■■ The bicarbonate ions are exchanged for
chloride ions and pass into the plasma
(chloride shift). The osmotic effect of the
chloride shift in venous blood is to slightly
increase the haematocrit in comparison
to arterial blood
2. Dissolved as carbonic acid in plasma
3. As carbamino compounds
■■ CO2 binds the amine groups of plasma
proteins to form carbamino compounds

Arterial blood
Carbon dioxide (% of total) Venous blood

Total CO2 (mL/100 mL) 50 54

As bicarbonate (mL) 45 (90) 47.5
In solution (mL) 2.5 (5) 3.0
As carbamino compounds (mL) 2.5 (5) 3.5
Carbon dioxide stores and transport (cont.)
●● The arteriovenous PCO2 difference is about 0.7 kPa/6 mmHg
●● This equates to 4 mL/100 mL blood depending on the respiratory quotient (RQ):

CO2 produced at equilibrium (steady state)

RQ =
O2 consumed

●● Of the CO2 added in systemic capillaries, 60% is added as HCO−3 , 30% as carbamino compounds
and 10% as dissolved CO2

Carbon dioxide dissociation curve

●● The carbon dioxide curve plots the CO2 content
54
of the blood against the PCO2

(mL/100 mL blood)
●● The Haldane effect is the increased ability of Sats 75%
(mixed venous)

CO2 content
the blood to carry CO2 when haemoglobin gives 52
Sats 97%
up its O2 (deoxyhaemoglobin is three times more
(arterial)
effective at forming carbamino compounds 50
PCO2 of 46 mmHg
than oxyhaemoglobin)
48

35 40 45 50 PCO2 (mmHg)
5.3 6.1 (kPa)
 Physiology

Respiration 129
Oxygen stores and transport
●● Total body oxygen stores are about 1.5 L
■■ 50% carried by haemoglobin
■■ 30% in lungs
■■ 20% in myoglobin
●● Oxygen is carried in two forms in the blood:
1. Dissolved in plasma
2. Bound to haemoglobin in red blood cells
●● Haemoglobin contains two alpha and two beta polypeptide chains, each of which con-
tain a haem group (a porphyrin ring with a Fe2+ atom that can reversibly bind one molecule
of O2)
●● The binding of one molecule of O2 increases the affinity of the other haem groups for O2 –
that is, it shows cooperativity
●● In a normal person breathing air:
■■ Arterial blood contains about 20 mL O2 per 100 mL blood
■■ Venous blood contains about 15 mL per 100 mL blood

Amount of oxygen Arterial blood Venous blood

Combined with Hb (mL/100 mL) 19.7 14.9

Dissolved in plasma (mL/100 mL) 0.3 0.1
Oxygen stores and transport (cont.)
Oxygen partial ●● Partial pressure of oxygen is proportional to the amount of O2 dissolved in
pressure blood (kPa/mmHg)
Oxygen content ●● Total amount of oxygen in a decilitre of blood and includes both dissolved and
haemoglobin-bound oxygen (mL/dL)
(1.34 × Hb × Sats)
●● Oxygen content = + 0.02 PO2
100
where 1.34 = the Hufner constant (the oxygen content of 1g of fully saturated
Hb), 0.02 = the solubility coefficient of O2 in blood at 37°C, which is used to
show the O2 carried in solution in mL/dL/kPa (= 0.003 mL/dL/mmHg)
Oxygen ●● Percentage saturation of haemoglobin with oxygen
saturation O2 content of Hb × 100
●● Oxygen saturation =
O2 capacity of Hb

Oxygen flux ●● Oxygen flux = Cardiac output (CO) × Arterial oxygen content

Oxygen delivery ●● Calculated oxygen flux
(DO2) ●● Amount of oxygen delivered to the peripheral tissue
●● About 1005 mL/min
Oxygen ●● VO2 = CO × (Arterial O2 content − Mixed venous O2 content)
consumption = 240 − 270 mL/min
(VO2)
 Physiology

Respiration 130
Control of breathing
Receptors
Central ●● Anterolateral surface of the medulla
chemoreceptors ●● Responsive to H+ concentration in cerebrospinal fluid (CSF) and thus
indirectly to CO2 via carbonic anhydrase
●● Respiratory acidosis generates a greater increase in ventilation than
metabolic acidosis as the blood–brain barrier is permeable to CO2 but
not H+ ions
●● CSF has less buffering ability (less protein), so pH changes are more
pronounced in the CSF than in the plasma
Peripheral ●● 6 mm3 in the carotid bodies (at carotid bifurcation) and the aortic bodies
chemoreceptors (aortic arch)
●● Sensitive to H+ (linear response) and PaO2 (non-linear response – fire
below 13 kPa) but relatively indifferent to PaCO2
●● Response time is 1–3 s
●● Receive 2 L/100 g tissue/minute, so have a low arteriovenous O2 difference
despite a high metabolic rate; this increases precision
●● Carotid body afferents via glossopharyngeal nerve
●● Aortic body afferents via the vagus
Receptors in the ●● Laryngeal epithelial receptors respond to irritants
lungs ●● Airway stretch receptors terminate respiration via the Hering-Breuer reflex
●● J receptors (juxtacapillary) inhibit respiration in response to capillary
engorgement (pulmonary oedema)
Control of breathing (cont.)
Controllers
●● These are influenced by the cortex and limbic system (e.g. anger/fear)
●● Inspiration is active and expiration is passive (except during exercise)
Medullary centre ●● Dorsal respiratory group (inspiratory centre) responsible for diaphrag-
matic contraction and the intrinsic pattern of breathing
●● Ventral respiratory group (expiratory centre) cause contraction of
accessory and intercostal muscles
Apneustic centre (lower ●● Causes excitation of medullary inspiratory neurones
pons) ●● Section above it causes prolonged inspiratory gasps
Pneumotaxic centre ●● ‘Fine tunes’ respiration to regulate respiratory rate
(nucleus parabrachialis)

Effectors
Diaphragm ●● Movement accounts for 75% of the intrathoracic volume change in
quiet inspiration (movement of 1.5–7 cm in deep inspiration)
●● Innervated by the phrenic nerve (C3, 4, 5)
●● Effects inspiration
Intercostals ●● External intercostals (inspiration)
●● Internal intercostals (expiration)
Accessory muscles ●● Used in respiratory distress or exercise
●● Include sternocleidomastoid, platysma, strap muscles of the neck
 Physiology

Respiration 131
Ventilation–perfusion relationships in the lungs
●● Both ventilation (V) and perfusion (Q) are greater in the lung bases (in the erect position)
●● Perfusion is relatively better than ventilation in the bases
●● Ventilation is more uniformly distributed than perfusion and therefore ventilation is relatively better
in the apices
●● Dependent regions of the lungs have better V/Q relationships
●● The diameter of blood vessels running through the lung parenchyma (extra-alveolar vessels) is
affected via lung volume while alveolar vessels’ diameters depends on the difference between
arterial (Pa), venous (P v) and alveolar pressures (PA) and thus on gravity

L/min of lung volume

V/Q

V
Q

Base Lungs Apex

West’s zones
West described an uneven distribution of blood flow through the lungs demonstrating 3 clear zones:
PA > Pa > Pv (collapse)

Hypovolaemia/IPPV
(but not normally in health) I I

Distance through lung

Pa > PA > Pv (Waterfall)

Blood flow determined by Pa/PA II

II
difference (Pv low)

Pa > Pv > PA (Distention) III III

Constant blood flow-most

normal healthy lung comprises
Blood flow
this zone
PA = Alveolar pressure Pa = Arterial pressure Pv = Venous pressure
 Physiology

Respiration 132
Dead space
Dead space Volume of inspired air that takes no part in gas exchange
Anatomical dead space Volume of the conducting airways (2 mL/kg)
Alveolar dead space Volume of alveoli ventilated but not perfused
Physiological dead space (VD) VD = anatomical dead space + alveolar dead space

Fowler’s method to measure anatomical dead space

●● The anatomical dead space can be determined by observing the change in nitrogen concen-
tration (using a rapid nitrogen analyser) against time (seconds) following a single vital capacity
breath of 100% oxygen with the person wearing a nose clip
●● Nitrogen concentration is measured
and increases from zero (at the start of 1 Air from the conducting airways
1 2 3 4 (pure O2, no N2)
expiration) to a plateau (where almost
2 Mixture of dead space and
pure alveolar gas is being expired)
N 2 concentration (%)
alveolar gas
●● If a vertical line is drawn, such that B 3 Alveolar gas – inspired O2 diluted
areas A and B are equal in the follow- by alveolar N2
ing diagram (after West), then the ana- 4 Occurs at closing volume; when the
vd
tomical dead space is the volume lower alveoli collapse, N2 is released
from the upper airways, giving an upstroke
A
vd Volume (L)

Closing Residual
volume volume
Dead space (cont.)
Bohr’s method to measure ●● VA = V T − VD, so
­physiological dead space FECO2 × V T = FACO2 × (V T − VD)
●● Expired CO2 = Inspired CO2 + CO2 produced ●● Partial pressure is proportional to concentra-
by the lungs tion, thus:
●● Inspired CO2 is negligible, so: VD P CO2 − PE CO2
= A
VT PA CO2
FECO2 × V T = FACO2 × VA
●● Tidal volume and the expired concentration
where FECO2 = fractional concentration CO2 of CO2 can be measured
in expired gas, V T = tidal volume, FACO2­ = ●● Alveolar PCO2 (PACO2) approximates arterial
fractional concentration CO2 in alveolar gas, PCO2 (PaCO2) and, in most cases, the two can
and VA = alveolar part of tidal volume be substituted

Factors that increase and decrease dead space

Increases dead space Decreases dead space
●● Dilation (bronchodilation) or increased volumes ●● Intubation or tracheostomy
●● Emboli (pulmonary embolism or air) ●● Supine position
●● Anaesthesia or apparatus ●● Decreased ventilation
●● Drugs (atropine or hyoscine)
●● Shock (haemorrhage, hypovolaemia or hypotension)
●● Pregnancy
●● Age (increasing)
●● Chronic lung disease (e.g. fibrosis)
●● Extension of the neck
 Physiology

Respiration 133
Lung volumes and capacities
●● Measured using spirometry
●● A capacity is two or more volumes
●● All volumes and capacities not including or involving residual volume (RV) can be measured by
spirometry
●● Residual volume is measured with helium dilution or body plethysmography techniques

Tidal volume (TV) ●● Volume of air moved in and out of the respiratory tract (breathed) during
each ventilatory cycle
Inspiratory reserve ●● Additional volume of air that can be forcibly inhaled after a normal inspiration
volume (IRV)
Expiratory reserve ●● Additional volume of air that can be forcibly exhaled after a normal expiration
volume (ERV)
Vital capacity ●● Maximal volume of air that can be forcibly exhaled after a maximal inspiration
(VC) ●● VC = TV + IRV + ERV
Residual volume ●● Volume of air remaining in the lungs after a maximal expiration
(RV) ●● RV = FRC − ERV
Functional residual ●● Volume of air remaining in the lungs at the end of a normal expiration
capacity (FRC) ●● FRC = RV + ERV (see FRC and closing capacity)
Total lung ●● Volume of air in the lungs at the end of a maximal inspiration
capacity (TLC) ●● TLC = FRC + TV + IRV
= VC + RV
Minute volume ●● Volume of air exhaled per minute
Lung volumes and capacities (cont.)

Max. inspiration
6.0

5.0 Inspiratory Inspiratory

reserve capacity
Vital
volume 2.5 L
capacity 3.0 L Total lung
4.0
Lung volume (L)

4.5 L capacity 6.0 L

Tidal volume 0.5 L
3.0
Expiratory reserve Functional
volume 1.5 L residual
2.0
capacity 3.0 L
Max.
1.0 Residual expiration
volume 1.5 L
0
Time (s)
Note that these are functional not anatomical values
 Physiology

Respiratory failure
●● Respiratory failure occurs when pulmonary
gas exchange is impaired enough to cause
hypoxaemia with or without hypercarbia
Respiration 134
●● It is defined as an arterial PO2 at sea level
breathing air and at rest below 8 kPa with-
out intracardiac shunting

Type I respiratory failure Type II respiratory failure

●● PaO2 <8 kPa with a normal or low PaCO2 (often low
because of hypoxia and subsequent hyperventilation)
●● Usually due to V/Q mismatch or right-to-left shunt
●● Causes:
■■ Chest infection or aspiration pneumonitis
■■ Pulmonary oedema
■■ ARDS
●● 100% O2 improves V/Q mismatch but not shunt
●● PaO2 low with PaCO2 high (>7 kPa)
●● Causes for hypoventilation:
■■ COPD
■■ Chest wall deformities
■■ Respiratory muscle weakness
(e.g. Guillain-Barré)
■■ Respiratory centre depression

Signs of hypoxaemia Signs of hypercapnia

●● Cyanosis ●● Increased respiratory rate (up to 12 kPa) and

●● Hyperventilation and use of accessory then decreased respiratory rate
respiratory muscles ●● Vasodilatation
●● Myocardial arrhythmias ●● Increased sympathetic activity (tachycardia,
●● Tachycardia hypertension)
●● Hypertension ●● Increased intracranial pressure
●● Confusion, drowsiness or agitation ●● CO2 flap
Treatment of respiratory failure
1. Sit up (increased FRC) ■■ Improve oxygenation
2. Oxygen therapy (caution in type II respira- ■■ Reduce airways resistance
tory failure because of loss of respiratory ■■ Alter relative compliance of upper and
drive from chronic hypercapnia) lower parts of lungs
3. Non-invasive ventilation (e.g. CPAP)
4. Invasive ventilation (e.g. intermittent posi- Cardiac
tive pressure ventilation [IPPV]) if patient is ●● ↑ Intrathoracic pressure → ↓ venous return,
exhausted and PaCO2 is increasing ↓ cardiac output, ↑ ADH, ↓ ANP release
5. Drugs ●● ↓ LVEDV, ↓ SV

■■ Doxapram (central respiratory stimulant) Renal

■■ Aminophylline (decreases respiratory ●● ↓ Cardiac output → ↓ Renal perfusion (con-
muscle fatigue [used in neonates]) cerns if comorbidities)
■■ Carbonic anhydrase inhibitors (may increase
respiratory drive in patients with COPD) Liver
6. Treat the cause ●● ↓ Cardiac output → ↓ Hepatic perfusion and
↑ hepatic venous congestion → ↓ portal vein
Systemic Effects of IPPV blood flow
Respiratory
Cerebrovascular
●● Reduces pulmonary shunt
●● ↑ intrathoracic pressure and ↓ venous return +
●● ↑ intrapleural pressure according to transmu-
↓ cardiac output → ↓ cerebral perfusion (nor-
ral pressure gradient
mally compensated for by autoregulation)
●● Dead space with prolonged use
●● Use PEEP cautiously if suspicion of cerebral
●● PEEP may
pathology
■■ FRC may exceed CC in those with high
closing volumes
 Physiology

Respiration 135
Oxygen cascade and alveolar gas equation
The oxygen cascade is the stepwise decrease in PO2 as the oxygen moves from inspired gas to con-
sumption in the mitochondria

Dry inspired air

20 21 kPa Inspired gas (saturated at 37 °C)
19.8 kPa Determined by Alveolar PO2 is calculated by the
Gas exchange alveolar gas equation:
in alveoli
15 Humidification PACO2
Alveolar gas Alveolar PO2 FiO2 (PB PAH2O)
Arterial blood R
14 kPa
PO2 (kPa)

13.3 kPa
Diffusion to cells PB Ambient barometric pressure (normally 101.3 kPa)
10 Venous
PAH2O Alveolar partial pressure of H2O (normally 6.3 kPa)
admixture
Capillary blood PACO2 Alveolar PCO2 (approximates arterial PCO2)
(shunt V/Q
mismatch) 6–7 kPa Consumption in cells R Respiratory exchange ratio (normally 0.8)
5
Mitochondria
1–5 kPa

Atmosphere Mitochondria

Pasteur point = 0.15–0.3 kPa

= Critical PO2 for oxidative phosphorylation in the mitochondria
2,3-Diphosphoglycerate and myoglobin
2,3-Diphosphoglycerate (2,3-DPG)
2,3-Diphosphoglycerate (2,3-DPG) is a gly-
colytic intermediate that accumulates to
uniquely high levels in red blood cells
●● It stabilizes the ‘tense’ (deoxygenated) form
of Hb by binding strongly to the b-polypep-
tide chains and reduces the affinity of Hb for
oxygen in hypoxic states, increasing oxygen
delivery
●● Increased levels increase P50; decreased lev-
els decrease P50
●● Increased levels may be seen in
■■ high altitudes
■■ chronic lung disease, emphysema
■■ anaemia
■■ hyperthyroidism
■■ right-to-left cardiac shunt
■■ congenital heart disease
■■ pulmonary vascular disease
Myoglobin
Myoglobin is a single polypeptide chain that
consists of one haem group and therefore
binds one molecule of oxygen per molecule
of myoglobin
●● It is a protein found in red muscle (skeletal
and cardiac)
●● Cells without myoglobin have O2 stores limited
by the solubility of O2
●● The myoglobin dissociation curve is not sig-
moid shaped and is shifted to the left of the
oxygen dissociation curve for haemoglobin.
At venous PO2, myoglobin is almost fully satu-
rated. The myoglobin will only unload its O2
when the PO2 is very low, such as during vigor-
ous exercise
●● Myoglobin’s functions are to
■■ buffer changes in tissue PO2 during
changes in cellular metabolism
■■ facilitate diffusion of O2 through the
cytoplasm into the mitochondria where it
is used
 Physiology

Respiration 136
Airways resistance and compliance
Airways resistance (AWR) describes the obstruction to airflow by the conducting airways (larger
airways) plus tissue resistance produced by friction as tissues of the lung slide over each other
during respiration
Driving pressure (body plethysmograph)
●● AWR =
Gas flow (pneumotachograph)
●● Increased by  ■ bronchoconstriction  ■ increased viscosity of gas forced expiration caus-
ing airway closure and air trapping  ■ low lung volumes (reduces radial forces holding alveoli
open)  ■  anaesthesia (tubing and connections of circuit)

Compliance is defined as the lung volume change per unit pressure change and is a measure
of distensibility (stretchiness)
●● Normal values are 1.5–2.0 L/Pa (200 mL/cmH2O)
●● It may be static (i.e. measured at zero flow) or dynamic (measured over a total tidal volume)
●● Total compliance is related to chest wall and lung compliance, thus:
1 1 1
= +
Total compliance Chest wall compliance Lung compliance
Compliance
Specific compliance =
Functional residual capacity

Decreases compliance Increases compliance

●● Restrictive lung disease (e.g. pulmonary fibrosis) ●● Old or young age

●● Pulmonary oedema ●● Emphysema
●● At extremes of lung volumes ●● Saline-filled lungs
Compliance curve
A pressure–volume curve of lung inflation and deflation shows hysteresis, which is thought to rep-
resent the effects of surface tension in the lungs. Compliance is the slope of the hysteresis curve
At FRC (healthy person)
the apices are well
inflated and less
TLC ventilated than
Apex
Lung volume (L)

Midzone The midzones and

FRC bases (on the
Base steeper, more
RV compliant part of
the curve)

0 –1 –2 –3
Pressure (kPa)

Intrapleural pressure
●● The pressure within the pleural cavity
●● Measured indirectly using a balloon in the lower third of the oesophagus
●● Lungs tend to collapse inwards and chest wall tends to spring outwards, so intrapleural pressure is
normally negative (–10 cmH2O at the apices and –2.5 cmH2O at the bases)
●● Becomes increasingly more negative in inspiration and less negative in expiration
●● In IPPV, it may exceed zero during inspiration and is also increased by CPAP and PEEP
 Physiology

Respiration 137
Flow-volume loops of the lungs
PEFR↓
Concave expiratory limb
Normal Obstructive disease ↑RV (premature airway
8 8 (Asthma, emphysema) closure)
Expiration TLC supranormal
4 4 (Hyperinflation + ↓Elastic
(L · sec–1)

recoil)

(L · sec–1)
TLC
Flow

RV

Flow
0 0
Volume in Volume in lungs (L)
–4 lungs (L) –4

–8 Inspiration –8

8 8

(L · sec–1)
4 4
(L · sec–1)

Flow
Flow

0 0
Volume in Volume in lungs (L)
–4 –4
lungs (L)
–8 –8

Restrictive disease (interstitial lung disease) Fixed large airway obstruction (e.g. tracheal mass, goitre)
Narrow loop (↓TLC + ↓RV) Constant flow reduction throughout
Airflow supranormal inspiration/expiration (dependent
(↑Elastic recoil) on orifice diameter)
TLC/RV generally unaffected
Non-respiratory functions of the lungs
Pulmonary circulation ●● Movement of blood to and from the blood gas barrier for gas exchange
●● Reservoir for blood in haemorrhage (450 mL)
●● Filters blood (thrombi or white blood cells)
Metabolic functions ●● Metabolism of vasoactive substances
■■ Peptides (e.g. angiotensin I [activated] → angiotensin II, bradykinin
[inactivated])
■■ Amines (e.g. serotonin, noradrenaline)
●● Synthesis of
■■ Glycolipids (surfactant)
■■ Proteins (collagen and elastin)
●● Catabolic functions
■■ Removal of proteases (e.g. alpha-1-antitrypsin)
●● Carbohydrate metabolism
Immune functions ●● Mucociliary clearance (pulmonary macrophages)
●● Secretion of immunoglobulin A
Heat regulation ●● Mainly upper respiratory tract
Acid–base balance ●● Via excretion of carbon dioxide and thus indirectly altering H+
concentration via the Henderson-Hasselbalch equation
 Physiology

Liver, GI and Metabolism 138

The liver
●● Largest gland of body, weighing 1200–1600 g ●● Venous drainage via central veins to hepatic
●● Wedge shaped and covered by network of veins and into IVC
connective tissue (Glisson’s capsule) ●● Bile canaliculi form networks between the
●● Divided by fissures into four lobes: the right hepatocytes towards the biliary tract
(largest lobe), left, quadrate and caudate
Hepatic artery
lobes in
●● Connected to diaphragm and abdominal Portal ve
walls by five ligaments: the membranous
falciform (also separates the right and left
lobes), coronary, right and left triangular Bile
duct
ligaments, and the fibrous round ligament
(derived from the embryonic umbilical vein)
●● Hepatic blood flow is 1800 mL/min (25%–30% Bile
flow Cords of hepatocytes
of CO) separated by
●● Dual blood supply Central vascular sinusoids
■■ Hepatic artery – 30% vein
Blood flow (mixed
■■ Hepatic portal vein – 70% portal and arterial
●● Blood flows to the central veins via the sinu- blood)
soids (lined by endothelial and phagocytic
cells), separated by hepatocytes
Functions of the liver
Bilirubin metabolism ●● Unconjugated bilirubin bound to albumin is conjugated with glucuronide
to water-soluble form in liver
Formation of bile ●● Secreted in bile and reabsorbed via enterohepatic circulation
acids from
cholesterol
Detoxification ●● Hormone metabolism and inactivation (steroids, aldosterone, vasopressin
and thyroxine)
●● Drug metabolism
Haematological ●● Site of haemopoiesis in fetal/early neonatal life
roles ●● Blood reservoir
●● Kupffer cells phagocytose antigens, bacteria and old red blood cells
Protein synthesis ●● Albumin (200 mg/kg/day – 4% of the total body pool); poor marker for
acute injury as half-life around 20 days
●● Globulins (e.g. haptoglobulin, ferritin) – lipoproteins and glycoproteins with
transport functions
●● Clotting factors
Protein catabolism ●● Amino acid deamination before interconversion and oxidation
●● Ammonia produced by deamination converted to urea via ornithine cycle
Carbohydrate ●● Glycogenesis and glycogenolysis
metabolism ●● Gluconeogenesis
Lipid metabolism ●● Synthesis – fatty acids and lipoproteins for export, endogenous cholesterol
and prostaglandins
●● Catabolism – breakdown of dietary triglycerides and fatty acids
Vitamin storage A, D, K, B12 and folate
 Physiology

Liver, GI and Metabolism 139

The pancreas
The pancreas produces enzymes that break down all categories of digestible foods (exocrine
pancreas – 80% volume) and secretes hormones that affect carbohydrate metabolism (endo-
crine pancreas – 2% volume)

Exocrine functions – produce:

●● Proteases – trypsin and chymotrypsin (as inactive proenzymes which are converted to active forms by
enterokinases in the small intestinal lumen)
●● Pancreatic lipase – converts triglyceride to monoglycerides and free fatty acids
●● Amylase – hydrolyses starch to maltose
●● Other digestive enzymes – ribonucleases, deoxyribonucleases, gelatinase and elastase
●● Bicarbonate secretion (similar secretion method to gastric parietal cells)

Endocrine functions – produce insulin, glucagon and somatostatin

Insulin
●● Major anabolic hormone that is crucial to prevent catabolism
●● Contains 51 amino acids in two polypeptide chains linked by disulphide bridges
●● Synthesized from proinsulin by b cells of the Islets of Langerhans
●● Acts on cell membrane receptors to result in autophosphorylation and activation of tyrosine
kinase residues on the intracellular part of the receptor and subsequent activation of protein
kinases
●● Insulin secretion is stimulated by increased levels of glucose and amino acids, b agonists, acetyl-
choline and glucagon
●● Insulin secretion is inhibited by decreased levels of glucose, b blockers, a agonists, diazoxide, thiazide
diuretics and somatostatin
The pancreas (cont.)
Glucagon
●● Catabolic hormone produced by α-cells of the Islets of Langerhans
●● Peptide hormone containing 29 amino acids
●● Acts via cyclic AMP as a second messenger
●● Glucagon secretion is stimulated by ↓ glucose, ↑ amino acids, β-agonists, acetylcholine, cortisol,
trauma and sepsis
●● Glucagon secretion is inhibited by ↑ levels of glucose, ↓ amino acids, ↑ free fatty acids, insulin,
somatostatin and α-agonists

Insulin effects Glucagon effects

●● ↑ Glucose uptake from blood into cells
(particularly adipose tissue, skeletal muscle
and liver)
●● ↑ Glycogenesis
●● ↑ Hepatic synthesis of amino acids and
uptake into cells
●● ↓ Breakdown of adipose tissue
●● ↑ Gluconeogenesis and ↑ glycogenolysis
●● ↑ β oxidation of fatty acids to form ketone
bodies
●● ↑ Lipolysis
●● ↑ Catecholamine production
●● Direct positive inotrope

Somatostatin (growth hormone-inhibiting hormone)

●● Secreted by pancreatic δ-cells and hypothalamus
●● Neurotransmitter (found particularly in the substantia gelatinosa – thought to be involved in pain
transmission)
●● Inhibits insulin and glucagon release
●● Inhibits gastric acid production and contraction of gallbladder
 Physiology

Liver, GI and Metabolism 140

Gastric secretion
Oxyntic glands ●  chief cells – secrete pepsinogen (precursor of pepsin) in response to
(fundus and body of neural stimulation and production of gastric acid  ●  mucous cells – secrete
stomach) mucous to protect mucosa  ●  parietal cells – secrete hydrochloric acid and
intrinsic factor
Pyloric glands ●  mucous cells  ●  g-cells – produce gastrin, which travels via bloodstream to
(antrum only) oxyntic glands to stimulate acid production

Regulation of gastric secretion

●● Gastric secretion is increased by acetylcholine (via vagal stimulation), gastrin, histamine (via H2
receptors on parietal cells), amino acids, alcohol and caffeine
●● Gastric secretion inhibited by prostaglandins (produced by intestinal mucosa), enterogastric reflex
and hormones, e.g. secretin in response to distension, osmolality and pH of fluid, proteins, fats or
duodenal irritation

Phases of gastric secretion

Cephalic phase ●● Thought, sight, smell or taste of food stimulates stomach via vagus nerve
Gastric phase ●● Food entering stomach elicits long vasovagal reflexes, local enteric reflexes
and release of gastrin
Intestinal phase ●● Food and chyme entering proximal small intestine stimulates modest gastric
secretion via duodenal gastrin release, absorbed amino acids and other
hormones
Gastric secretion (cont.)
Control of gastric secretion Production of gastric acid
Parasympathetic stimulation Parietal cell
G-cells ECF Gastric lumen

ACH
Cl
Gastrin H2CO3

HCO3 HCO3 H
Paracrine Gastrin Alkaline tide K K
cells receptor CO2 H2O
Muscarinic PGE H ATPase
2
receptor
OH H H
Gi
Histamine
Parietal cell
H2R
Gi Inhibitory G-protein Gs
Gs Stimulatory G-protein via
↑ CAMP ↑ Acidity
H2R Histamine receptor
 Physiology

Liver, GI and Metabolism 141

Gut motility – functional anatomy
●● The gastrointestinal tract (GIT) has five layers –
serosa, longitudinal muscle, circular muscle, submu-
cosa and mucosa
●● Two movements – peristaltic (propulsive) and local
constrictive (mixing)
●● Bundles of smooth muscle fibres joined at multiple
points allow propagation of action potentials along
gut
●● Two types of electrical activity:
■■ slow waves of fluctuating transmembrane poten-
tial between −40 and −70 mV 3–12 times per min-
ute modify spike potentials
■ spike potentials occur when resting membrane
potential (RMP) is more positive than –40 mV and
causes contraction (RMP modified by hormones,
catecholamines and autonomic nervous system
[ANS])
●● The intensity of contraction is determined by the fre-
quency of spike potentials
●● Movements and secretions are controlled by enteric
nervous system, which comprises two plexuses influ-
enced by ANS
■■ myenteric (Auerbach’s) plexus between longitu-
dinal and circular muscle layers
■■ submuscosal (Meissner’s) plexus
●● Autonomic nervous system
■■ craniosacral parasympathetic outflow (via
vagus to proximal GIT and sacral fibres to distal
GIT) increases motility
■■ sympathetic supply (T5–L1) stimulates sphinc-
ter contraction and relaxes non-sphincteric
muscle

Swallowing
●● There are three phases in which 26 muscles are coordinated

Oral preparatory (voluntary) ●● Food bolus formed

Pharyngeal (involuntary) ●● Soft palate rises against posterior pharyngeal wall

■ Pharyngeal constrictors propel bolus to cricopharyngeal sphincter
■ Larynx raises (closes glottis) and epiglottis covers

Oesophageal (involuntary) ●● Upper oesophageal sphincter relaxes

●● Peristalsis propels bolus to stomach
Gut motility – functional anatomy (cont.)
Stomach
●● Stores up to 1.5 litres
●● Mixes food with gastric secretions – slow
waves in stomach wall spread towards
antrum; constriction of pyloric sphincter
encourages further mixing
●● Emptying – more intense contractions pro-
mote antral emptying; rate of fluid empty-
ing influenced strongly by duodenal factors
(pH/osmolality of duodenal juices, proteins,
duodenal distension and hormones, e.g.
cholecystokinin)
Small intestine
●● Mixing contractions – presence of chyme
encourages alternating contraction and
relaxation
●● Propulsive movements – peristalsis slows
from proximal to distal intestine; mean tran-
sit time is 3–5 hours; increased by chyme
in duodenum, gastroenteric reflex and hor-
mones (e.g. cholecystokinin and gastrin);
decreased by secretin and glucagon; fasting
initiates peristaltic wave (migrating motor
complex) to prevent accumulation of secre-
tions; ileocaecal valve slows flow from ileum to
caecum and prevents backflow
Colon
●● Slow proximal movements promote reabsorp-
tion of fluid and electrolytes
●● Gastrocolic and duodenocolic reflexes after
meals cause distal ‘mass movements’ that
promote movement of faeces to rectum
Defecation
●● Two anal sphincters
■ internal – circular, involuntary smooth
muscle
■■ external – striated, voluntary muscle;
continually contracted unless consciously
inhibited
●● Myenteric plexus mediates relaxation of inter-
nal sphincter; reflex reinforced by PNS
●● Defaecation can be inhibited by conscious
control
 Physiology

Liver, GI and Metabolism 142

Nutrition overview
●● An adequately balanced daily supply of carbohydrates, fats, proteins, vitamins, electrolytes, trace elements and
water which are essential to maintain normal health
●● Requirements per kg per day
Water 30–40 mL Protein 1–2 g Na+ 1 mmol
Energy 30–40 kcal Carbohydrate 10 g K+ 1 mmol
Nitrogen 0.2 g Fats 1–2 g Ca2+/Mg2+ 0.1–0.2 mmol

●● Energy requirements increase in catabolic states (trauma, burns) and pyrexia

Artificial nutrition
Enteral nutrition (via gastrointestinal tract)
●● Indicated when swallowing inadequate but
gastrointestinal function otherwise intact
●● Preferable to parenteral nutrition in critically
ill patients or postoperatively, as
■ maintains intestinal barrier integrity
■ helps prevent stress ulcers
■ improves bowel adaptation after resection
●● Complications include displacement of
nasogastric tube (tracheobronchial
intubation, oesophageal perforation),
aspiration, reflux, nausea, vomiting, diarrhoea,
constipation and metabolic disturbances
Parenteral nutrition
●● Indicated where gastrointestinal absorption cannot provide
adequate nutritional support (e.g. obstruction, ileus, malabsorption)
●● Given via dedicated central venous catheter or peripheral cannula
(feed of osmolality <800 mOsm/kg)
●● Routine monitoring includes
■ daily – fluid balance, plasma levels and osmolality of urea
and electrolytes, urinary levels and osmolality of urea
■ twice weekly – full blood count, liver function tests and Ca2+
■ weekly – iron, folate and vitamin B12
●● Complications related to catheter (misplacement, infection,
thromboembolism), electrolyte imbalances, hyperglycaemia or
rebound hypoglycaemia, hypophosphataemia, vitamin
deficiencies or excess and metabolic acidosis
Carbohydrates, proteins and fats
Carbohydrates
●● Found as monosaccharides (simple sugars
such as glucose, galactose and fructose), oli-
gosaccharides and polysaccharides (large
polymers of simple sugars or starches)
●● Only monosaccharides can be absorbed via
active transport mechanisms in the small
intestine
●● Digestion of larger sugars occurs by:
■■ amylases (salivary and pancreatic) to
oligosaccharides
■■ maltases, lactases and sucrases (small
intestine) to monosaccharides
Proteins
●● Large complex molecules made of numerous
amino acids
■■ Primary proteins – a chain of amino acids
■■ Secondary proteins – amino acid chains
linked by hydrogen bonds to form alpha
helices and pleated sheets
■■ Tertiary proteins – alpha helices and ter-
tiary sheets are attracted to each other
■■ Quaternary proteins – more than one
amino acid chain
●● Proteins in the gut are broken down by pep-
sin and trypsin in the stomach and chymo-
trypsin in the small intestine where they are
absorbed and transported to the liver in the
portal vein
Fats
●● Fat in the diet is found as triglycerides (the
majority), phospholipids, cholesterol and fat-
soluble vitamins
●● Triglycerides are hydrolysed by pancre-
atic lipases to free fatty acids (FFAs) and
monoglycerides
●● Glycerides and cholesterol combine with
micelles in the small intestine
●● The fats are then reconstituted in the muco-
sal cells of the intestine and incorporated into
large molecules called chylomicrons (hydro-
phobic lipid core and a hydrophilic shell of
phospholipid and protein)
●● These chylomicrons move by pinocytosis into
the extracellular fluid (ECF) and then into the
circulation via the lymphatic system
 Physiology

Liver, GI and Metabolism 143

Essential amino acids and fatty acids
●● Amino acids are the building blocks of proteins
●● Twenty amino acids exist in nature
●● The main carbon atom is asymmetrical and has four different chemical groups attached
■■ –COOH, which is a carboxyl group (acidic)
■■ –NH2, which is an amino group (basic)
■■ –H, which is a hydrogen atom
■■ –R, which is a residue that varies depending on the particular amino acid

Essential amino acid

●● For an organism, an essential amino acid is an amino acid that cannot be synthesized by the organism
from other available resources and therefore must be supplied as part of its diet
●● Eight amino acids are generally regarded as essential for humans. Two others, histidine and arginine, are
essential only in children
These Ten Valuable Amino acids Have Long Preserved Life In Man
Threonine Tryptophan Valine Arginine Histidine Lysine Phenylalanine Leucine Isoleucine Methionine

Essential fatty acids (EFAs)

●● Cannot be synthesized by the body from other fatty acids and must be obtained from food
●● Originally designated as Vitamin F, until it was realized that they are best classified with the fats
■■ Arachidonic acid
■■ Linoleic acid
■■ Linolenic acid
●● Support the cardiovascular, reproductive, immune and nervous systems
●● Required to manufacture and repair cell membranes, to produce prostaglandins and for adequate neu-
ral development in children
Vitamins and minerals
●● Compounds required in small amounts to maintain health that cannot be synthesized by an organism and must
be derived from diet
●● Vitamins may be fat soluble (A, D, E and K) or water soluble (B vitamins, C vitamins, folic acid)

Vitamin/ Daily
mineral Source Function requirement
A (retinol) Liver, kidney, oily fish, dairy Retinal growth, night vision, development of skin and mucosa 3300 IU
D Sunlight, eggs, oily fish Calcium and phosphorous homeostasis 200 IU
E Dark green vegetables, pulses Antioxidant 10 IU
K Dark green vegetables, fruit, dairy Blood coagulation 2–4 mg/wk
B1 (thiamine) Fortified cereals, milk, vegetables Carbohydrate metabolism coenzyme 3 mg
and fruit
B2 (riboflavin) Fortified cereals, milk Coenzyme in metabolism 3.6 mg
B3 (niacin) Fortified cereals, meat fish Coenzyme in oxidation/reduction 40 mg
B6 (pyridoxine) Eggs, meat, fish Haemoglobin production 4 mg
Folic acid Green vegetables, fortified cereals DNA synthesis, RBC production 0.4 mg
B12 Dairy, eggs, fish meat RBC production, myelination of nerves 5 mg
C (ascorbic Citrus fruits and vegetables Antioxidant, Collagen, bone and connective tissue synthesis 100 mg
acid)
Calcium Dairy Bones, teeth, muscle strength, cardiac 1000 mg
Chromium Cereals, yeast Glucose metabolism 35 mcg
Fluoride Fluorinated water, fish Stimulates bone development, inhibits dental caries 4 mg
Iodine Seafood, iodinised salt Thyroid metabolism 150 mcg
Magnesium Nuts, green vegetables, grains Acid–base balance, cardiac function, carbohydrate metabolism 420 mg
Manganese Nuts, grains Enzyme activation, sex hormone production 2.3 mg
Phosphorous Fish, meat, poultry, eggs Bone development, protein, fat and carbohydrate utilisation 700 mg
Selenium Seafood, lean meat, grains Antioxidant, metabolic processing 55 mcg
Zinc Lean meats, liver, eggs Digestion and metabolism, development of reproductive 11 mg
system, immune function
 Physiology

Liver, GI and Metabolism 144

Carbohydrate metabolism – overview
●● Carbohydrates have generic formula Citric acid cycle (CAC/TCA/Krebs)
Cn(H2 O)n Sequence of reactions that occur within the
●● Ingested as simple or complex carbohydrates, mitochondria that form the final common
absorbed as monosaccharides and passed pathway for the oxidation of carbohydrate,
to liver or muscle for further metabolism lipids and some amino acids to carbon diox-
ide and water
Glycolysis ●● It produces ATP, replenishes NADH and pro-
●● Initial process of many pathways of carbohy- vides nicotinic precursors
drate metabolism
●● Series of biochemical reactions by which Acetyl CoA
glucose (C6) is oxidized to two molecules of C2
Citrate
pyruvate, with production of two adenosine C6
3 steps
triphosphate (ATP) molecules
●● Under aerobic conditions, pyruvate oxidized
Oxaloacetate α-ketoglutarate
to acetyl CoA (C2) by pyruvate dehydroge-
C4 C5
nase and fed into the citric acid and oxi-
dative phosphorylation cycles to generate
Succinate
total of 36 molecules of ATP 3 steps 2 steps
C4
●● Under anaerobic conditions, pyruvate con-
verted to lactate (as may happen in red

{ }
blood cells or exercising muscle) with genera- High potential 2 FADH2 per molecule
tion of only two molecules of ATP 2 GTP
electron carriers 6 NADH of glucose
Oxidative phosphorylation
Oxidative phosphorylation
●● Final metabolic pathway of cellular respiration that occurs on inner mitochondrial membrane
●● Tendency for electrons to be transferred from activated carriers (e.g. NADH – ‘loaded’ during CAC)
to cascade of lower potential carriers (electron transfer chain)
●● Process involves many enzymes, including those of cytochrome oxidase system
●● Proton pumps in inner mitochondrial membrane are activated by flow of electrons through them
pumping H+ ions out and creating gradient that generates ATP (via ATP synthase) by driving H + ions
back across inner membrane
●● Requires oxygen and results in liberation of 30 ATP molecules per molecule of glucose

Glycogenolysis
●● Breakdown of glycogen stores to produce glucose
●● Controlled by hormonal and local factors
●● Occurs in
■■ skeletal muscle – releases glucose for muscular contraction
■■ liver – for glycolysis and to release glucose into bloodstream (due to presence of
glucose-6-phosphatase)

Gluconeogenesis
●● Generation of glucose from organic molecules such as lactate and amino acids
●● Not the reverse of glycolysis
●● Lactate from anaerobic respiration in skeletal muscle converted to pyruvate as part of Cori cycle
●● Most gluconeogenesis takes place in liver (small amount in kidney) and occurs during starvation
or intense exercise
 Physiology
Metabolism
The biochemical modification of chemical
compounds in living organisms and cells,
including the biosynthesis of complex organic
molecules (anabolism) and their breakdown
(catabolism)
●● Exergonic reactions (catabolism, oxidation
and reactions breaking chemical bonds)
release energy
●● Endergonic reactions (anabolic, reduction
reactions and maintenance of acid–base
balance) require energy
Basal metabolic rate
Basal metabolic rate (BMR) is the rate of
metabolism that occurs when an individual
is at rest in a thermoneutral environment, is in
the post-absorptive state and has not eaten
for at least 12 hours
●● Average BMR is 2000 kcal/day
●● Determined by one of two methods:
■■ whole body calorimetry, which mea-
sures the amount of heat produced by
Liver, GI and Metabolism 145
an individual in an insulated room by the
temperature rise in water passing through
ceiling coils
■■ oxygen consumption, which is measured
with a modified Benedict-Roth spirom-
eter that incorporates a carbon dioxide
absorber. A graph of volume of oxygen
consumed against time is created, and
the volume of oxygen consumed is mul-
tiplied by 4.8 kcal/L to convert to the
amount of energy used
Factors that affect the BMR
Muscular activity
Emotional state
Temperature (environmental)
Age/sex/height/surface area
Body temperature
Obesity (i.e. body weight)
Labour/pregnancy
Ingestion of food
Catecholamines/thyroxine
Starvation
Starvation is the complete absence of dietary intake and can lead to death within 60 days. (Malnutrition is a
medical condition caused by an insufficient diet)

Biochemical changes
The main priority in starvation is to maintain the glucose supply to the brain

Stage 1 – glycogenolysis ●● Mobilization of glycogen stores

(1–2 days) ●● Initially increased insulin production spares protein (and therefore muscle)
metabolism

Stage 2 – gluconeogenesis
(1 week)
●● Once glycogen stores depleted, β-oxidation of fatty acids occurs with production
of ketone bodies (accumulation of acetyl coenzyme A saturates citric acid cycle
[CAC], which leads to ketosis)
●● Mobilization of muscle protein (alanine for hepatic gluconeogenesis and
glutamine for renal gluconeogenesis) remains low but constant to supply glucose
to the brain and replace intermediates of CAC

Stage 3 – catabolism ●● Production of ketone bodies decreases as lipids are used

(2 weeks) ●● Plasma and urinary levels of nitrogen increase as protein catabolism increases
●● Loss of lean mass in organs (heart and kidney) leads to irreversible damage and
death

Hormones in starvation
●● Insulin initially increases and then decreases, increasing levels of free fatty acids
●● Glucagon levels are high, stimulating β-oxidation
●● Levels of growth hormone increase, stimulating lipolysis
●● Levels of catecholamines initially are high but decrease in the long term
●● Cortisol is increased (stress response)
●● Thyroxine increases in the first 3 days then declines
 Physiology

Liver, GI and Metabolism 146

Obesity
Defined as an individual with a body mass BMI values
index (BMI) greater than 30 kg ⋅ m –2 ●● Normal BMI <25 kg ⋅ m −2
Weight (kg) ●● Overweight >25 kg ⋅ m−2
BMI = ●● Obese class I >30 kg ⋅ m−2
Height (m)2
●● Obese class II >35 kg ⋅ m−2
●● Obese class III >40 kg ⋅ m−2

Obesity causes increased Morbidity and Mortality

Cardiovascular Gastrointestinal
Respiratory system system tract Miscellaneous

●● ↑ basal metabolic rate (BMR) ●● ↑ cardiac output ●● ↑ intra-abdominal ●● Type 2 DM

●● ↑ consumption of oxygen and ●● ↑ blood volume pressure may ●● ↑ operative times
production of carbon dioxide ●● Hypertension result in hiatus ●● Hypercholesterolaemia
●● ↑ work of breathing common hernia ●● Arthritis
●● ↑ V/Q mismatch, which results in ●● Atherosclerosis ●● Obese patients ●● Deranged LFTs
hypoxaemia and IHD likely to secrete ●● ↑ risk of wound
●● ↓ FRC and compliance (closing ●● Hypertrophy and more acidic infection
capacity approaches or exceeds FRC) failure of LV or RV gastric juices ●● ↑ risk of thromboem-
●● Hypoxic pulmonary vasoconstriction ●● Difficult IV access bolic events
increases right ventricle’s work and and NIBP
may lead to pulmonary hypertension measurement
and right-sided heart failure
●● OSA
Anaesthesia for obese patients
Preoperatively ●● Regional anaesthesia may be more tech-
●● Patients must be assessed for the comorbidi- nically difficult and adequate doses of local
ties of obesity anaesthetic more variable
●● Lifting and positioning the patient may be
●● Prophylaxis for deep vein thrombosis (DVT)
difficult
Perioperatively ●● Surgery may be prolonged, with increased
blood loss
●● Monitoring may be difficult, and appropri-
●● Drug metabolism may be altered (e.g.
ately sized blood pressure cuffs should be
increased metabolism of inhalational agents)
used. ECG complexes may appear small
and appropriate doses of drugs should be
●● Airway maintenance may be difficult
given (e.g. use lean body mass for neuromus-
because of increased soft tissue mass in the
cular blocking agents)
neck
●● Anticipated difficult intubation – reduced
Postoperatively
neck movement, large breasts
●● Obese patients are at risk of atelectasis and
●● Spontaneous ventilation may be difficult
hypoventilation, with subsequent risk of chest
because of respiratory impairment; if positive
infection and respiratory failure
pressure ventilation (PPV) is used, high air-
●● Weaning from ventilation may be more diffi-
way pressures may occur, especially if head
cult than in thinner patients and admission to
down
●● Hypoxaemia may occur rapidly in periods of ITU may be needed, with physiotherapy, oxy-
apnoea, so preoxygenation is essential gen therapy and adequate analgesia
●● Intravenous access may be difficult
 Physiology

Liver, GI and Metabolism 147

Temperature regulation
●● Core body temperature is tightly regulated at 37 ± 0.2°C to optimize enzyme activity and is
controlled centrally by the hypothalamus
●● Variation in temperature occurs daily (circadian rhythm) and within the menstrual cycle

Detectors and effectors

●● Peripheral temperature receptors in skin and core tissues convey information to hypothalamus
via Aδ (hot) and C (cold) fibres
●● Central temperature sensitive cells in brainstem, spinal cord and anterior hypothalamus
●● Efferents (SNS) to blood vessels, sweat glands, piloerector muscles, brainstem and higher centres

Thermoregulatory responses
●● Behavioural
■■ Adding or removing clothing
■■ Moving towards or away from heat sources
■■ Increasing or decreasing body surface area
●● Cutaneous blood flow
■■ Vasoconstriction or vasodilation
■■ Heat transfer from arterial to venous supply (countercurrent mechanism)
■■ Thermoneutral range – the range in which temperature regulation can occur by changes in
skin blood flow alone. 20°C–28°C in adults, 35°C–37°C in neonates
●● Shivering (brainstem) in adults and non-shivering thermogenesis (brown fat metabolism) in
babies
●● Sweating
●● Piloerection
Hypothermia
●● Core temperature <36°C
●● Causes of hypothermia
Abnormal heat conservation and reduced
Excessive heat loss heat production Defective heat regulation
●● Cold weather ●● Hypothyroidism  ● Hypoglycaemia ●  Hypothalamic lesions, including Wernicke’s
●● Immersion in ●● Hypopituitarism  ● Hypoadrenalism encephalopathy  ● CVA  ● Tumours
cold water ● Uraemia ●  Spinal cord transection ●  Head trauma  ●  Congenital abnormalities
above T1  ●  Peripheral neuropathy (e.g. Shapiro’s syndrome)
●  Autonomic neuropathy  ●  Certain drugs
(alcohol, barbiturates, neuroleptics)

●● Physiological changes in hypothermia

Cardiovascular Respiratory Neurological Other
●● Bradycardia and reduced cardiac output ●● Apnoea (<24°C) ●● Confusion (<35°C), ●● Diuresis
●● J waves on the ECG (30°C) and subsequent Coma (<30°C) ●● GFR 50% of
●● Arrhythmias (<30°C), VF (<28°C) respiratory ●● ↓ MAC normal at 30°C
●● Initially, vasoconstriction and then acidosis ●● EEG (<18°C) ●● Hyperglycaemia
vasodilatation (20°C) ●● ↓ oxygen delivery ●● Hyperkalaemia
●● Coagulation ●● Shift in the ●● ↓ BMR
■ platelet function becomes ineffective oxygen
(inhibition of thromboxane B2) Increased dissociation
fibrinolysis and reduced enzymatic curve to the left
activity leads to an increased bleeding ●● ↓ O2 demand
tendency and DIC-like syndrome and CO2 delivery

● Management
■■ ABC, invasive monitoring  ■  treat hypoxia, hypoventilation and acidosis  ■  investigate the cause
■■ rewarm patient – rapidly if rapid onset of hypothermia, slowly if insidious onset
● non-invasive – blankets, radiant heaters, heat and moisture exchanger
● invasive – warmed IV fluids, peritoneal dialysis or bladder irrigation and possibly cardiopulmonary bypass,
if available
 Physiology

Liver, GI and Metabolism 148

Control of blood glucose
●● Normal blood glucose 4–7mmol/L
●● Brain can only use glucose as a substrate – avoid hypoglycaemia
●● Hyperglycaemia → dehydration, glycosuria, osmotic diuresis and long-term end-organ damage
●● Tight glycaemic control improves outcome in acute illness and after major surgery
●● Blood glucose depends on:
■■ uptake from the gut (episodic)
■■ liver – intermediate metabolism maintains stability (glycogenolysis, glycogenesis)
■■ hormones (especially insulin and glucagon)
●● Other hormones Homeostatic control of blood glucose
■■ Corticosteroids – ↑ secretion in Negative feedback
hypoglycaemia, permissive for Adipose tissue
glucagon’s effects on the liver Glycerol/fatty acids
→ Lipids
■■ Catecholamines – ↑ glycogenol- Blood
Pancreatic Liver cells Blood
ysis and ↑ hepatic glucose output glucose
islet β-cells Insulin Glucose → Glycogen glucose
( 7 mmol/L)
■■ Growth hormones – Opposes
Other cells
insulin by ↑  hepatic glucose out- (not brain) Homeostasis
Glucose uptake
put and ↓ muscle glucose uptake
■■ Thyroid hormones – ↑ gut absorp- Blood
Pancreatic Liver cells Blood
glucose Glucagon
islet α-cells glucose
tion of glucose and ↑ hepatic glu- ( 4 mmol/L) Glycogen → Glucose
Amino acids → Glucose
cose output
■■ Oestrogen and progesterone – Negative feedback
Insulin resistance
Stress response
Metabolic, hormonal, immunological and
haematological changes that occur in
response to injury or trauma. Response aims
to increase catabolism and to maintain car-
diovascular homeostasis
Pathophysiology
●● Tissue trauma, hypovolaemia and pain cause
a neuroendocrine reflex releasing:
■■ ACTH → increased cortisol (within a few
minutes)
■■ endorphins and prolactin (may affect
immune function)
■■ growth hormone (promotes tissue
repair and helps prevent muscle protein
breakdown)
■■ antidiuretic hormone (vasopressor,
promotes water retention, K+ loss and
enhances haemostasis)
●● Increased cortisol → skeletal muscle protein
breakdown, lipolysis, hyperglycaemia and
anti-inflammatory effect
●● Failure of normal negative feedback (e.g. cor-
tisol does not inhibit ACTH production)
●● SNS activity increases plasma catecholamines
●● → increases renin → increases angiotensin II
→ increases aldosterone
●● → Water and sodium retention
●● ↑ Catabolism
■■ Fatty acid mobilization and utilization
■■ Amino acids → carbohydrate (loss of up to
500 g lean body mass/day)
■■ Negative nitrogen balance
■■ ↑ metabolic rate, body temperature, oxy-
gen consumption and carbon dioxide
production
●● ↑ cytokine production, acute phase reac-
tions, leucocytosis and lymphocytosis
●● ↓ anabolic hormones (e.g. insulin and
testosterone)
Anaesthesia
●● High-dose opioids reduce the response
●● Etomidate inhibits 11-β hydroxylase and pre-
vents cortisol production for up to 8 hours
●● Neuraxial block prior to surgery prevents
stress response but cytokine activity remains
unchanged
●● Normothermia → decreased metabolic
response
●● Minimally invasive surgery reduces severity of
stress response
 Physiology

Endocrinology 149
Hormones
Chemical messengers that enter blood directly upon secretion from endocrine glands
●● Single gland or cell may secrete multiple hormones, and multiple glands may secrete the same
single hormone
●● Almost without exception a hormone affects target tissues by first activating target receptors in
those tissues
●● Three broad classes of hormones

Peptide Steroid Amino acid derivative

●● Often synthesized as (pre)
prohormones requiring
processing and cleavage to
be active
●● Stored in cell vesicles prior
to release
●● Act on receptors in target cell
membrane and transduce
through second messenger
systems
●● Fast onset transient changes
in protein activity, though
gene expression changes
may be seen
●● Examples – insulin, glucagon,
ACTH, gastrin, PTH
●● Synthesized from ●● Two major classes derived from
cholesterol tyrosine: catecholamines and
●● Released upon synthesis – thyroid hormones
not stored ●● Generally stored before release
●● Generally non-polar thus ●● Adrenaline
require carrier proteins ■■ Polar, water soluble
●● Act through intracellular ■■ Acts at membrane receptors
nuclear receptors to ■■ Produces similar responses
directly alter gene to peptide hormones
expression ●● Thyroid hormones
●● Slower onset but longer ■■ Protein bound
duration ■■ Acts on nuclear receptors
●● Examples – cortisol, ●● Similar responses to steroid
aldosterone, testosterone, hormones
oestrogen, progesterone
Control of secretion of hormones
Hormones are crucial to homeostatic reflexes, so Feedback control of endogenous
there must be methods to regulate their secretion ­corticosteroid production
●● Negative feedback control Autonomic Chemical
■■ most important control system where output of input stimuli Higher CNS
pathway inhibits inputs to pathway (noradrenaline) (5HT3)
■■ used extensively to regulate secretion of hormones
in hypothalamic–pituitary axis Hypothalamus
●● Control by plasma concentrations of specific ions or
(CRH )
nutrients (e.g. Na+ or glucose)
●● Neuronal control by autonomic or CNS Ant. pituitary
●● Control by other hormones (trophic hormones) or
paracrine agents (e.g. prostaglandins) Negative
feedback
●● Direct chemical or physical stimulation (e.g. release of Blood
gut hormones) pituitary hormone Negative
(ACTH) feedback

Target gland
(adrenal cortex)

Hormone
(cortisol)
 Physiology

Endocrinology 150
Hypothalamus
●● Located behind optic chiasm in part of brain forming the floor of the third ventricle
●● Main function is homeostatic control of the internal environment
●● Extensively connected to brainstem, pituitary gland, limbic system and higher centres
●● Connected anatomically and functionally to the anterior pituitary via neuronal and vascular tis-
sue (the hypophyseal portal system) that forms the infundibular stalk passing through the dia-
phragma sellae
●● Blood supply is via the circle of Willis
●● Involved in regulation of
■■ autonomic nervous system (ANS) – posteromedial part controls SNS, anterior part controls PNS
■■ body temperature
■■ thirst, water intake and hunger
■■ sexual activity
■■ emotions and behaviour
■■ pituitary gland
Pituitary gland
●● Consists of anterior and posterior lobes
●● Located in pituitary fossa of sphenoid bone
below optic chiasm
●● Anatomically and functionally linked to hypo-
thalamus via infundibular stalk, which con-
tains the hypophyseal portal system and
neuronal tissue
●● Secretes large number of hormones
●● Oxytocin stimulates contraction of uterus
and ejection of breast milk (contraction
of myoepithelial cells). Also has natriuretic
effects
Hypothalamic hormones and their relation-
ship to pituitary function
Hypothalamus

Anterior pituitary GnRH GHRH SS TRH DA CRH

●● Regulated by hormones secreted from hypo-

thalamus into hypophyseal portal blood
●● Secretes six peptide hormones – ACTH, TSH,
FSH/LH Growth hormone TSH Prolactin ACTH
FSH, LH, prolactin and growth hormone
Anterior pituitary

Posterior pituitary TRH = Thyrotropin-releasing hormone

●● Secretes ADH (vasopressin) and oxytocin,
which are synthesized in hypothalamus
(supraoptic and paraventricular nuclei
respectively) and then transported via axons
GnRH = Gonadotrophin-releasing hormone
GHRH = Growth hormone–releasing hormone
SS = Somatostatin
CRH = Corticotrophin-releasing hormone
DA = Dopamine (prolactin-inhibiting hormone)

in infundibular stalk to be stored in vesicles

before release
 Physiology

Endocrinology 151
Adrenal gland
●● Adrenal glands are located on upper poles of kid- Structure of adrenal cortex
neys in retroperitoneum Zona glomerulosa
●● Two distinct parts: cortex and medulla. Cortex has – Secretes aldosterone
Adrenal
three histological layers, all synthesizing and secret- cortex Zona fasciculata
ing distinct hormones – Secretes glucocorticoids
●● Adrenal medulla contains neuroendocrine Adrenal Zona reticularis
medulla – Secretes sex hormones
chromaffin cells that synthesize adrenaline and – Secretes
catecholamines
noradrenaline

Glucocorticoids – cortisol and

corticosterone
●● Release from adrenal cortex stimulated by adreno-
corticotrophic hormone (ACTH) from anterior pituitary
●● Aim to stabilize blood glucose levels in times of stress – ↑ gluconeogenesis and glycogen synthesis
at the expense of fats and protein
●● Permissive for action of catecholamines on metabolism, bronchi and CVS
●● Needed for efficient muscle contraction and nerve conduction
●● Anti-inflammatory (via inhibition of phospholipase A 2, which ↓ prostaglandin production and also
↓ tissue transudate and cell oedema)
●● Suppression of immune system (depression of macrophage function, inhibition of interleukin pro-
duction and reduction in number of circulating lymphocytes)
Adrenal gland (cont.)
Mineralocorticoids – aldosterone
●● Responsible for salt and water reabsorption
and control of blood pressure
●● Regulates transport of Na+ and K+ ions in kid-
ney and other organs
●● Release stimulated by
■■ renin–aldosterone–angiotensin system (RAAS)
■■ trauma, anxiety (ACTH)
■■ ↑ K+ and ↓ Na+ through direct effect on
adrenal cortex
Catecholamines
●● Adrenal medulla thought to be derived from
sympathetic ganglion where postsympa-
thetic neurons have lost axons
●● Stimulated by SNS to release adrenaline and
some noradrenaline during times of acute
stress (fight-or-flight response)
Hypersecretion of adrenal gland
●● Hyperaldosteronism (e.g. Conn’s syndrome)
■■ ↑ BP, hypovolaemia, ↓ K+ and metabolic
alkalosis
●● Excessive corticosteroid secretion (e.g.
Cushing’s syndrome)
■■ obesity, poor wound healing, ↑ BP, cardiac
failure, ↑ Na+, ↓ K+ and diabetes mellitus
■■ patients need steroid cover for surgery
●● virilization/feminization
●● Phaechromocytomas may cause ↑ BP, vaso-
constriction, tachyarrhythmias, cardiomyop-
athies and glucose intolerance
Hyposecretion of adrenal gland
●● Adrenocorticoid insufficiency (e.g. Addison’s
disease)
■■ acute insufficiency leads to ↓ BP, ↓ Na+,
↓ glucose and ↑ K+, ↑ Ca2+
■■ Addison’s disease may be autoimmune
and associated with other diseases (e.g.
diabetes, thyroid disease, tuberculosis
and amyloidosis)
 Physiology

Endocrinology 152
Catecholamines
●● Substances that contain a catechol group (a benzene ring with –OH [hydroxyl] groups at positions
3 and 4) and an amine group
●● Act at adrenergic receptors within CNS

Catecholamine synthesis and metabolism

Neuronal body Granulated storage Chromaffin cells of adrenal

cytoplasm vesicles medulla

Tyrosine DOPA Do pamine Phenylethanolamine

Hydroxylase decarboxylase B-Hydroxylase N-methyltransferase (PNMT)

Tyrosine L-DOPA Dopamine Noradrenaline Adrenaline

MAO-A MAO-B
COMT
COMT

DOPAC Nor-metanephrine Metanephrine

COMT

Homovanillic Vanillylmandelic
acid acid (VMA)*

MAO, monoamine oxidase (nerve endings)

COMT, catechol-O-methyl transferase (most tissues, especially liver and kidneys)
* Urinary levels of VMA important in phaeochromocytoma diagnosis.
Adrenergic receptors
●● G-protein membrane receptors that are specifically acted on by catecholamines to produce effects medi-
ated by second messengers
●● Subdivided into a and b subtypes

Receptor Second
subtype Receptor messenger effects Location Systemic effects

α1 Gq protein Activation of Postsynaptic ●● Contraction of visceral, cystic, cardiac and vascular

phospholipase C smooth muscle
●● Mydriasis
●● Antidiuresis
●● Relaxation of intestinal sphincters
α2 Gi protein Decreased levels Presynaptic ●● Inhibition of noradrenaline release
of cAMP ●● Aggregation of platelets
Postsynaptic ●● Contraction of smooth muscle, including constriction
of coronary arteries
β1 Gs protein Increased levels Postsynaptic ●● Positive inotrope and chronotrope effects on heart
of cAMP ●● Breakdown of adipose tissue to fatty acids
●● Increased secretion of renin
β2 Gs protein Increased levels Presynaptic ●● Facilitate release of noradrenaline or adrenaline
of cAMP ●● Relaxation of vascular, bronchial and intestinal muscle
●● Relaxation of bladder sphincter
Postsynaptic
●● Glycogenolysis
●● Lipolysis
●● Increased secretion of insulin and glucagon
●● Relaxation of uterine muscle
β3 Uncertain Uncertain Postsynaptic ●● Regulation of lipid metabolism in adipose tissue
 Physiology

Endocrinology 153
Thyroid gland
The function of the thyroid gland is to produce thyroid hor- Control of thyroid function feedback
mones that are essential to maintain the metabolic rate loop
optimal for normal cellular function
Hypothalamus –
Anatomy TRH
●● Largest endocrine gland in body – extends from attach-
ment of sternothyroid muscle to thyroid cartilage supe- +
riorly and sixth tracheal ring inferiorly
●● Two lobes that lie lateral to the oesophagus and pharynx
●● Thyroid isthmus overlies second to fourth tracheal rings
Pituitary gland
●● Supplied by superior and inferior thyroid arteries (branches – TSH
of external carotid and subclavian arteries, respectively)
●● Nerve supply from recurrent and external laryngeal
nerves +

Calcitonin
●● 32 amino acid polypeptide hormone that is produced Thyroid gland
primarily by the C-cells of the thyroid
●● Used to treat osteoporosis, Paget’s disease and T4 T3
hypercalcaemia
●● Reduces plasma calcium levels by three methods
■■ ↓ activity of osteoclasts in bones
■■ ↓ absorption of calcium in the GIT Peripheral
■■ ↓   calcium and phosphate reabsorption by kidney tissues
tubules T4 → T3
Thyroid hormones
Production ●  Absorption of iodine (as iodide) from gut  ●  Iodide trapping within thyroid by
active transport; carrier subjected to competitive inhibition by other anions  ● Iodide
converted to iodine, which diffuses into lumen of thyroid follicle  ●  Iodine reacts with
tyrosine (an amino acid residue present as thyroglobulin) to form monoiodotyrosine
(MIT); this reaction occurs mainly at cell–colloid interface and is catalyzed by thyroid
peroxidase  ●  Further iodination of MIT leads to formation of diiodotyrosine
(DIT)  ●  Thyroxine (T4) (DIT + DIT) mostly (95%) bound by thyroid-binding globulin
(TBG), transthyretin and albumin  ● ­Triiodothyronine (T3) (MIT + DIT) 3–4 times more
potent than T4 and bound equally by TBG and albumin
Mechanism ●  Thyroid hormones diffuse intracellularly  ●  Large proportion of T4 converted to T3
of action (higher affinity for thyroid hormone receptors than T4)  ● T3 acts on nuclear receptors
to alter cellular function via messenger RNA
Metabolism ● T4 and T3 de-iodinated in tissues, especially liver and kidneys  ●  33% of T4 converted
to T3 and 45% to reverse T3
Function ● Stimulates oxygen consumption and ↑ metabolic rate  ●  Regulation of carbohy-
drate (↑ absorption from the gut) and lipid (↑ lipolysis) metabolism  ●  Needed for
normal growth and maturation  ●  Sensitizes myocardium to catecholamines by
↑ synthesis and sensitivity of β adrenoceptors
 Physiology
Changes in pregnancy
Physiological and anatomical due to ↑ metabolic
demands of the uterus, placenta and fetus
Cardiovascular changes
●● Intravascular volume – plasma volume ↑ by
50%, red cell mass ↑ by 20% – relative haemo-
dilution and anaemia
●● Cardiac output ↑ by 30%–40% (35% ↑ in SV
and 15% ↑ in HR)
●● Reduction in SVR and diastolic BP (vascular
smooth muscle relaxation)
●● Venous distention delays absorption of SC/
IM drugs and reduces the volume extradural
and intrathecal spaces (less LA for a given
increase in height of block)
●● Aortocaval compression – ↓ cardiac output
by up to 24%, even in some patients in the left
lateral tilt position
●● The heart is displaced left and anteriorly,
and undergoes hypertrophy. This leads to a
displaced apex beat and LAD and T-wave
inversion in lead III on ECG
Pregnancy 154
●● Clotting – pregnancy is a relatively hyper-
coagulable state although clotting and
bleeding times remain normal
■■ ↑ fibrinogen and factors VII, X and XII
■■ ↑ platelet count
Respiratory changes
●● Capillary engorgement and swelling of
upper airway due to hormonal changes lead
to potential airway difficulties
●● ERV, RV and FRC ↓ by approximately 20% at
term
●● Preoxygenation prior to anaesthesia is
essential
●● Minute ventilation ↑ by 50% during the first
trimester due to 40% ↑ in TV and a 15% ↑ in RR
●● Decreased PaCO2 (4.3 kPa) and ↑ PaO2
(13.7 kPa)
●● Oxygen consumption ↑ by 20% (at term)
more so in labour
Changes in pregnancy (cont.)
Gastrointestinal changes
●● ↑ gastro-oesophageal reflux and decreased
pH of gastric secretions leads to ↑ risk of aspira-
tion and Mendelson’s syndrome
●● Normal gastric emptying
Renal changes
●● Renal blood flow and GFR ↑ by 40%
●● Urea and creatinine ↓ by 40% because of ↑
reabsorption of Na+ and water
●● ↑ GFR may overwhelm reabsorptive capac-
ity of tubules, which leads to mild glycosuria
and/or proteinuria
Hepatic and metabolic changes
●● ↓ requirements of all anaesthetic agents,
including 30% ↓ in MAC (potentially because
of ↑ levels of progesterone) and ↑ elimination
half-life of thiopentone
●● ↓ albumin lead to ↑ free drug concentrations
and potentially ↓ dosage requirements of
albumin-bound drugs
●● ↓ levels of cholinesterase (30%) in plasma,
so potential prolongation of effects of suxa-
methonium particularly in heterozygotes (e.g.
UA genotype)
●● Pregnant women are in a state of ‘accelerated
starvation’ and have ↑ energy requirements;
hypoglycaemia in pregnant women is defined
as a glucose concentration <3.3 mmol/1
 Physiology

Pregnancy 155
Placenta
Temporary organ present only during pregnancy, which interfaces the fetal and maternal
circulations

Development
●● About 5–6 days after conception, the fertilized egg attaches to the endometrium, which is invaded
by the syncytiotrophoblast (outer layer of the egg trophoblast)
●● Chorionic villi (finger-shaped masses of tissue) form from further proliferation of the trophoblast
and are separated by spaces (lacunae)
●● Villi erode the walls of the endometrial spiral arteries, so the lacunae fill with maternal blood
●● Primitive blood vessels form in the villi after about 18 days and eventually join the fetal umbilical
vessels
●● Dense masses of fetal villi (cotyledon) form a single placental lobe
●● Barrier between fetal and maternal circulations is two cells thick and consists of the fetal capillary
endothelium and syncytial trophoblast
Placenta (cont.)
Blood supply
●● Maternal blood supply of uterus via uterine arteries
●● Term uterine blood flow (UBF) = 500–700 mL/min
●● UBF = UAP - UVP / UVR
where UAP is uterine artery pressure, UVP is uterine venous pressure and UVR is uterine vascular
resistance
●● Uterine blood flow reduced by maternal hypotension, hyperventilation and stress and vasopres-
sor drugs
●● Fetal blood supply to placenta via two umbilical arteries; blood leaves by single umbilical vein
●● Umbilical blood flow up to 100 mL/min at 22 weeks and 300 mL/min at term
●● Placental function relates to total surface area of placenta and UBF
●● Acutely impaired function causes fetal hypoxaemia and acidosis
●● Chronic impairment may lead to delayed fetal growth

Functions
●● Gas exchange – O2 and CO2 exchange favoured by fetal haemoglobin and double Bohr effect,
respectively
●● Nutrient exchange – all by facilitated or active transport
●● Hormonal synthesis – oestrogens, progesterones, prolactin, chorionic gonadotrophin, human
placental lactogen and renin
 Physiology

Pregnancy 156
Fetal circulation
●● The fetal left and right hearts pump in parallel in order to supply the brain (and coronary
arteries) with the most highly oxygenated blood
●● Oxygenated blood (S aO2 80%) comes from the placenta via the single umbilical vein and
­50%–60% bypasses the liver through the ductus venosus
●● Blood from the inferior vena cava (IVC) (SaO2 25%) mixes with the blood in the ductus venosus
in the right atrium (SaO2 65%), and about 60% is shunted into the left atrium through the foramen
ovale
■■ The most highly oxygenated blood from the placenta thus flows preferentially through the duc-
tus venosus, right atrium, foramen ovale, left atrium, left ventricle and aorta to the brain
●● Blood from the superior vena cava (SVC) (SaO2 25%) is directed mainly to the right ventricle (SaO2
50%) and pulmonary artery
■■ Pulmonary vascular resistance (PVR) is high because of lung collapse, so 90% passes through
the ductus arteriosus into the aorta downstream to the origin of the carotid arteries to per-
fuse the lower half of the body
●● Deoxygenated blood returns to the placenta via the two umbilical arteries, which are branches of
the internal iliac arteries
■■ Placental blood flow comprises about 60% of cardiac output
Changes in fetal circulation at birth
●● After the first breath of life, the heart changes from a parallel system to a series system which
allows the cardiac output to flow through the lungs
●● At birth, the first breath results in a reduction in PVR (due to expansion, increased pH and increased
oxygenation) and increased blood flow through the lungs to the left atrium
■■ The systemic vascular resistance (SVR) rises because of clamping of the umbilical arteries,
so aortic and left-sided pressures increase and pulmonary right-sided pressures decrease,
which results in reversal of flow through the foramen ovale and ductus arteriosus
■■ This causes closure of the foramen ovale by a flap valve effect and closure of the ductus
arteriosus in response to increased PaO2 and reductions in levels of prostaglandins, bradykinin
and acetylcholine
●● Complete closure of the ductus arteriosus takes a few days to 2 weeks
■■ If this fails, a left-to-right shunt may cause cardiac and respiratory failure, which may be
treated with the prostaglandin antagonist indomethacin
■■ Prevention of closure of a patent ductus arteriosus with prostaglandin E1 may be used before
surgery in neonates with ductal-dependent congenital cardiac disease such as hypoplastic
left-heart syndrome
 Physiology

Pregnancy 157
Lactation
●● From 24 weeks gestation, oestrogen stimu- Positive feedback loop
lates growth and differentiation of the milk +
duct system
●● High levels of prolactin and human placental Hypothalamus
lactogen (HPL) increase alveoli, breast and
nipple development during pregnancy
●● High levels of oestrogen and progesterone Sensory
input Posterior Anterior
inhibit milk production before birth pituitary pituitary
●● Positive feedback loop under control of oxy-
tocin and prolactin leads to let-down reflex
resulting in milk secretion from the lactocytes Oxytocin Prolactin

into the alveoli of the breast

●● Milk drains into the lactiferous ducts, collects
Suckling Milk ejection Milk production
in the lactiferous sinuses and discharges
through the nipple pores Stimulus Responses
●● Colostrum secreted 48–72 hours postpartum –
rich in IgA for GI and (likely) systemic immu- +
nity for the newborn
Massive obstetric haemorrhage
Defined as >1500 mL/Drop in Hb of 4g/dL or ■■ 2× large bore cannulae, blood for FBC/
transfusion of >4U blood X-match/Coag
■■ Warm fluids – max 2 L crystalloid/1.5 L col-
Aetiology loid – consider Level 1 infuser
●● Antenatal ■■ Blood – group specific if possible or O
■■ Abruption negative
■■ Placenta praevia/accreta (abnormal ■■ Consider immediate delivery if applicable
placentas) ■■ Appropriate monitoring (CVP/Art line)
■■ Uterine rupture ■■ Monitor FBC and coagulation (consider
●● Postpartum point of care testing such as ROTEM/TEG
■■ Uterine atony to guide treatment)
■■ Retained placenta ■ Consider FFP, cryoprecipitate, platelets,
■■ Genital tract traumas fibrinogen concentrate, prothrombin com-
■■ Uterine inversion plex concentrate
●● Beware concealed haemorrhage and appar- ●● Drugs to consider
ent CVS stability masking true blood loss ■ Oxytocin/Carbetocin
■ Ergometrine
Management ■ Carboprost
●● Call for help ■ Antifibrinolytics
■■ Senior obstetrician/anaesthetist ●● Emergency surgery
■■ Mobilize porters/theatre staff/blood bank/ ■ Remove placenta
haematologist (code blue) ■ Uterine packing
●● Airway, breathing (O2) ■ Embolization
●● Circulation ■ Hysterectomy
■■ Full left lateral position ●● Appropriate post-haemorrhage monitoring –
HDU/ITU
 Pharmacology

Principles 158
Drug interactions
●● Drug interactions describe the actions of one drug on the metabolism, effect or toxicity of another drug
●● They are a common cause of morbidity and mortality

Physicochemical interactions
Pharmaceutical ●● Acidic heparin has its action terminated by strongly basic protamine
incompatibility ●● Thiopentone and suxamethonium form a complex when mixed in the same syringe
Chelating agents ●● Desferrioxamine chelates iron
●● Penicillamine is used to chelate heavy metals and in Wilson’s disease
●● Tetracycline may chelate with Ca2+ or Fe3+ in the intestine to reduce absorption

Pharmacokinetic interactions
Absorption ●● Activated charcoal adsorbs drugs
●● Metoclopramide, antimuscarinics and opioids affect gastric emptying
●● Vasoconstrictors delay local anaesthetic absorption
Distribution ●● Aspirin can displace bilirubin from albumin in neonates, which causes basal ganglia disorders
●● Aspirin and sulphonamides can alter the protein binding of phenytoin, which decreases the
therapeutic window
Metabolism ●● Enzyme induction can cause ineffectiveness of oral contraceptives, corticosteroids and
anticoagulants
●● Enzyme inhibition
■■ allopurinol inhibits xanthine oxidase, which leads to increased toxicity of mercaptopurine
■■ echothiopate or organophosphorus pesticides inhibits cholinesterase, which leads to
prolonged action of suxamethonium and mivacurium
■■ phenelzine inhibits monoamine oxidase, which may lead to hypertensive crisis
Drug interactions (cont.)
Pharmacokinetic interactions (cont.)
Excretion ●● Aspirin, indomethacin and sulphonamides all compete for active transport systems that secrete
them, so they can all increase the plasma concentrations of each other
●● Prostaglandins cause renal capillary vasodilatation, and non-steroidal anti-inflammatory drugs
decrease renal blood flow (decreased levels of prostaglandins)
●● Drugs used to alter urinary pH can affect elimination of weak acids and bases, and are used to
enhance their elimination in drug overdose

Pharmacodynamic interactions
●● Most important drug interactions
●● May be direct or indirect responses
●● May be beneficial or detrimental
●● Additive reactions may be
■■ Summative, where the net effect is the sum of the individual actions (e.g. reduction in requirements of inha-
lational anaesthetics when opioids and sedatives are used)
■■ Synergistic, where the net effect is more than the sum of the indi-
vidual actions (e.g. sulphonamide and trimethoprim antibiotics are
bacteriostatic in isolation but bactericidal when combined)
■■ Potentiation, where one drug increases the effect of another (e.g.

Dose of drug B

In
hi
aminoglycoside antibiotics increase competitive neuromuscular

bi
Su

tio
blockade)
m

n
●● Antagonism m
■■ competitive (e.g. naloxone, atracurium and beta-blockers)
at
ive

Sy
ne
■■ non-competitive (e.g. ketamine antagonism of glutamate at NMDA

rg
receptor)

ist
ic
■■ physiological (e.g. histamine and adrenaline on airways)
●● Indirect interactions – for example
■■ interaction of pethidine and monoamine oxidase inhibitors
■■ diuretics induce hypokalaemia, which increases digoxin toxicity Dose of drug A

Lipid solubility and protein binding
Lipid solubility
●● The higher the lipid solubility of a drug, the faster
it passes through the cell membrane
●● Meyer–Overton rule – Potency of inhalational anaes-
thetic agents depends on their lipid solubility
Clinical nugget
●● With local anaesthetics, the higher the lipid
solubility the greater the potency, rate of
onset, duration of action, toxicity and local
irritancy
●● Highly lipid-soluble fentanyl can be adminis-
tered transdermally by patch
●● Intrathecal diamorphine has a fast onset
of action because of its high lipid solubility
●● Morphine is less lipid soluble and stays in
the cerebrospinal fluid (CSF) longer, which
increases the risk of cranial spread and late
respiratory depression
Pharmacology
Principles 159
Protein binding
●● Only free drug can pass through the cell mem-
brane, be metabolized or excreted
●● Albumin binds ions and acidic drugs (thiopentone,
warfarin and salicylates)
●● Alpha-1 acid glycoprotein binds basic drugs (local
anaesthetics and propranolol)
●● Globulins bind tubocurarine
●● >90% plasma protein binding is needed for a clini-
cally important effect
●● Hypoalbuminaemia in liver failure (reduced synthe-
sis) and kidney failure (increased loss) increases the
amount of free drug
●● Alpha-1 glycoprotein is increased in obesity, burns,
trauma, MI, malignancy, inflammatory conditions,
postop
●● Binding of one drug can affect the binding site of
another drug (e.g. the binding of aspirin to albumin
affects the binding of diazepam)
●● Free drug fraction is affected by drug concentration
and pH
●● Albumin concentration falls in acute infective or
inflammatory conditions, cirrhosis and burns, which
causes an increase in the proportion of unbound drug
●● More highly protein bound drugs have a longer
duration of action
Drug mechanism of action
Pharmacodynamics is the effect of drugs on the body,
which may be by a simple physicochemical effect or
highly selective mechanism
Physicochemical effects
●● Antacids neutralize gastric acid
●● Adsorption (e.g. activated charcoal)
●● Sugammadex chelates either rocuronium or
vecuronium
Effects on enzymes
●● Competitive reversible inhibition (e.g. NSAIDs for
cyclooxygenase)
●● Non-competitive reversible inhibition (e.g. neostig-
mine for acetylcholinesterase)
●● Irreversible inhibition (e.g. aspirin for cyclooxygen-
ase and omeprazole for Na+/H+ ATPase)
●● Inhibition of angiotensin converting enzyme prevent-
ing the conversion of angiotensin I to angiotensin II
(e.g. ramipril)
Effects on voltage-gated ion channels
●● Local anaesthetics inhibit sodium channels in the
nerve membrane
●● Calcium channel blocking agents block vascular
smooth muscle ion channels
●● Antiarrhythmics block myocardial ion channels
Effects on receptors
●● Altered ion permeability (e.g. nicotinic receptor)
●● Production of intermediate messengers (e.g. cAMP,
cGMP, and tyrosine kinase)
●● Regulation of gene transcription (e.g. steroids)
Enzyme inducers
●● Induction occurs due to increased enzyme synthesis
or decreased breakdown
●● Cytochrome P450 inducers include barbiturates,
phenytoin, carbamazepine, rifampicin, griseofulvin,
tobacco and chronic alcohol
Enzyme inhibitors
●● Inhibition is due to reduction of the amount of
enzyme or its activity
●● Cytochrome P450 inhibitors include imidazoles
(e.g. ketoconazole, omeprazole, cimetidine and
etomidate), erythromycin, clarithromycin, most anti-
depressants, HIV protease inhibitors, cyclosporin,
amiodarone and grapefruit juice

Isomerism
Isomers are compounds with the same atomic
formulae (same molecular weight) but differ-
ent structural arrangements, and often differ-
ent properties
●● They may be structural isomers or stereo-
isomers
Structural isomers
●● Structural isomers have different chemical
structures with the same molecular weight
●● They may be
■■ positional isomers (e.g. enflurane and
isoflurane), in which the atoms occupy
different positions on an identical carbon
skeleton
■■ chain isomers (e.g. butane and isobu-
tane), in which the carbon skeleton varies
but the functional groups remain the same
■■ functional group isomers (e.g. proprano-
lol and methyl-ethyl ether), in which the
functional groups vary
●● Tautomerism is a type of structural isomer-
ism, in which the two isomers exist in equi-
librium determined by the surrounding pH
Pharmacology
Principles 160
■■ for example, thiopentone in the syringe
is water soluble and ionized, but after
intravenous injection it is converted to an
unionized, lipid-soluble compound
Stereoisomers
●● Stereoisomers have the same chemical
constituents and structure, but different 3D
spatial configurations
●● Geometric isomerism (cis–trans isomerism)
refers to the different arrangement of atoms
around a double bond
■■ if both constituents are on the same side
of the double bond, it is a ‘cis’ isomer, if
on opposite sides, it is a ‘trans’ isomer – for
example, mivacurium and cisatracurium
●● Optical isomers (enantiomers) are com-
pounds that are mirror images of each other
around a central atom (chiral centre)
■■ Originally classified according to their
ability to rotate the plane of polarized
light in opposite directions (levo/dextro
isomers)
Isomerism (cont.)
Stereoisomers (cont.)
■■ This classification has been superseded
by the R (rectus)/S (sinister) system, which Clinical nugget
describes the configuration of the atoms
●● Many anaesthetic drugs are chiral in
around the chiral atom according to the
nature (e.g. atropine, morphine, vola-
molecular weights of the other atoms
tile agents [but not sevoflurane] and
■■ A racemic mixture contains equal
adrenaline)
amounts of the two isomers and conse-
●● Enantiomers may have differing activity
quently has no optical activity
spectra
■■ Diastereoisomers have more than one
■■ s(+) ketamine has greater affin-
chiral centre and are not mirror images of
ity for the N-methyl-D-aspartic acid
each other
(NMDA) receptor and produces
more anaesthesia and analgesia
1 1 with faster recovery and less emer-
gence phenomenon than the R(–)
isomer
4 Chiral centre
■■ Levobupivacaine has fewer cardio-
4 vascular side effects and is safer in
2 3 overdose than racemic bupivacaine
3 2
■■ Many drugs are now available in
enantiopure preparations (e.g.
etomidate and ropivacaine)

Malignant hyperpyrexia
Malignant hyperpyrexia (MH) is an autoso-
mal dominant condition characterized by
increased temperature and rigidity under
anaesthesia triggered by suxamethonium or
volatile anaesthetics.
Pathophysiology
●● Incidence: 1:5000–1:200,000
●● Abnormal skeletal muscle contraction
●● Abnormal metabolism
●● 50%–70% caused by abnormal ryanodine
receptor gene on chromosome 19
●● May not occur on first exposure – 75% have
had previous uneventful anaesthetics
●● Risk factors include central core disease,
orthopaedic surgery and squint surgery
Clinical features
●● Increased ETCO2 (or hyperventilation if spon-
taneously ventilating) and tachycardia
●● Masseter spasm early sign
●● Sustained muscle contraction (excitation–con-
traction uncoupling) with generalized rigidity
Pharmacology
Principles 161
●● Unrelieved by neuromuscular blockers
●● ↑ oxygen consumption with desaturation or
cyanosis
●● Hyperpyrexia and sweating late signs with
core temperature ↑ 2°C/hour
Investigations
●● ↑ potassium (leading to arrhythmias, e.g.
multiple ventricular ectopics and peaked
T waves)
●● ↑ myoglobin
●● ↑ creatine kinase (check 12 hourly for 36–48
hours)
●● Metabolic and respiratory acidosis
●● First urine sent for myoglobin
Management
●● ABC and fluids
●● Stop trigger and surgery if possible (senior
surgeon to help)
●● Hyperventilate with 100% oxygen
●● Inform theatre team and get help
●● Change anaesthetic machine and soda lime
Malignant hyperpyrexia (cont.)
Management (cont.)
●● Change from circle to non-rebreathing
system
●● Dantrolene 1 mg/kg intravenously repeated
up to 10 mg/kg (takes time to reconstitute)
●● Propofol TIVA (total intravenous anaesthesia)
to maintain anaesthesia
●● Correction of acidosis with bicarbonate
●● Cooling with cold fluids, fans, sponging, ice
to groins and axillae, and irrigation of body
cavities (urinary catheter, stomach via naso-
gastric tube or peritoneal cavity if open)
●● Treat hyperkalaemia
●● Consider mannitol or frusemide to reduce
renal damage caused by myoglobin
●● Symptomatic treatment of arrhythmias
●● ITU for 36–48 hours
●● Treat renal failure and disseminated intravas-
cular coagulation (DIC)
Later investigation
●● Refer to malignant hyperpyrexia investigation
unit
●● Muscle biopsy may be normal
●● Caffeine and halothane contraction tests
may be positive, negative or equivocal
●● In vitro contracture testing has 99% sensitivity
and 94% specificity
●● If diagnosis confirmed, DNA test family
Anaesthetic management
of known case
●● Avoidance of trigger
●● TIVA or regional technique
●● Flush anaesthetic machine for 20–30 minutes
and change breathing system
●● Standard monitoring, temperature
●● Consider arterial-line
●● Have dantrolene nearby
 Pharmacology

Principles 162
Materno-fetal drug distribution
●● The placenta is a lipid membrane, so lipid-soluble drugs pass through more easily
●● It is significantly less selective than the blood–brain barrier so drugs with low lipid solubility may pass

Rate of placental drug transfer

●● Fick’s law explains the rate of transfer of drugs across the placenta:
Q/t = KA(Cm − C f)/D
where Q/t = rate of diffusion, K = diffusion constant of drug, A = surface area of membrane,
Cm = maternal drug concentration, C f = fetal drug concentration and D = thickness of membrane
●● High K – low molecular weight, low protein binding, high lipid solubility and low ionization
●● High Cm – high dose, slowly metabolized drugs given in highly vascular areas
●● Increased placental blood flow causes increased transfer
●● Fetal blood has lower pH, so plasma protein binding may differ
●● Fetus may metabolize some drugs
●● Some drugs readily cross placenta
■■ non-polar compounds such as respiratory gases and inhalational anaesthetics
■■ compounds that can exist in non-ionized state
● weak acids (thiopentone, non-steroidal anti-inflammatory drugs)
● weak bases (local anaesthetics and opioids)
Materno-fetal drug distribution (cont.)
Local anaesthetics ●● Lignocaine readily crosses placenta because of
■■ low plasma protein binding
■■ relatively low ionization at physiological pH
■■ high lipid solubility
●● Bupivacaine crosses placenta less than lignocaine, as its pKa makes it more
ionized at maternal plasma pH
●● If fetal acidosis occurs, fetal bupivacaine becomes ionized, and ‘ion trapping’
may cause fetal toxicity
●● Fetal/maternal plasma concentration ratios for local anaesthetics <0.5, so
fetal toxicity will only occur during maternal toxicity
Opioids ●● Pethidine is highly lipid soluble, so can cross placenta
●● Toxic metabolite norpethidine less lipid soluble, so can accumulate
Anaesthetic agents ●● Thiopentone crosses placenta within 30 seconds of maternal administration
and peaks at 3 minutes but causes no harm to fetus
●● Inhalational anaesthetics cross placenta, which results in fetal plasma
concentrations of 50%–90% of maternal plasma concentrations
●● Isoflurane, sevoflurane and nitrous oxide rapidly excreted from neonates’
lungs, so sedation brief
Neuromuscular ●● Non-depolarizing neuromuscular blocking agents are large polar molecules
blocking agents that do not cross placenta
●● Suxamethonium crosses the placenta in very small amounts with minor effect
 Pharmacology

Principles 163
Addiction and dependence
Addiction State of compulsive use of a drug associated with physical, psychological or
social harm and despite evidence of that harm
Dependence Physiological adaptation associated with withdrawal symptoms when
ingestion of the drug ceases
Tolerance Progressively decreasing response to repeated dosage of a drug
●● Mechanisms
■■ altered numbers of drug receptors
■■ altered response to drug receptor activation
■■ pharmacokinetic alterations (e.g. induction/inhibition of enzymes)
■■ development of physiological compensatory mechanisms
Tachyphylaxis Rapid decrease in response after multiple doses over short period of time. With
ephedrine, depletion of noradrenaline occurs because it is not synthesized fast
enough between doses

Tobacco
●● Smoking increases perioperative risk of atelectasis, sputum retention, coughing, bronchospasm,
chest infection and impaired wound/bone healing
●● Pulmonary effects of smoking include impaired ciliary and leucocyte function, and increased risk
of bronchial carcinoma, bronchial reactivity and COPD
●● Sympathetic stimulation by nicotine increases heart rate, SVR, BP, and myocardial oxygen demand
●● Oxygen delivery is reduced (up to 15% carboxyhaemoglobin, left shift of the oxyhaemoglobin dis-
sociation curve and increased blood viscosity)
●● Increased risk of ischaemic heart disease, ventricular arrhythmias and DVT
Addiction and dependence (cont.)
Chronic alcohol use
●● CNS effects – cerebral/cerebellar degeneration, peripheral neuropathy, Wernicke’s encephalop-
athy and Korsakoff’s psychosis
●● GI effects – gastritis, peptic ulcers, oesophageal varies, haemorrhage and pancreatitis
●● Liver effects – fatty liver, enzyme induction, cirrhosis and coagulopathy
●● Malnutrition, immunodeficiency, myopathy and cardiomyopathy
●● Withdrawal causes anxiety, tremor, convulsions, hallucinations and delirium tremens

Non-legal drugs
●● May be resistant to IV anaesthetic drugs
●● Difficult IV access
●● Difficult opioid drug dosing
●● Withdrawal may occur
■■ opioids – tachycardia, tremor, ‘cold turkey’
■■ barbiturates – anxiety, tremor, hallucinations
●● IV drug use – increased risk of sepsis, thrombophlebitis, bacterial endocarditis, hepatitis and HIV
●● Chronic effects of substance (e.g. enzyme induction, cardiomyopathy, hepatic impairment,
thrombocytopenia)
●● Acute excitatory effects (e.g. tachycardia, hypertension, arrhythmias and pyrexia with amphet-
amines, LSD and cocaine)
●● Acute depressant effects (e.g. respiratory depression and hypotension with opioids and barbiturates)

Pharmacokinetics is the study of what the body
does to a drug and encompasses absorption,
distribution, metabolism and excretion
Absorption of drugs
●● Variety of routes – oral, intravenous, intramuscular, sub-
lingual, buccal, rectal, inhalational, transtracheal, sub-
cutaneous, transdermal, intrathecal, epidural or topical
●● Most drugs absorbed by diffusion; some have
active transport mechanisms (e.g. L-dopa and
alpha-methyldopa)
●● Time course for systemic appearance of PO drugs is
dependent on:
■■ drug characteristics
■■ gut motility
■■ vomiting
■■ digestive enzymes
■■ interaction with other drugs and foods
■■ disease of the gastrointestinal tract
■■ intestinal microflora
Bioavailability
Fraction of drug that reaches the systemic circulation
●● If a graph of plasma concentration versus time is plot-
ted, bioavailability is the ratio of the areas under the
curve of an identical dose given orally and intravenously
●● Oral route usually has lowest bioavailability
Pharmacology
Pharmacokinetics 164
Plasma
AUCiv
AUCnon-iv
Time
Factors that affect bioavailability
●● Pharmaceutical preparation – small particles
and liquid are more rapidly absorbed than enteric-
coated preparations
●● Ionization – highly ionized drugs have low bioavail-
ability (e.g. vecuronium and streptomycin)
●● Metabolism of drugs in the stomach (benzylpenicillin)
or gut wall (tyramine) reduces bioavailability
●● First-pass metabolism in the liver reduces bioavail-
ability (lignocaine and morphine)
●● Route – ketamine has 20% bioavailability orally but
90% IM
Drug entry into cells
●● The ability of a drug to pass through a membrane depends on:
■■ lipid solubility
■■ pH
■■ size of drug molecule (the smaller the molecule, the more quickly it will diffuse)
■■ carrier processes
■■ pinocytosis (e.g. insulin)
■■ partition coefficients
●● Carrier-mediated transport is used by certain drugs that are similar to physiologically important
molecules, such as methyldopa, levodopa and thyroxine
■■ May be active or passive
■■ May involve
● two molecules being transported in the same direction via a co-transporter down a con-
centration gradient (e.g. Na+ and glucose) OR
● two molecules being transported in opposite directions against a concentration gradient
(e.g. Na+/K+/ATPase)
●● In the lipid bilayer of the cell membrane are aqueous channels through which certain drugs, such
as ethanol, pass
●● Fick’s law states that the rate of transfer across a membrane is proportional to the concentration
gradient across the membrane and can be expressed as:
K AC
Rate of diffusion across the cell membrane, Q = p
T
where C = concentration difference, A = area of membrane, Kp = membrane permeability and
T = membrane thickness
●● Graham’s law states that the rate of diffusion is inversely proportional to the square root of the
molecular size
 Pharmacology

Pharmacokinetics 165
Drug distribution
●● Drug distribution throughout the body is related to ability of the drug to cross the cell membrane, which is affected by:
■■ lipid solubility – more lipid-soluble drugs are distributed more widely
■■ protein binding – highly protein bound drugs are unavailable to cross membranes
■■ ionization – pK and body pH; polar drugs have reduced distribution
■■ regional blood flow (vessel-rich group > muscle group > fat group)
■■ redistribution of drug, which reduces blood levels and thus the drug’s effect (e.g. thiopentone)
■■ tissue/blood partition coefficients

Clearance
Volume of plasma completely cleared of drug in unit time
Urinary concentration (mmol /L) × urine volume (mL / min)
●● For kidney, renal clearance =
Plasma concentration (mmol /L)
●● A substance is incompletely removed if clearance is less than GFR and secreted if GFR less than clearance

Compartmental models
●● Distribution of drugs can be described using one-, two-or three- compartmental models
●● Processes are exponential
●● When plotted semi-logarithmically (log10 concentration vs. time) can lead to calculation of half-life and clearance

One-compartment model
Two-compartment model
Three-compartment model
●● Concentration declines exponentially over time (never occurs clinically)
●● Drug redistributed from central compartment (plasma) to peripheral compartment
●● Biexponential fall in plasma level – initial rapid alpha decrease followed by slower
beta elimination
●● One central compartment and two peripheral compartments (most anaesthetic drugs)
Dose–response curves
100 100

Agonist 1 Agonist 2
Maximum response

Agonist +
(< potent) competitive
antagonist

Response
50 50

Non-competitive
antagonist
EC50 ED50 Partial
0 0 agonist
Drug concentration (mg · mL–1) Log10 dose Log dose

Compartmental models
Bolus (I) Bolus (I) Bolus (I)

K21 K13
K12 V3
V2
Volume V1
V2 V1 K12 K31
V
K21

K (elimination) K10 K10

Single-compartment model Two-compartment model Three-compartment model

V = Volume of distribution K = Rate constant
 Pharmacology

Pharmacokinetics 166
Drug metabolism
Drug metabolism is the chemical alteration of a drug by the body
●● Metabolites may be inactive or may be similar to or different from the original drug in therapeutic activity or toxicity
●● Prodrugs (e.g. enalapril and methyldopa) are administered in an inactive form, which is metabolized into an
active form, with the resulting metabolites producing the desired therapeutic effects

The liver in drug metabolism

Metabolism of drugs by the liver aims to convert a lipid-soluble substance into a water-soluble substance that
can be excreted by the kidneys
●● It consists of two phases
■■ Phase 1 – oxidation, reduction or hydrolysis
■■ Phase 2 – conjugation to produce a more water-soluble product

Phase 1 reactions Phase 2 reactions

●● Almost entirely oxidative (although a small amount of hydrolysis and ●● Phase 1 modification usually leaves
reduction occurs) drug with reactive end group that
●● Carried out by cytochrome P450 in smooth endoplasmic reticulum can be conjugated with more
■■ cytochome P450 is a diverse enzyme superfamily (so-called because it hydrophilic compounds
absorbs light at a wavelength of 450 nm when in the reduced form ■■ glucuronidation – morphine
and combined with carbon monoxide) ■■ sulphation – benzodiazepines
■■ subdivided into families (40% sequence homology), subfamilies (55% ■■ acetylation – hydralazine
sequence homology) and individual isoforms ■■ methylation – catecholamines
■■ isoforms important for metabolism of anaesthetic drugs include: ■■ glycination – aspirin
●● CYP2E1 – paracetamol, Fl–-containing volatiles
●● CYP3A4 – midazolam, alfentanil
●● CYP2C19 – phenytoin, diazepam
●● CYP1A2 – induced by smoking and increases metabolism of some
drugs (e.g. theophyllines)
Drug metabolism (cont.)
Factors that affect liver metabolism of drugs
●● Genetic polymorphism ●● Environmental factors
■■ Slow and fast acetylators (e.g. hydralazine) ■■ Diet
■■ Suxamethonium apnoea (genetic abnor- ■■ Smoking
malities of plasma cholinesterase) ■■ Alcohol
●● Age ■■ Insecticides
■■ CYP1A2 is not expressed in neonates, so ●● Enzyme inhibitors and inducers
they are particularly susceptible to toxicity
from drugs such as caffeine

Non-liver metabolism of drugs

Plasma Lung Kidney Gut
●● Plasma cholinesterase ●● Angiotensin I ●● Midazolam ●● Isoprenaline
■■ suxamethonium ●● Prilocaine ●● Dopamine ●● GTN
■■ mivacurium ●● Monoamines ●● Lignocaine
■■ ester local anaesthetics
●● Non-specific esterases
■■ esmolol
■■ remifentanil
●● Ester hydrolysis
■■ atracurium
 Pharmacology

Pharmacokinetics 167
Elimination and excretion
Elimination Removal of active drug from the plasma (including distribution, metabolism and
excretion)
Excretion Removal of drug from the body which primarily occurs in the urine and bile. It also
occurs in the lungs (volatile anaesthetics), faeces, tears and breast milk
●● Filtration at the glomerulus occurs of small, non-protein-bound water-soluble drugs
●● Proximal tubule secretion is an active-transport process by different carrier systems
for acidic and basic drugs
●● Distal tubule diffusion occurs down the concentration gradient.
●● Acidic drugs are excreted more in alkaline urine as more ionized drugs exist which
cannot be reabsorbed
●● Basic drugs are excreted more in acidic urine
●● High molecular weight compounds are not filtered or secreted by the kidneys so
are excreted in the bile

Kinetics of elimination
First-order kinetics ●● Rate of elimination is proportional to amount of drug in body (i.e. simple
exponential decay)
Zero-order kinetics ●● Constant amount of drug eliminated per unit time (e.g. phenytoin and
alcohol)
●● First-order kinetics may convert to zero-order kinetics at high concentra-
tions where excretion pathways saturate
Elimination and excretion (cont.)
Volume of distribution (Vd)
Theoretical volume the drug would occupy
if the concentration throughout the body was
the same as the concentration in the plasma
●● Initial Vd refers to the apparent Vd in the central
Vd = volume of distribution (L)
compartment immediately after drug injec-
t0 = time zero
tion but before redistribution to the tissues
C 0 = plasma concentration at time zero
●● Vd at steady state is more commonly quoted
●● Large or charged drugs that cannot enter cells
have low Vd (e.g. vecuronium and atracurium)
●● Drugs that are highly lipid soluble have large
Vd (e.g. propofol)
●● Inversely proportional to protein binding (e.g.
propofol is 98% protein bound which increases
its central compartment volume to about
16 litres)
●● Indication of amount of drug within tissues:
■■ If Vd = blood volume (3.5 L), drug is con-
fined to the plasma
■■ If Vd = total body water (42 L), drug is dis-
tributed evenly throughout body
■■ If Vd > total body water (>42 L), the drug is
concentrated within tissues
Vd =
Amount of drug in body at t 0
C0
Dose
Vd =
C0
Clinical nugget – Critical illness
and the effects on volume of
distribution
●● Increased synthesis of α-1-acid glyco-
protein reduces binding of basic drugs.
Unbound drug fraction is therefore
reduced and efficacy may be reduced
●● Increased capillary membrane per-
meability results in fluid shifts which
may increase volume of distribution
and reduce effective plasma drug
concentration
●● Hypoalbuminaemia may increase
unbound drug fraction of acidic drugs
(e.g. warfarin) and increase distribution
 Pharmacology

Pharmacodynamics 168
Agonists and antagonists
Affinity ●● Ability of a drug to bind a receptor
Intrinsic ●● Ability of a drug to interact with a receptor to produce a response (i.e. the efficacy)
activity ●● Represented by height of dose–response curve
Agonist ●● Drug that binds to a receptor and causes a response or effect
●● Intrinsic activity of 1
Antagonist ●● Drug that binds to a receptor and does not produce a response
●● Affinity but intrinsic activity of 0
●● Reversible/competitive antagonists
■■ Dose–response curve shifts to right but Cmax remains the same (e.g.
displacement of acetylcholine by non-depolarizing muscle relaxants)
■■ Action of competitive antagonist can be overcome by increasing dose of agonist
●● Non-competitive antagonists
■■ Prevent receptor activation through conformational distortion of the receptor
■■ Non-competitive antagonist has different binding site to agonist and so
cannot be overcome by increasing the dose of agonist (e.g. ketamine at the
N-methyl-D-aspartic acid [NMDA] receptor)
■■ Shift dose–response curve to right and reduce Cmax
Partial ●● Drug that binds to receptor and causes partial response
agonist ●● Intrinsic activity <1
Inverse ●● Drug that binds to receptor and has an effect opposite to that of an agonist (e.g.
agonist flumazenil)
Agonists and antagonists (cont.)
Agonist–antagonist ●● Drug that acts as agonist at some receptors and antagonist at others (e.g.
pentazocine)
Potency ●● Ability of drug to produce certain effect
●● Influenced by pharmacokinetics of drug
●● Represented by position on abscissa of dose–response curve
Physiological ●● Cause the opposite effect via a different receptor (e.g. histamine causes
antagonist bronchoconstriction and adrenaline causes bronchodilation)
Non-competitive ●● Antagonists that bind to a site distant to the agonist receptor site and cause a
antagonist change in the binding characteristics of the agonist
●● This may reduce or enhance the agonist effect (e.g. benzodiazepines increase
the activity of gamma-aminobutyric acid [GABA] at the GABAA receptor
complex)
Spare receptors ●● Exist where a full response occurs when only a fraction of the receptors are
occupied (e.g. acetylcholine receptors at the neuromuscular junction)
Relative affinity (Kd) ●● The dissociation constant at equilibrium and is a measure of affinity:
Number of bound receptors
Kd =
Total number of receptors

Therapeutic index ●● Relation between doses of drug needed to produce desirable and undesirable
effects
●● Low therapeutic index indicates that levels of drug should be monitored (e.g.
warfarin and aminoglycosides)
Median lethal dose LD50
Therapeutic index = =
Median effective dose ED50
 Pharmacology

Pharmacodynamics 169
Ionization and pKa
●● Ionized (charged) particles are relatively lipid insoluble and do not easily cross cell membranes
●● Degree to which drug is ionized depends on molecular structure of drug and ambient pH of solu-
tion in which it is dissolved
●● pK is negative logarithm to base 10 of the dissociation constant for the chemical reaction
●● pKa is pH at which 50% of drug is ionized; independent of whether drug is acidic or basic, and
depends on molecular structure
●● Degree of ionization expressed by Henderson–Hasselbalch equation:
(proton acceptor)
pH = pK a + log
(proton donor)
●● At 50% ionization, pH = pKa
●● For an acid (e.g. salicylates, barbiturates, penicillin):
(ionized drug)
pH = pK a + log
(unionized drug)
●● For a base (e.g. local anaesthetics, opioid analgesics):
(unionized drug)
pH = pK a + log
(ionized drug)
●● The stronger an acid, the lower its pKa
●● The stronger a base, the higher its pKa

Ambient pH < pKa Ambient pH > pKa

Weak acid More unionized More ionized
Weak base More ionized More unionized
Ionization and pKa (cont.)

Clinical nugget – ionization

Aspirin
●● Acidic and ionized at physiological pH (pKa = 3.0)
●● Unionized in stomach acid
●● Absorbed in stomach and small intestine (limited surface area in stomach)

Acidosis
●● Local anaesthetics less effective in infected tissue, as acidosis reduces unionized fraction
available to diffuse into nerve
●● For example, lignocaine pKa = 7.9 (weak base)
■■ at pH 7.4, 25% is unionized
■■ at pH 7.1, 14% is unionized
●● Thiopentone is a weak acid, pKa = 7.6
■■ presented as salt of weak acid and thus alkaline in solution (pH 10.5)
■■ in blood, unionized portion (available to cross to brain) increases in acidic conditions,
so less is needed for same effect

Forced diuresis
●● Drugs in ionized form may be ‘trapped’ in urine by manipulation of urinary pH

Receptors
●● Ligands are substances that bind to a specific site
on a receptor.
●● Receptors are proteins to which ligands bind to
produce a response within the cell
●● Receptors often span the cell membrane (i.e. are
transmembrane). Receptors work by opening ion
channels, producing intermediate messengers, or
regulating gene transcription
Ligand gated ion channel receptors
●● The transmembrane channel opens to allow passage
of ions down their concentration gradient (e.g. Na+ with
acetylcholine receptors and Cl− with GABA receptors).
They work in milliseconds
Intermediate messenger systems
●● Transduction systems cause a response in the cell by
transmitting ligand-generated signals through inter-
mediate messenger systems. Intermediate messen-
ger systems include the G-protein coupled receptor,
tyrosine kinase, and guanylyl cyclase systems
G protein–coupled receptors
●● Examples are beta-agonists and opiates
●● G proteins (guanine nucleotide-binding pro-
teins) are cell membrane proteins that mediate
Pharmacology
Pharmacodynamics 170
the intracellular response to coupled membrane
receptors
●● G proteins are so called because they bind GDP and GTP
●● Consist of three subunits: alpha (α), beta (β) and
gamma (γ)
●● At rest, the G protein is a trimer, with the α-subunit
bound to guanosine diphosphate (GDP)
●● When an agonist binds the G protein–coupled recep-
tor, it undergoes a conformational change that results
in increased affinity of the receptor for the G protein
●● This leads to guanosine triphosphate (GTP) displac-
ing the GDP on the α-subunit
●● The α-subunit dissociates from the αβγ trimer; the
βγ-complex is hydrophobic and remains as such
●● The αGTP complex is active and binds to intracellu-
lar targets such as adenylate cyclase, cAMP, phos-
pholipase C and IP3. This leads to an intracellular
cascade of protein phosphorylation and can lead
to protein synthesis, gene activation and changes in
ionic permeability of the cell
●● G proteins can interact with several different recep-
tors and effectors
●● GTPase on the α-subunit hydrolyses GTP to GDP and
terminates the process
●● G-protein coupled receptors respond in millisec-
onds to seconds
Receptors (cont.)
Tyrosine kinase receptors
●● The ligand binds to the transmembrane
receptor to activate tyrosine kinase inside the
cell, using energy from ATP to catalyze target
proteins. Insulin, epidermal growth fac-
tor and platelet-derived growth factor are
examples. Insulin binds to the alpha subunits
of the insulin receptor to activate the intracel-
lular responses such as insertion of glucose
transport protein into the cell membrane and
gene transcription. They work in minutes to
hours
Guanylyl cyclase systems
●● Natriuretic peptide activates membrane-
bound receptors with guanylyl cyclase activ-
ity causing increased cGMP levels leading
to phosphorylation of intracellular enzymes.
Nitric oxide increases cGMP levels by stimu-
lating cytosolic guanylyl cyclase
Intracellular/nuclear receptors
●● The ligand passes through the cell mem-
brane to bind the intracellular/nuclear recep-
tor, causing alteration of DNA transcription.
Examples include thyroid hormones and
corticosteroid hormones. Glucocorticoid
receptors are wide spread but mineralocor-
ticoid receptors are restricted to epithelial tis-
sue such as in the colon and renal collecting
tubules. Nuclear receptors work in a few hours
Receptor regulation and
tachyphylaxis
●● Upregulation is an increase in the number of
receptors due to under stimulation (e.g. after
spinal cord injury).
●● Down regulation is a decrease in the number
of receptors following chronic over stimula-
tion (e.g. insulin in obese patients).
●● Tachyphylaxis is the reduced response to a
drug after repeated exposure. It is usually due
to reduction of number of receptors (or deple-
tion of neurotransmitter).
 Pharmacology

Pharmacodynamics 171
G protein–coupled receptor
Ligand binding domain buried
within the membrane on 1/>
α-helices

G-protein coupled
receptor 7 Transmembrane
α-helices

Cell membrane
C-terminal cytoplasmic
tail has sites for the
Long 3rd cytoplasmic activity of kinase enzymes
loop couples to (protein phosphorylation)
G-protein γ
α Inactive G-protein
β – Trimer
GDP

γ
α +
β
GTP

Active
NMDA receptors
N-methyl-D-aspartate receptors are CNS receptors that are activated by glutamate with glycine
as a co-agonist. They are involved in the mechanism of action of ketamine, nitrous oxide and
xenon
●● Glutamate is an amino acid that is the main excitatory neurotransmitter in the CNS. It acts presyn-
aptically via AMPA, kainate and NMDA receptors
●● The NMDA receptor is involved in long-term signal potentiation in the brain for learning and
memory
●● Activation of the NMDA receptor by glutamate released by C-fibre stimulation causes phosphor-
ylation of intracellular proteins and opening of the ion channels
●● This increases intracellular calcium and the response to glutamate with positive feedback
●● In pain physiology continual stimulation of NMDA receptors causes hyperexcitability or ‘wind-up’
with increasing pain from an enlarging area
●● NMDA receptor antagonists (e.g. ketamine) can therefore be used in pre-emptive analgesia if
given before the painful stimulus
●● Nitrous oxide and xenon also cause inhibition at the NMDA receptor
●● Barbiturates also inhibit glutamate at the NMDA receptor but with less of the effect than at the
GABA A receptor
 Pharmacology

Pharmacodynamics 172
Gamma aminobutyric acid (GABA)
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the CNS and binds
to ­s pecific transmembrane GABA A and GABAB receptors
●● GABA is important in epilepsy, as many anticonvulsants facilitate the action of GABA
●● GABA A receptors are ligand-gated ion channel receptors composed of five subunits (two α, β, γ,
δ) with a chloride channel
●● The binding sites for GABA are associated with the α-subunit
●● There are modulatory sites on the β-subunit for anaesthetic drugs
●● There are modulatory sites on the α/γ interface for benzodiazepines
●● GABA binds to the GABA A receptor to allow chloride into the cell and decrease neuron excitability
●● The β-subunit of the GABA A receptor is associated with the site of action of propofol, thiopentone,
volatile anaesthetics, and R-etomidate
●● S-etomidate is clinically inactive at the GABA A receptor
●● Low concentrations of anaesthetics potentiate the action of GABA at the GABA A receptor
●● Higher concentrations directly activate the receptor
●● There is a different binding site on the GABA A receptor for benzodiazepines
●● There are at least 30 different types of GABA A receptor, all having different compositions of
subunits
●● GABAB receptors are G protein coupled receptors which are linked to K+ and Ca2+ channels through
phospholipase C and adenylate cyclase. They are the site of action of baclofen
Adverse drug reactions
Adverse drug reactions are harmful drug effects which may be predictable (type A) or
idiosyncratic (type B)
●● Type A effects are dose-related expected effects (e.g. hypotension with propofol)
●● Type B effects are idiosyncratic unpredictable effects that are not related to overdose or usual
expected effects and usually involve the immune system
●● Mechanisms on first exposure include direct histamine release (e.g. atracurium) and prior sensi-
tization to environmental antigen (e.g. dextrans). Prior exposure may cause anaphylaxis or classi-
cal pathway complement activation
●● Clinical features may be mild (rashes) to anaphylaxis. Reactions requiring prior exposure are usu-
ally more severe and rarer
●● Urgent management is as for anaphylaxis. Blood test for mast cell tryptase ASAP, at 1–2 hours
and at 24 hours if anaphylaxis is considered. Skin testing for IgE-mediated reactions includes prick
testing, intradermal testing and patch testing
●● Referral for appropriate testing should be made by the anaesthetist after a severe reaction or
perioperative collapse

Anaphylaxis
Anaphylaxis is a severe life-threatening systemic allergic reaction
●● Mechanism in type 1 hypersensitivity involves IgE-mediated release of vasoactive and broncho-
constrictive substances. May be triggered by perioperative drugs such as muscle relaxants or
antibiotics. Anaphylactoid reactions have the same clinical features without IgE release; acute
mechanism differentiation is not important
●● Clinical features commonly include flushing, CVS collapse and wheezing.
●● Urgent management is to stop the drug, call for help,ABC, 100% oxygen, adrenaline and fluid. Secondary
treatment includes antihistamine, corticosteroid, supportive management and airway evaluation
●● Investigations and referral as above
 Pharmacology

Analgesia 173
Aspirin
Analgesic drug commonly used for its antiplatelet effect
Structure ●  Aromatic ester of acetic acid
Presentation ●  75, 100, 300, 600 mg tablets
Indications ● Analgesia ●  Anti-platelet (in MI)  ●  Prophylaxis of deep vein thrombosis  ●  Anti-inflammatory 
●  Pre-eclampsia  ●  Anti-pyretic  ●  Prevention of transient ischaemic attacks
Mechanism of ●  Irreversible inhibitor of COX-1 and COX-2  ●  Prevents prostaglandin and thromboxane formation
action ●● Does not affect endothelial cyclooxygenase, so vessels remain dilated
Onset ●  1–2 hours bioavailability 70%
Duration ●  7–10 days until new platelets formed
Dose ●  300–900 mg orally 3–4 times daily
Effects ● Analgesic ●  Increased bleeding time  ●  Uncouples oxidative phosphorylation: increased consump-
tion of oxygen and increased production of carbon dioxide  ●  Antipyrexial: inhibits consumption of oxygen
and increased production of carbon dioxide; inhibits hypothalamic synthesis of prostaglandin
●● Increases production of gastric acid
Side effects ●  Mainly due to COX-1 inhibition:  ●  Gastrointestinal disturbances, haemorrhage or ulceration secondary
to inhibition of production of gastric prostaglandins  ●  Hepatic impairment  ●  Chronic renal failure
●  Reye’s syndrome – aspirin-induced mitochondrial damage, fatty liver, encephalopathy and cerebral
oedema; occurs in children but rarely seen now as aspirin no longer given to children unless specifically
indicated, for example for Kawasaki syndrome
Contraindications ● Breastfeeding ●  Haemophilia  ●  Peptic ulceration  ●  Bleeding
Metabolism ●  Half-life varies with dose because of saturable liver enzymes: 50% metabolized to salicylurate and 20% to
salicylphenolic glucuronide  ●  Also metabolised by esterases in gut wall
Pregnancy ●● Caution in third trimester: impaired platelet function, increased haemorrhage, closure of ductus
arteriosus in utero and possible persistent pulmonary hypertension of newborn
Comments ●● Overdose results in metabolic acidosis (from salicylate) and hyperventilation to keep down the carbon
dioxide level
●  Increasing aspirin levels cause direct stimulation of the respiratory centre and respiratory alkalosis
Paracetamol
Most commonly used analgesic, often formulated with another analgesic or an antiemetic
Structure ●  Para-aminophenol derivative
Presentation ●  Tablets and suppositories  ●  Oral suspension  ●  Often formulated with other analgesics or antiemetics 
●  IV preparation of 10 mg/mL
Indications ● Analgesic ●  Antipyretic – reduces febrile convulsion risk
Mechanism ●  Undetermined, possibly multiple pathways  ●  Inhibits prostaglandin synthesis and blocks generation of
of action afferent nociceptive impulse  ●  May inhibit COX-3 enzyme
Onset ●  Unpredictable onset and duration PO/PR due to variable bioavailability of 63%–89% PO and 24%–98% PR 
●  IV onset in 5 minutes, peaks at 40–60 minutes
Duration ●  Half-life 2 hours  ●  PO/PR: 40 minutes to peak effect in 1 hour  ●  IV: 4–6 hours (100% bioavailability)
Dose ●  Adults: 500 mg–1 g every 4–6 hours to a maximum of 4 g/day
●  If 10–50 kg PO/IV 15 mg/kg 4–6 hourly, max 75 mg/kg/day orally or 60 mg/kg/day IV
Effects ● Analgesia ●  Opioid sparing effect
Side effects ●  Few seen at therapeutic doses  ●  Rarely gastrointestinal upset  ●  Rashes  ●  Hypotension on infusion
●  Rarely thrombocytopenia  ●  Leucopenia  ●  Neutropenia  ●  5% of aspirin allergic patients also allergic to
paracetamol
Metabolism ●● 95% to hepatic conjugates that are renally excreted. 5% by cytochrome P450 to toxic metabolite NAPQI which
(if not conjugated with glutathione), causes acute centrilobular necrosis of the liver. This results in toxicity in
overdose when glutathione supplies are exhausted
Pregnancy ●  Not known to be harmful
Paediatrics ●  IV 15 mg/kg  ●  PO 15 mg/kg  ●  Neonates up to 30 mg/kg/day
Comments ●  Overdose results in depletion of glutathione stores  ●  Reaction of the highly reactive metabolite with hepatic
cell membranes causes liver necrosis  ●  Nausea, vomiting, epigastric/right subcostal pain may occur after 24–48
hours  ● Intravenous N-acetylcysteine (within 24 hours) or oral methionine (within 12 hours) given to restore
glutathione supply  ●  High international normalized ratio poor prognostically  ●  Co-proxamol withdrawn on
advice of Committee for Safety of Medicines (CSM) because of danger in overdose and little better analgesia than
paracetamol alone
Note:  The first rung on the WHO analgesic ladder and causes liver failure in overdose.
 Pharmacology

Analgesia 174
Opioids – definitions and receptors
Opioids Substances that bind to opioid receptors
●● Include naturally occurring compounds, endogenous compounds and synthetic drugs

Opiates All naturally occurring substances with morphine-like properties

Opioid receptors ●● 1970s classification of subtypes according to dog experiments: mu (m), delta (d), kappa (k)
and sigma (s)
●● Sigma not considered an opioid receptor, as stimulatory effects not reversed by naloxone
●● Reclassified into MOP (m), DOP (d), and KOP (k) and then more recently into OP1 (d), OP2 (k)
and OP3 (m)
●● Mainly in CNS and gut
●● Presynaptic Gi protein–coupled membrane-bound receptors that increase K+ efflux from the
cell and decrease voltage-gated Ca2+ movement across the cell membrane, which leads to
hyperpolarization, prevention of neurotransmitter release and subsequent pain transmission

●● Acute pain management commonly includes Partial agonists

systemic simple and opioid analgesia as well as
regional techniques.
●● Opioid use in chronic pain is mostly reserved for
short duration acute severe pain or cancer pain, and
may require antiemetics and laxatives
Sites of action on pain pathways
●● Opioid receptors are found throughout the CNS, particu-
larly in the nuclei of the tractus solitarius, the peri-aque-
ductal grey area, the cerebral cortex and the thalamus
●● They are also present in the spinal cord, the GI tract, periph-
eral afferent nerve terminals and many other organs
●● Pentazocine is rarely used due to side effects includ-
ing vomiting, dysphoria and hallucinations
●● Buprenorphine is given sublingually and trans-
dermally and lasts up to 10 hours. At higher doses
Nociceptin Opioid Protein (NOP) effects cause anti-
analgesia and side effects include prolonged and
severe nausea and vomiting
●● Nalbuphine is equally potent as morphine and
seems to have a ceiling analgesic and respiratory
depression effect
Opioids – definitions and receptors (cont.)
Receptors
Receptor
subtype Effects of stimulation Agonist Partial agonists Antagonists
μ, MOP ●● Responsible for ‘supraspinal analgesia’ ●● Most opioid ●● Buprenorphine ●● Naloxone
– drugs act at brain level analgesics ●● Meptazinol ●● Nalorphine
●● µ1 (specific µ1) ●● Nalbuphine
■■ analgesia ●● Pentazocine
■■ meiosis
■■ euphoria
●● µ2
■■ respiratory depression
■■ bradycardia
■■ nausea and vomiting
■■ inhibition of gut motility
δ, DOP ●● Experimentally shown to produce spinal ●● Enkephalins ●● Naloxone
analgesia; precise role unclear
■■ decreased sympathetic response to
hypovolaemia
■■ analgesia
■■ respiratory depression
κ, KOP ●● Also responsible for spinal analgesia ●● Morphine ●● Nalorphine ●● Naloxone
■■ sedation ●● Pentazocine ●● Nalbuphine
■■ analgesia ●● Butorphanol
■■ miosis ●● Dynorphins
NOP ●● Spinal and supraspinal ●● Orphanin FQ
●● Hyperalgesia at low doses
●● Analgesia at high doses
●● Anxiety, depression
●● Appetite modulation
 Pharmacology

Analgesia 175
Opioids – common effects
● Opioids are indicated for analgesia, premedication, anxiolysis, cough suppression, chronic d
­ iarrhoea and LVF
● Some opioids cause histamine release, which leads to bronchospasm, hypotension, urticaria, pruritus
● Dependence, tolerance or addiction may occur with longer term use

Effects
Respiratory system ●● Respiratory depression and decreased response to hypoxia and hypercapnia
●● Suppression of protective reflexes including cough reflex
●● Chest wall rigidity may occur, especially with high doses
Cardiovascular system ●● With histamine release leads to decreased systemic vascular resistance and pos-
tural hypotension
●● Bradycardia with high doses
CNS ●● Analgesia, anxiolysis, euphoria and drowsiness
●● Miosis
Gastrointestinal system ●● Stimulate chemoreceptor trigger zone, which causes nausea and vomiting
●● Delayed gastric emptying, decreased gastrointestinal motility and secretions
●● Constipation
●● Spasm of sphincter of Oddi
Genitourinary system ●● Urinary retention
Interactions ●● Stronger and longer lasting effects if given with monoamine oxidase inhibitors
(especially pethidine)
●● Reduce the minimum alveolar concentration (MAC) of inhaled volatile anaes-
thetic agents
Opioids – dosage and other properties
Drug Dose Elimination Stimulates Releases Nausea and
half-life (minutes) receptors histamine vomiting

Morphine 5–20 mg oral 170 MOP, KOP Y Y

0.1–0.2 mg/kg intramuscular
0.05–0.1 mg/kg intravenous
0.1–0.4 mg intrathecal

Fentanyl 1–100 mcg/kg intravenous 190 MOP Minimal Y

50–100 mcg epidural

Alfentanil 10–50 mg/kg intravenous 100 MOP Minimal Y

0.5–1 mg/kg/min infusion

Remifentanil 1 mg/kg intravenous bolus 10 MOP N Minimal

0.05–2 mg/kg/min infusion

Codeine 30–60 mg oral or intramuscular 170 Prodrug Y Mild

four times daily

Diamorphine 5–10 mg intramuscular or 3 Prodrug Y Y

intravenous
1–5 mg epidural
100–400 mg intrathecal

Pethidine 50–150 mg oral 210 MOP, KOP(?) Y Y

25–150 mg intramuscular
25–100 mg intravenous

Tramadol 50–100 mg oral, intramuscular, 300 MOP, KOP, Y(?) Y

intravenous DOP

Note:   These ? marks denote that the evidence is uncertain.

 Pharmacology

Analgesia 176
Comparative features of opioids
Morphine ●● Phenanthrene derivative naturally occurring in opium poppy
●● Relatively lipid insoluble compared with diamorphine
●● Metabolized in liver to morphine-3-glucuronide (70%, inactive), morphine-6-glucuronide
(5%–10%, active) and normorphine
●● Morphine-6-glucuronide 10–20 times more potent than morphine and may accumulate in
renal failure
●● May cause encephalopathy in patients with hepatic failure
●● Intrathecal and epidural morphine may cause pruritus and late respiratory depression
●● Routes of administration: PO, PR, IV, SC, IM, intrathecal or epidural
Fentanyl ●● Aniline–piperidine opioid
●● 100× more potent than morphine
●● pKa is 8.4; only 9% unionized at physiological pH
●● Rapid peak effect at 5 minutes because highly lipid soluble and crosses blood–brain
barrier readily
●● Routes of administration: intravenous, intrathecal, epidural, transdermal and intranasal
Alfentanil ●● Synthetic aniline–piperidine derivative given by IV bolus or infusion
●● 10%–20% as potent as fentanyl
●● Highly lipid soluble but less than fentanyl
●● Faster onset of action than fentanyl; 89% unionized at physiological pH
●● Shorter terminal half-life than fentanyl despite lower clearance because of lower lipid
solubility and hence lower Vd
Remifentanil ●● Synthetic aniline–piperidine with faster onset and offset than alfentanil
●● Metabolized by rapid hydrolysis by plasma and tissue esterases
●● Similar potency to fentanyl
●● Given as intravenous infusion
Comparative features of opioids (cont.)
Codeine ●● Naturally occurring phenanthrene alkaloid with 20% potency of morphine
●● 10% metabolized to morphine (enzyme lacking in some patients)
●● Fast metabolizers have more side effects so restricted use in children under 12
Diamorphine ●● Synthetic diacetylated derivative of morphine
●● Prodrug
●● Metabolized in liver and plasma to monoacetylmorphine, which is more lipid soluble than
morphine (as is diamorphine itself)
●● Converted to morphine after crossing blood–brain barrier
●● 1.5 times more potent, faster onset and shorter duration than morphine
●● Routes of administration: IV, IM, SC, intrathecal or epidural
Pethidine ●● Synthetic phenylpiperidine
●● Atropine-like effect may block vagus at high dose
●● 10% potency of morphine
●● Local anaesthetic effect
●● Toxic metabolite norpethidine may cause seizures
●● Routes of administration IV and IM
Tramadol ●● Synthetic phenylpiperidine analogue of codeine
●● 10% potency of morphine
●● Weak opioid agonist
●● Blocks reuptake of norepinephrine and serotonin to activate descending inhibitory pathways
in CNS
●● Routes of administration PO, IV, IM
Oxycodone ●● Route of administration: PO, PR, IV and SC
●● Alternative to morphine-may be better tolerated
●● Higher bioavailability than morphine so twice as potent PO
●● IV approximately same potency as morphine
●● Available as slow release PO and in combination with naloxone (reduced constipation)
 Pharmacology

Analgesia 177
Non-steroidal anti-inflammatory drugs (NSAIDs)
Structure ●● Differs: salicylic acids, propionic acids, acetic acids, fenamates, pyrazolones, oxicams and
pyrroles
Indications ●● Analgesia – reduces sensitization of nociceptive nerve endings to inflammatory mediators
produced from tissue injury
●● Anti-inflammatory
●● Antipyrexial – prevention of prostaglandin synthesis in the CNS resets the hypothalamic
thermostatic control during fever
●● Closure of patent ductus arteriosus in neonate
Mode of action ●● Inhibition of cyclooxygenase (COX). COX-1 is the constitutive form and COX-2 the inducible
form
●● COX-1 inhibition decreases PGE2 and prostacyclin (PGI2) synthesis, increasing the risk of
bleeding and perforation, and decreasing renal blood flow
●● COX-2 inhibition appears responsible for the analgesic, anti-inflammatory and anti-pyretic effects
●● COX-2 may also mediate prostacyclin production in vascular endothelium increasing platelet
aggregation, vasoconstriction and thromboembolism
●● Some NSAIDS are selective for COX-2 (e.g. parecoxib and celecoxib)
Effects
Cardiovascular ●● COX-2 inhibitors, ibuprofen and diclofenac increase risk of major coronary events
system
Respiratory system ●● May induce asthma in up to 20% of asthmatics (less risk in children)
Gastrointestinal ●● Gastric bleeding, erosion and ulceration (COX-2 inhibitors lower risk)
tract ●● Combination with aspirin may increase the risk of gastrointestinal side effects and should only
be used if completely necessary
●● Risks of serious upper gastrointestinal side effects vary: ibuprofen is lowest risk; piroxicam,
ketoprofen, indomethacin, naproxen and diclofenac are intermediate risk; selective COX-2
inhibitors lower risk than non-selective
NSAIDs (cont.)
Genitourinary tract ●● Renal impairment from hypoperfusion due to
■■ inhibition of prostaglandin-mediated renal vasodilatation (more common with dehydra-
tion, sodium depletion (diuretics) and coexisting renal disease)
■■ acute interstitial nephritis (usually after chronic use)
■■ systemic vasculitis (rare)
Haematological ●● Platelet dysfunction (COX-2 has no effect on platelet function)
Metabolic ●● Hyperkalaemia
●● Metabolic acidosis
Other ●● Adverse drug reactions frequent
●● Hepatotoxicity
●● Fluid retention
Contraindications ●● Hypersensitivity to aspirin/other NSAIDs
●● History of GI bleeding/perforation due to NSAIDS
●● Active GI bleeding or ulceration
●● Celecoxib and etoricoxib (selective inhibitors of COX-2) – ischaemic heart disease,
cerebrovascular disease, peripheral arterial disease and congestive heart failure
Pregnancy ●● Cause fetal pulmonary hypertension, premature closure of ductus arteriosus, delayed onset of
and prolongation of labour and neonatal platelet dysfunction
Paediatrics ●● Ibuprofen not licensed in infants less than 3 months old or body weight 5 kg
Comments ●● Because of concerns about cardiovascular safety, COX-2 inhibitors should be used only when
specifically indicated (i.e. high risk of peptic ulcer, perforation or bleeding) and after assessing
cardiovascular risk. The Committee for the Safety of Medicines (CSM) advised that patients
with ischaemic heart disease or cerebrovascular disease who are taking COX-2 inhibitors
should be changed to other treatment as soon as possible
 Pharmacology

IV Anaesthetics 178
General principles
Intravenous (IV) anaesthetic drugs are agents that will induce loss of consciousness in one arm–
brain circulation and may be used for induction of anaesthesia, maintenance of anaesthesia
and sedation

Classification
Rapid onset
●● Barbiturates (e.g. thiopentone)
●● Phenolic derivatives (e.g. propofol)
●● Imidazole compounds (e.g. etomidate)
Slow onset
●● Benzodiazepines (e.g. midazolam)
●● Phencyclidine derivatives (e.g. ketamine)
●● Opioids (e.g. remifentanil)

Advantages of intravenous induction agents over orally administered drugs

●● Bioavailability 100% (no first-pass effect)
●● Faster onset and offset (no reliance on absorption and no gut reservoir of drug)
●● Lower total dose needed (drug should be titrated against effect, especially if reduced cardiac output)

Pharmacokinetics
●● Initial rapid transfer of drug from blood to brain (affected by degree of protein binding within blood,
degree of ionization, cerebral blood flow and lipid solubility)
●● Subsequent rapid distribution to other tissues rich in blood vessels reduces levels of anaesthetic in
plasma, so agent diffuses out of brain, which results in rapid recovery from anaesthesia
●● Slow distribution to and from fat (poor blood supply), which leads to prolonged metabolism and
elimination
General principles (cont.)
Fate of thiopentone after injection
Blood
60
Vessel rich tissue

Injected dose (%)

(e.g. brain) Vessel intermediate
40 tissue (muscle, skin)

20 Vessel poor tissue

(fat, ligaments)

10 30 100
Time (min)

Properties of the ideal IV anaesthetic agent

Physical Pharmacological
●● Stable under diverse conditions ●● Rapid, smooth and predictable onset of anaesthesia
●● Soluble in water ●● Pain free injection without thrombophlebitis
●● Compatible with other agents ●● Safe on intra-arterial injection
●● Reactivity – no local reaction ●● Rapid initial recovery without emesis or emergence phenomena
●● Clear-headed later recovery to enable day case anaesthesia
●● No unwanted effects in CNS or other systems
●● Rapid metabolism to non-toxic metabolites without accumulation in
hepatic or renal disease
●● Safe in pregnancy and for all ages
●● No histamine release and low risk for anaphylaxis
 Pharmacology

IV Anaesthetics 179
TIVA and context-sensitive half-time
Total intravenous anaesthesia (TIVA) is an anaesthetic technique that uses intravenous agents alone while the
patient breathes oxygen, air or mixture of both
●● First used in Bristol in 1988, with a bolus of 1 mg/kg propofol, then infusion of 10 mL/kg/hr for 10 minutes, then 8 mL/kg/hr
for 10 minutes, then 6 mL/kg/hr aiming for target of approximately 3 mcg/mL plasma propofol
●● Based on a three-compartment pharmacokinetic model
●● Uses drugs with a short half-life to avoid accumulation and prolonged recovery (e.g. propofol with remifentanil,
alfentanil or fentanyl)

Advantages of TIVA Disadvantages of TIVA

●● Possible to use without anaesthetic ●● Repeated boluses or infusion needed

machines, cylinders and vaporisers
(e.g. prehospital)
●● Avoids pollution by anaesthetic
vapours
●● Avoids adverse effects of vapours
●● Once infused, the drug can be removed only by metabolism (inhala-
tional agents can be ventilated off)
●● Increased likelihood of awareness because of difficulties in predicting
plasma concentrations and variation in patient response; spontaneously
ventilating patients under inhalational anaesthesia will regulate their
depth of anaesthesia

Target-controlled infusions (TCI)

●● TCI uses pharmacokinetic models to predict the plasma and/or target site concentration of drug after bolus and
infusion
●● The target value concentration is set and a bolus then infusion is automatically given until the concentration is
reached
●● Marsh model originally targeted plasma propofol concentration and Schnider model originally targeted effect
site propofol concentration. Now both can calculate both plasma and effect site concentration
●● The Minto TCI model for remifentanil targets 8 ng/mL effect site concentration
●● Microprocessor-controlled infusion pump
●● Patient’s weight, age and target plasma concentration entered
TIVA and context-sensitive half-time (cont.)
●● TIVA requires purpose made infusion sets with one-way and anti-siphon valves
●● Once target reached, pump reduces infusion to match transfer and uptake of drug to different body compartments
●● Children have disproportionately higher volumes of distribution and clearance
●● The calculated plasma and effect site concentrations displayed on the pump are only accurate to within 25%
of the true concentrations due to pharmacokinetic variation between patients. The infusion must therefore be
adjusted to effect

Context-sensitive half-time (CSHT)

Time taken for plasma drug concentration to halve after termination of an infusion of drug
●● CSHT propofol is 3–20 minutes
●● Half-time increases with duration of drug infusion,
which reflects the peripheral compartments becom-
350 Fentanyl
ing saturated with drug
●● CSHT depends upon rate of elimination and distribution 300

Half-life (min)
●● Fentanyl has a much higher rate of distribution than 250
elimination so has an increasing CSHT
200
●● Remifentanil has a much higher rate of elimination than
distribution so has a constant CSHT 150
●● The rates of distribution and elimination of propofol 100 Propofol
are more similar 50
●● CSHT after 1 CSHT will be longer hence pump displays Remifentanil
0
decrement time for plasma concentration of propofol
to fall to default value of 1.2 mcg/mL when average
2 4 6 8 10
patient is predicted to awaken Duration of infusion (h)
 Pharmacology

IV Anaesthetics 180
Propofol
Used for IV induction, TIVA, and sedation
Structure ●● 2,6 di-isopropylphenol; a derivative of phenol
Presentation ●● Various formulations of 1% or 2% oil-in-water emulsion (originally presented in soya bean oil)
Indications ●● Induction and maintenance of general anaesthesia, sedation, intractable nausea and
vomiting in chemotherapy, status epilepticus
Mechanism of action ●● Potentiates GABA chloride current, and inhibits acetylcholine release in the hippocam-
pus and prefrontal cortex
Onset ●● 30 seconds
Duration ●● 10 minutes for single dose  ●  Context-sensitive half-life increases with duration of infusion
Dose ●● Induction: 1.5–2.5 mg/kg  ●  Maintenance: 4–12 mg/kg/hour
Effects
  Respiratory system ●  Bolus: apnoea, suppression of laryngeal reflexes  ●  Infusion: decrease in tidal volume,
tachypnoea, decrease in response to hypercarbia and hypoxia, bronchodilation
  Cardiovascular system ●● Decrease in blood pressure, cardiac output and systemic vascular resistance
●● Bradycardia
  CNS ●● Decrease in intracranial pressure, cerebral perfusion pressure and cerebral oxygen
consumption
  Gastrointestinal tract ●● Antiemetic
Side effects ●● Pain on injection  ● Anaphylaxis
Contraindications ●● Allergy to formulation
Metabolism ●  95%–99% protein bound  ●  Metabolized in liver to glucuronide (49%–73%) and
hydroxylation followed by sulphate and glucuronide conjugation
Pregnancy ●● Causes neurobehavioural depression and possibly decreases in APGAR score in neonates
Paediatrics ●● Induction: 2–4 mg/kg  ●  Maintenance: 9–15 mg/kg/hour
Comments ●  Not used for sedation in ITU in children after five deaths in paediatric intensive care
unit (PICU); reportedly resulted in metabolic acidosis, myocardial failure and lipaemic
serum  ●  Required dose is reduced by opioid co-administration  ●  May be mixed with
5% glucose, 1% lidocaine or alfentanil (other agents may cause cracking of the emulsion,
changes in pharmacokinetics or degradation)
Thiopentone
Thiopentone is used for induction of anaesthesia and occasionally in status epilepticus
Structure ●● Thiobarbiturate
Presentation ●● Hygroscopic yellow powder of sodium thiopental, with 6% anhydrous sodium
carbonate in atmosphere of nitrogen
Indications ●● Induction of anaesthesia  ●  Status epilepticus  ●  Brain protection
Mechanism of action ●● Depresses postsynaptic sensitivity to neurotransmitters and impairs presynaptic release
Onset ●● One arm–brain circulation time (usually 10–20 seconds)
Duration ●● Redistribution half-life 5–10 minutes
Dose ●● Intravenous: 3–6 mg/kg  ●  Infusion: 2–3 mg/kg/hour for status epilepticus
Effects
  Respiratory system ●● Respiratory depressant  ●  Laryngeal spasm after laryngeal stimulation
●● Bronchoconstriction
Cardiovascular system
  ●● Decrease in cardiac output, venous vascular tone and blood pressure
CNS ●● Decrease in cerebral blood flow, decrease in intracranial pressure, decrease in
intraocular pressure, anticonvulsant and antanalgesic in small doses
  Gastrointestinal tract ●● Depresses intestinal activity, decreases hepatic blood flow and induces hepatic enzymes
  Genitourinary tract ●● Decrease in renal blood flow  ●  Decrease in secretion of antidiuretic hormone
●● No effect on uterine tone
Side effects ●  Severe anaphylactoid reactions (one in 14,000–one in 35,000)  ●  Tissue necrosis after
extravasation  ●  Tissue damage after accidental arterial injection
Contraindications ●● Porphyria  ● Allergy  ●  Upper airway obstruction
Metabolism ●● Hepatic oxidation
Pregnancy ●● Crosses placenta, so will cause effect in neonate
Paediatrics ●● 2–4 mg/kg
Comments ●  Accidental arterial injection may cause arterial constriction, blistering, oedema,
thrombosis and gangrene  ●  Treatment includes brachial plexus block or stellate
ganglion block and injection through cannula of saline, vasodilators such as papaverine
or phentolamine, local anaesthetic such as procaine and heparin
 Pharmacology

IV Anaesthetics 181
Ketamine
Used for anaesthetic, sedative, bronchodilatory and analgesic effects
Structure ●● Phencyclidine derivative
Presentation ●● Racemic mixture or single (more potent) S(+) enantiomer of 10, 50 or 100 mg/mL solution
with or without one in 10,000 benzethonium chloride preservative
Indications ●● Induction of anaesthesia (especially if bronchospasm or hypotension), analgesia and
sedation; additive for epidural/caudal route
Mechanism of action ●● Antagonist at calcium channel pore of N-methyl-D-aspartic acid (NMDA) receptor and
inhibitor of NMDA receptor at phencyclidine binding site
Onset ●● Intravenous: 30 seconds  ●  Intramuscular: 2–8 minutes
Duration ●● Intravenous: 5–10 minutes ●● T½α (intravenous): 11–15 minutes
●● Intramuscular: 10–20 minutes ●● T½β: 2–4 hours
Dose ●● Intravenous: 1.5–2 mg/kg  ●  Intramuscular: 10 mg/kg
Effects
  Respiratory system ●● Stimulation of respiration  ● Bronchodilation  ●  increased salivation
  Cardiovascular ●● Sympathetic stimulation with increase in circulating adrenaline and noradrenaline, which
system leads to tachycardia, increased central venous pressure, increased blood pressure and
increased cardiac output
  CNS ●● ‘Dissociative anaesthesia’ (strong analgesia and light sleep), amnesia, increased
cerebral metabolic rate (CMR), increased cerebral blood flow (CBF) and increased
intracranial pressure (ICP), increased intraocular pressure, increased muscle tone,
twitching and nystagmus
  Gastrointestinal tract ●● PONV and salivation
  Genitourinary tract ●● Increased uterine tone
Side effects ●● Rashes ● Hallucinations ●  Emergence delirium and unpleasant dreams
●● Pain on injection (may be reduced by premedication with benzodiazepines or opioid
and hyoscine; less likely in the elderly or children)
Contraindications ●● Severe ischaemic heart disease ●● Hypertension ●● Porphyria
Metabolism ●● Hydroxylation and N-demethylation (hepatic P450); active metabolites
Ketamine (cont.)
Pregnancy ●● Neonatal respiratory and behavioural depression, so usually avoided unless severely
compromised placental blood flow
Paediatrics ●● Intravenous: 0.5–2 mg/kg  ●  Intramuscular: 4–13 mg/kg
Comments ●● Useful for analgesia/sedation in positioning patients for regional anaesthesia, burns and
dressings changes

Etomidate
IV anaesthetic induction agent useful due to less hypotensive effect than alternatives. Limited use due to sup-
pression of stress response and associated increased postoperative mortality risk
Structure ●● Carboxylated imidazole compound
Presentation ●● 2 mg/mL solution of 35% propylene glycol and water
Indications ●● Induction of anaesthesia
Mechanism of action ●● Possibly via enhancing inhibition of gamma aminobutyric acid (GABA) inhibition and activation
of Cl− channel
Onset ●● 10–65 seconds
Duration ●● 6–8 minutes  ● T½a: 2–4 minutes  ● T½b: 3.5 hours
Dose ●● 0.3 mg/kg  ●  0.2 mg/kg in elderly
Effects
  Respiratory system ●● Respiratory depression, coughing and hiccupping stimulated
 Cardiovascular system ●● Slightly decreased cardiac output and systemic vascular resistance
●● Less hypotension than other induction agents
  CNS ●  Increase in muscle tone, involuntary movements and tremor at induction (minimised by
pretreatment with opioid or benzodiazepine)  ●  Decreased cerebral metabolic rate, cerebral
blood flow, intracranial pressure intraocular pressure
  Gastrointestinal tract ●● Postoperative nausea and vomiting
Side effects ●  Pain on injection into small veins  ● Antiplatelet  ●  Inhibits cortisol and aldosterone synthesis
by suppressing enzymes 11b-hydroxylase and 17a-hydroxylase
Contraindications ●● Porphyria
Metabolism ●● By esterases in plasma and liver to inactive metabolites that are conjugated with glucuronide
Pregnancy ●● Clinically harmless to neonate
Paediatrics ●● 0.15–0.4 mg/kg
Comments ●● Sedation by infusion with etomidate associated with increased mortality in intensive care
 Pharmacology

IV Anaesthetics 182
Benzodiazepines – general principles
Drugs that are used in anaesthesia for premedication and sedation, and also more generally as hypnotics,
anxiolytics and anticonvulsants
●● All benzodiazepines have a benzene ring and a diazepine ring (seven-member ring with five carbon and
two nitrogen molecules)
Receptors ●● Form part of gamma-aminobutyric acid (GABA)A receptor complex
●● BZ1 in spinal cord and cerebellum (anxiolysis)
●● BZ2 in spinal cord, hippocampus and cerebral cortex (sedative, anticonvulsant)
Mechanism of action ●● Increase frequency of opening of GABAA ligand-gated chloride channels
●● Enhance fast inhibitory synaptic transmission within CNS
Uses ●● Premedication (midazolam, temazepam, lorazepam)
●● Sedation (midazolam)
●● Anticonvulsant in status epilepticus (diazepam, lorazepam, midazolam)
●● Induction of anaesthesia (midazolam) with a synergistic effect with other IV
anaesthetics
Benzodiazepine overdose ●● Most common overdose with prescription drugs
●● Death is rare but may occur from respiratory depression and pulmonary aspiration
●● Treatment is supportive

Flumazenil
Competitive benzodiazepine antagonist structurally related to midazolam
●● Inverse agonist activity and may lead to seizures (especially in mixed overdose and those on long-term
benzodiazepines)
●● Given in 0.2 mg increments up to 2 mg
●● Acts within 2 minutes but half-life <1 hour, so infusion may be necessary
Benzodiazepines – general principles (cont.)
Midazolam structure Metabolism of benzodiazepines

Closed at physiological pH Open at pH 3.5 Chlordiazepoxide

CH3 N CH3 N
Desmethylchlordiazepoxide
t½ 24–48 h Oxidation
N N Diazepam Desmethyldiazepam Active
CH2 +NH
3
Temazepam Oxazepam Inactive
C N C O t½ 3–8 h
CI CI t½ 6–8 h
F F t½ 1–3 h
Midazolam Lorazepam
Hydroxylation t½ 12 h
Conjugation c
1α hydroxymidazolam Glucoronic acid
Active

Renal excretion
 Pharmacology

IV Anaesthetics 183
Midazolam
Benzodiazepine used to treat seizures and for premedication, sedation, and induction of anaesthesia
Structure ●● Benzodiazepine
Presentation ●● Solution for injection
Indications ●● Premedication  ● Sedation  ●  Induction of anaesthesia
Mechanism of action ●● Acts on benzodiazepine receptors in CNS
●● Appears to facilitate action of gamma aminobutyric acid (GABA) receptors
Onset ●● Intravenous <90 s
Duration ●● Half-life 2 hours
Dose ●● Premedication 0.1 mg/kg intramuscular and 0.5 mg/kg oral  ●  Sedation 0.5–2 mg IV
●● Induction 0.3 mg/kg IV
Effects
  Respiratory system ●● ↓ tidal volume but ↑ respiratory rate, so minute volume is not affected
●● ↓ hypercarbic drive
  Cardiovascular system ●● ↓ SVR and ↑ BP
  CNS ●● Hypnosis, sedation and anterograde amnesia
Side effects ● Drowsiness ● Confusion  ● Ataxia  ● Amnesia  ●  Paradoxical increase in
aggression
Contraindications ●● Marked neuromuscular respiratory weakness  ●  Severe respiratory depression
●● Acute pulmonary insufficiency
Metabolism ●  Hydroxylation in liver to active metabolites  ●  Conjugation to glucuronides then
occurs  ●  Excretion by kidney  ●  Elimination half-life 1–4 hours
Comments ●  ↓ MAC of volatile anaesthetic agents  ●  Effects prolonged by alfentanil, which is
metabolized by same hepatic P450 isoenzyme  ●  At pH 3.5, open ring structure with
ionized molecule makes it water soluble  ●  At pH >4, ring structure closes, so not
ionized and therefore lipid soluble
Diazepam
Benzodiazepine used to treat seizures and for sedation and induction of anaesthesia
Structure ●● Benzodiazepine
Presentation ●● Tablets  ●  Oral solution  ● Suppositories  ●  Emulsion in soya bean oil for injection
Indications ●● Anxiety  ● Seizures  ●  Muscle spasm  ●  Alcohol withdrawal  ● Premedication
●● Sedation  ●  Induction of anaesthesia
Mechanism of action ●● Acts on benzodiazepine receptors in CNS
●● Seem to facilitate action of gamma aminobutyric acid (GABA) receptors
Onset ●● 2–3 minutes
Duration ●● Amnesia 10–30 minutes  ●  Sedation 60 minutes
Dose ●● 2 mg PO for anxiety  ●  10–30 mg PO for premedication (0.5 mg/kg in children)
●● 5–10 mg IV for sedation/anticonvulsant
Effects
  Respiratory system ●● Respiratory depression (hypoxic drive inhibited more than hypercarbic drive)
  Cardiovascular system ●● Small decrease in cardiac output and BP
  CNS ●● Anxiolysis, sedation, anterograde amnesia and hypnosis
Side effects ●● Drowsiness  ●  Light headedness  ● Confusion  ● Ataxia  ● Amnesia
●● Dependence  ●  Paradoxical increase in aggression
Contraindications ●  Respiratory depression  ●  Marked neuromuscular respiratory weakness  ● Acute
pulmonary insufficiency  ●  Sleep apnoea  ●  Severe hepatic impairment
Metabolism ●● Metabolized in liver by oxidation to active metabolites including oxazepam and
temazepam
●● Glucuronide derivatives excreted by kidney with elimination half-life of 20–70 hours
Pregnancy ●● Crosses placenta to cause low APGAR scores, hypoactivity, hypotonia, poor feeding
and impaired metabolic responsiveness in fetus
Comments ●● Reduces minimum alveolar concentration of volatile anaesthetics and potentiates
non-depolarizing muscle relaxants
●● Liver failure and cimetidine decrease its clearance, which increases plasma levels
 Pharmacology

Inhaled Anaesthetics 184

Inhalational anaesthetics – general principles
Inhalational anaesthetic agents are volatile vapours used to induce and/or maintain anaesthe-
sia via respiratory tract and pulmonary alveolar capillaries
●● Advantages include ease of controlling alveolar (and therefore arterial) levels of agent by ventila-
tion, but disadvantages include need for special vaporizers and storage methods, pollution and
adverse effects

Properties of ideal inhalational anaesthetics

Physical properties Pharmacological properties

●● Stable in heat or light, with long shelf life ●● Low minimum alveolar concentration (MAC)
●● Non-flammable and non-corrosive ●● Smooth rapid induction
●● Non-irritant, pleasant smell ●● CNS – analgesic, antiemetic, anticonvulsant
●● Saturated vapour pressure (SVP) sufficiently without increasing cerebral blood flow
high to allow easy vaporization ●● No respiratory depression or suppression of
●● Low blood–gas partition coefficient hypoxic pulmonary vasoconstriction reflex
●● High oil–gas partition coefficient ●● No cardiovascular depression or excitation
●● Non-pollutant ●● Skeletal muscle relaxation
●● Cheap ●● Safe in hepatic or renal failure
●● Minimal metabolism
●● Safe in pregnancy
●● Not a trigger for malignant hyperthermia
Theories of anaesthetic action
●● Meyer–Overton hypothesis states the potency of anaesthetic agents is increased with increasing
oil–gas partition coefficient. Disruption of lipid bilayer of cell membrane of neurones was thought
to alter function of membrane proteins
●● However, many compounds with high lipid solubility cause no anaesthetic effect, some larger mol-
ecules with increasing lipid solubility have reduced potency and temperature disrupts cell mem-
branes without potentiating general anaesthesia
●● Volume expansion and pressure reversal – membranes expand by 0.4% while volume of anaes-
thetic is only 0.02% of the membrane. Increased ambient pressure can reverse anaesthesia but
effect varies with different anaesthetics
●● Ligand-gated membrane ion channels including gamma–aminobutyric acid (GABA), glycine,
glutamate, serotonin (5-HT3) and nicotinic cholinergic receptors have their function altered by
many different compounds
●● GABA A is major inhibitory neurotransmitter, and alteration of GABA A receptor by virtually all gen-
eral anaesthetic agents (apart from xenon and ketamine) has been shown. The domain is not the
same for all anaesthetics
●● The glycine receptor is the spinal cord and brainstem equivalent of the GABA A receptor and
altered by many general anaesthetics
●● Glutamate receptors are NMDA (N-methyl-D-aspartate) or non-NMDA. Glutamate is main central
excitatory neurotransmitter, so inhibition could cause anaesthesia. Ketamine acts at NMDA recep-
tor. Non-NMDA receptors are altered by ethyl alcohol but not volatile anaesthetics
 Pharmacology

Inhaled Anaesthetics 185

Minimum alveolar concentration (MAC)
MAC of a volatile agent is defined as minimum alveolar concentration in air at steady state that
prevents reaction to standard surgical stimulus in 50% of unpremedicated people of defined
population at sea level
●● Useful to compare volatile agents and as a guide to clinical dosage with end-tidal anaesthetic
concentration
●● MAC–BAR (blocks adrenergic response) used to refer to MAC at which increase in heart rate and/or
blood pressure prevented

Reduces MAC Increases MAC

●● Extremes of age ●● Children
●● Pregnancy ●● Hyperthermia
●● Depressant drugs (opioids, acute alcohol, sedatives and other ●● Hyperthyroidism
inhalational agents) ●● Catecholamines
●● Hypothermia ●● Chronic opioids
●● Hypotension ●● Chronic alcohol
●● Drugs that reduce catecholamine synthesis (e.g. a2 agonists such as ●● Acute amphetamines
clonidine)
Minimum alveolar concentration (MAC) (cont.)
Potency of inhaled anaesthetics
●● Potency of inhaled anaesthetics depends on their solubility in CNS, which is estimated by the oil/
gas partition coefficient
●● Meyer–Overton hypothesis of the mechanism of action of anaesthetics relates MAC and oil/gas
coefficients for various agents at 37°C using logarithmic scales
■■ When potency is represented by MAC, the partition coefficient is changed, relating lipid solubil-
ity to the alveolar gas phase
■■ The oil–gas coefficient is similarly correlated to the potency of an inhaled anaesthetic
■■ However there are limitations with this theory:
●● Structural isomers such as enflurane and isoflurane exhibit differing potencies despite hav-
ing similar oil:gas partition coefficients
●● Some gases with a high oil:gas partition coefficient are unable to produce anaesthesia
Minimum Alveolar Concentration

100 Nitrous oxide

(MAC) – Volume %

10 Desflurane
Sevoflurane
1.0 Enflurane
Isoflurane Halothane

0.1
1 10 100 1000
Oil/gas partition
coefficient (37°C)
 Pharmacology

Inhaled Anaesthetics 186

Speed of onset of volatile anaesthetics
●● Brain partial pressure approximates arterial partial pressure, which approximates alveolar partial
pressure
●● Factors that affect speed at which volatile agent reaches equilibrium include ABCCC
A Alveolar ventilation ●● Hyperventilation leads to faster rise in alveolar partial pressure and thus
partial pressure of anaesthetic agent in brain
●● Large functional residual capacity (FRC) dilutes anaesthetic agent and
prolongs onset of action of volatile agent
●● Ventilation(V)/perfusion(Q) mismatch also affects alveolar and thus arterial
concentration of volatile anaesthetic agent
B Blood/gas partition ●● Ratio of amount of anaesthetic in blood and gas phases when two are of
coefficient equal volume and pressure and in equilibrium at 37°C
●● High blood–gas coefficient (i.e. increased solubility in blood phase) means
agent exerts low partial pressure in blood and thus will have slow onset and
offset
C Concentration (inspired) ●● Increased inspired concentration increases alveolar partial pressure of
anaesthetic agent and results in rapid onset
C Cardiac output (CO) ●● Increased CO maintains concentration gradient between blood and
alveolus, so partial pressure in alveolus rises more slowly
●● Low CO favours fast onset of action
C Concentration effect and ●● Concentration effect: effect of rapid alveolar extraction of gas introduced
­second gas effect at high concentration (such as N2O)
●● Second gas effect: Nitrous oxide 20× more soluble in blood than oxygen or N2
●● Results in higher transfer of N2O into blood than N2 out of blood and
augments ventilation, as tracheal gas (containing volatile agent) is drawn
into alveoli
Speed of onset of volatile anaesthetics (cont.)
Mapleson’s compartments

Viscera

Mouth Lungs Muscle

Ventilation

Fat

Mapleson’s compartments explain the distribution of inhalational anaesthetics, which are all fat sol-
uble. The depot effect of the fat compartment is emphasized in long exposure, soluble anaesthetic
agents and obese patients, hence the long time to emergence for obese patients after long opera-
tions using more soluble vapours

Wash-in curves of volatile anaesthetics

Numbers next to the agents denote
approximate blood:gas partition
coefficient
1.0
N2O (0.5)
Desflurane (0.4)
Fractional alveolar concentration/

Sevoflurane (0.6)
fractional inspired concentration

0.8 Isoflurane (1.4)

Enflurane (1.8)

0.6
Halothane (2.3)
0.4

0.2 Diethyl-ether (12)

0
Time (min)
 Pharmacology

Inhaled Anaesthetics 187

Important structures – inhaled anaesthetics
F H F F F F F H F

H C O C C F H C O C C H H C O C C F

F Cl F F F Cl F F F

Isoflurane (halogenated ethyl Enflurane (halogenated ethyl Desflurane (halogenated ethyl

methyl ether) methyl ether) methyl ether)

Cl F F CF3 F O CH2F

H C C F H C O C H C C

Br F H CF3 F CF3

Halothane (halogenated Sevoflurane (polyfluorinated Compound A (halogenated

hydrocarbon) isopropyl methyl ether) hydrocarbon)
Important structures – IV anaesthetics
Intravenous anaesthetics
H O OH

N C C2H5
(CH3)2·CH CH·(CH3)2
S C C
N C CHC3H7
Propofol (phenolic
H O CH3 derivative)
Thiopentone (sulphur
analogue of
phentobarbitone)

Suxamethonium Morphine
O OH
2 molecules 3
CH2 C O CH2 CH2 N (CH3)3 of acetylcholine joined
back to back
CH2 C O CH2 CH2 N (CH3)3 through their O
acetyl groups N CH3
O

HO
 Pharmacology

Inhaled Anaesthetics 188

Inhaled anaesthetics – common properties
Presentation ●● Clear, colourless liquids
Indications ●● Maintenance of general anaesthesia
Effects
  CNS ●● Anaesthesia
●● ↓ cerebral vascular resistance and cerebral metabolic rate and ↑ ICP
  Cardiovascular system ●● ↓ SVR and hence decreased ↓ BP
  Respiratory system ●● ↓ minute volume and hypercapnia
●● Bronchodilation
Side effects ●● Potentiate muscle relaxants
Contraindications ●● Malignant hyperpyrexia
Pregnancy ●● Reduces uterine tone

Notable differences
Desflurane Enflurane Halothane Isoflurane Seroflurane Xenon
Boiling point (°C) 23.5 56.5 50.2 48.5 58.5 −108
Saturated vapour pressure (kPa 88.5 23.3 32 32 21
at 20°C)
Oil/gas partition coefficient 19 98 220 98 53 1.9
Blood/gas partition coefficient 0.42 1.9 2.5 1.4 0.6 14
Minimum alveolar concentration 6.35 1.7 0.76 1.15 2.0 71
(MAC)
Metabolism 0.02% 2.4% 25% 0.2% 5% 0%
Inhaled anaesthetics – noticeable differences
Structure ●● All are ethers except halothane, which is a hydrocarbon
●● Desflurane and sevoflurane contain fluoride
●● Enflurane and isoflurane contain fluoride and chloride
●● Halothane contains fluoride, chloride and bromide
Presentation ●● Halothane with 0.1% thymol to prevent decomposition by light
Indications ●● Halothane and sevoflurane used for inhalational induction of general anaesthesia
Speed of onset ●● Desflurane > sevoflurane > isoflurane > enflurane > halothane
Effects
  CNS ●● Enflurane is epileptogenic and causes excitatory muscular effects
  Cardiovascular system ●● Halothane causes bradycardia and decreased contractility and sensitizes heart to
catecholamines, which can lead to arrhythmias
●● Isoflurane possibly causes coronary steal by dilating normal coronary arteries, which
diverts blood from diseased arterioles
●● Rapid increases in concentration of desflurane may cause tachycardia and ↑ BP because
of sympathetic stimulation and can cause breath holding making desflurane difficult to
use for inhalational induction
  Respiratory system ●● Isoflurane and desflurane are irritant to airways
  Genitourinary system ●● Halothane ↑ renal blood flow (by 40%) and ↓ GFR (by 50%)
Paediatrics ●● Halothane and sevoflurane are useful for inhalational induction
Comments ●● When sevoflurane is administered in circle system with soda lime or baralyme,
Compounds A to E are produced. At temperatures reached clinically, only Compounds A
and B are produced. Lower concentrations found with soda lime than baralyme because
lower temperatures attained. Concentrations found clinically less than those that cause
toxicity in animal models. Toxic effects theoretically could occur in kidney, liver and brain
●● Halothane hepatitis occurs after repeated exposure in susceptible individuals and may
result from immune reaction to metabolite; obesity, hypoxaemia and short time period
between exposures are risk factors
●● Desflurane must be administered by special electronic vaporizer (Tec 6) because of its low
boiling point
 Pharmacology

Inhaled Anaesthetics 189

Oxygen
Non-metallic element existing as colourless, odourless diatomic (O2) gas in lower atmosphere and triatomic
­oxygen (O3) in upper atmosphere
●● Most plentiful element in Earth’s crust
●● Constitutes 21% air by volume

Physical properties
Boiling point Critical temperature Critical pressure Melting point Atomic weight Molecular weight
−182°C −119°C 50 bar −218°C 16 32

Uses
●● Essential for respiration and to prevent hypoxaemia
●● Adjunct to shock management
●● Treatment of carbon monoxide poisoning, decompression sickness, pneumocystis coli and anaerobic infections

Manufacture
●● Fractional distillation of air
●● Oxygen concentrator using zeolite mesh that absorbs nitrogen from air leaving (97% O2)

Storage
●● Gas in black-coloured cylinders with white shoulders at 137 bar
●● Liquid in vacuum-insulated evaporator (VIE) at 10 bar and −180°C

Measurement
●● In mixture of gases with mass spectrometer, fuel cell and paramagnetic analysers
●● In blood with Clarke electrode or transcutaneous electrode or indirectly with a pulse oximeter
Oxygen (cont.)
Methods of administration
●● Fixed performance devices that deliver constant
fraction of inspired oxygen (FiO2) despite change in
inspiratory flow rate
■■ Examples include oxygen tent, anaesthetic
breathing systems and high airflow oxygen
entrainment (HAFOE) devices
●● Variable performance devices in which FiO2
depends on inspiratory flow rate such as nasal can-
nulae and plastic masks (e.g. Hudson mask)
●● Intermittent positive pressure ventilation (IPPV)
●● Continuous positive airway pressure (CPAP)
●● Hyperbaric oxygen
Indications for oxygen therapy
●● Cardiac and respiratory arrest (give 100%
oxygen)
●● Hypoxaemia (PaO2 <7.8 kPa [59 mmHg], SaO2 <90%)
●● Systemic hypotension (systolic blood pressure
<100 mmHg)
●● Low cardiac output and metabolic acidosis (bicar-
bonate <18 mmol/L)
●● Respiratory distress (respiratory rate >24/min)
Dangers of oxygen therapy
1. High flow oxygen given to patients with chronic
obstructive pulmonary disease (COPD) may
cause respiratory depression, as they have high
levels of carbon dioxide and depend on hypoxia to
stimulate respiration (hypoxic respiratory drive)
2. High flow oxygen to patients in danger of hypoventi-
lation can hide respiratory insufficiency if the pulse
oximeter is being over-relied upon as the respiratory
monitor (the SpO2 can be satisfactory but the CO2
will accumulate)
3. Fire
■■ Oxygen supports combustion of other fuels
4. Absorption atelectasis
■■ Prolonged administration of high concentrations
of oxygen can result in atelectasis, particularly at
lung bases
■■ Most common after chest or upper abdominal
surgery and in those patients with poor lung
function and sputum retention
5. Retinopathy of prematurity
■■ High arterial oxygen tensions are major factor
in causing retrolental fibroplasias in neonates,
which may result in blindness
■■ Condition is caused by blood vessels growing
into vitreous, which is followed later by fibrosis
■■ If neonate is hypoxic or requires resuscitation,
however, oxygen must be given
■■ Oxygen in normal concentrations is also safe for
short periods during anaesthesia
 Pharmacology

Inhaled Anaesthetics 190

Nitrous oxide
Structure ●● Inorganic gas with critical temperature of 36.5°C, so exists as vapour at normal room temperature
Presentation ●● Liquid in blue cylinders at 51.6 bar at 20°C
●● Piped gas
●● 50/50 mixture with oxygen in blue cylinders with white shoulders at 137 bar
Indications ● General anaesthesia  ●  Pain relief during labour  ● Cryotherapy
Mechanism of ●● Unknown
action ●● Modulation of enkephalins and endorphins in CNS
Onset ●● Minutes
Duration ●● Termination of effects within minutes
Effects
 Respiratory system ●● Decreased tidal volume and increased respiratory rate
  Cardiovascular ●● Decreased contractility
system ●● Reflex increased peripheral vascular resistance
  CNS ●● Anaesthesia and analgesia
Side effects ●● Nausea and vomiting
●● ↑ size of air-filled cavities (e.g. pneumothorax, intestines, middle ear), diffusion hypoxia at
termination of anaesthesia
●● Prolonged administration: megaloblastic anaemia, pancytopenia and peripheral neuropathy
(due to interference with the action of methionine synthase containing vitamin B12 as a co-factor)
Contraindications ●● Undrained pneumothorax  ●  Air emboli
Metabolism ●● Negligible  ●  Excreted by lungs unchanged
Pregnancy ●● Thought to be safe
Paediatrics ●● Good for inhalational induction in conjunction with sevoflurane
Comments ●  Causes second gas effect and concentration effect  ●  Reduces MAC of co-administered
anaesthetic agents  ●  Boiling point −88°C  ●  Critical temperature 36.5°C  ●  MAC 105% 
●  Oil/water solubility coefficient 3.2  ●  Blood/gas solubility coefficient 0.47
Nitric oxide
Structure ●● Inorganic gas
Presentation ●● Cylinders containing 100, 1000 or 2000 ppm nitric oxide in nitrogen
Indications ●● Severe acute respiratory distress syndrome (ARDS)  ●  Pulmonary hypertension
●● Severe right-sided heart failure
Mechanism of action ●● Smooth muscle relaxation and vasodilation by stimulation of guanylate cyclase
Onset and duration ●● Rapid  ●  Half-life <5 seconds
Dose ●● 5–80 ppm injected into inspiratory limb of ventilator
Effects
  Respiratory system ●● Reduces hypoxic pulmonary vasoconstriction and preferentially increases blood flow to
well-ventilated lung, so lessens ventilation:perfusion mismatch
Cardiovascular system
  ●● Dilates pulmonary but not systemic blood vessels
●● Inactivated by binding with haemoglobin before reaching systemic circulation
  CNS ●● Increased cerebral blood flow  ●  CNS and autonomic neurotransmitter
  Haematological ●● Inhibits platelet aggregation
Side effects ●● Methaemoglobinaemia and pulmonary oedema with >500 ppm
●● Nitrogen dioxide impurities may cause pneumonitis or pulmonary oedema
Contraindications ●● Methaemoglobinaemia
Metabolism ●● Conversion to nitrates and nitrites in presence of oxygen
Paediatrics ●● Used in neonatal and paediatric pulmonary hypertension
Comments ●● Seems to be effective molecule in nitrate vasodilators
●● Endogenous production catalyzed by nitric oxide synthase, which
■■ constitutive (eNOS) produced in endothelial, cardiac, skeletal muscle and brain
tissue and platelets
■■ inducible (iNOS) produced in macrophages, neutrophils, myocytes, endothelium
and vascular smooth muscle
●● Sepsis increases iNOS-mediated NO production by endotoxin and cytokines
 Pharmacology

Other Anaesthetic Drugs 191

Non-depolarizing muscle relaxants
Classification
●● Chemical – aminosteroids (rocuronium, vecuronium, and pancuronium) or benzylisoquinoliniums (atracurium
and mivacurium)
●● Speed of onset (rocuronium fast, others medium)
●● Duration of action (short: mivacurium; intermediate: atracurium, rocuronium and vecuronium, long: pancuronium)

Properties of an ideal muscle relaxant

●● Physical – cheap, water soluble, with long shelf-life and no special storage requirements
●● Pharmacokinetic – short duration of action with predictable reversal, non-cumulative so can be given as an infusion,
completely metabolized to inactive metabolites, and metabolism unaffected by renal or hepatic disease
●● Pharmacodynamic – non-depolarizing, rapid onset, high potency, no cardiovascular or respiratory system side
effects, safe to use in pregnancy and children

General comparison of aminosteroids and benzylisoquinoliniums

●● Aminosteroids have no effect on the CNS, do not raise ICP or intraocular pressure
●● Vecuronium and rocuronium have very little effect on the CVS
●● Pancuronium causes tachycardia
●● Aminosteroids cause no histamine release – related bronchospasm
●● Benzylisoquinoliniums cause local and/or systemic histamine release which can lead to hypotension or
bronchospasm

Mivacurium
●● Mivacurium is a non-depolarizing muscle relaxants with a short duration of action due to rapid enzymatic
metabolism
Structure ●● Cis-cis, cis-trans and trans-trans isomers of a benzylisoquinolinium
Presentation ●● 2 mg/mL solution
Onset ●● 2.5 minutes
Duration ●● 10–20 minutes
Non-depolarizing muscle relaxants (cont.)
Mivacurium (cont.)
Dose ●● Intubation: 0.07–0.15 mg/kg
●● Infusion: 200–500 µg/kg/hour
Effects
  Respiratory system ●● Bronchospasm (histamine release)
  Cardiovascular system ●● Decrease in BP and increase in HR at higher doses
Side effects ●● Cutaneous flushing
●● Histamine release
Metabolism ●● Hydrolysis by plasma cholinesterases
Cautions ●● Hypersensitivity ●● Elderly ●● Burns
●● Myasthenia gravis ●● Hepatic impairment ●● Low plasma cholinesterase
●● Hypothermia ●● Renal impairment activity

Pancuronium and vecuronium

●● Pancuronium is a long-acting, non-depolarizing muscle relaxant that causes tachycardia
●● Vecuronium is a medium-acting, non-depolarizing muscle relaxant that may cause bradycardia
Pancuronium Vecuronium
Structure ●● Bis-quaternary aminosteroid ●● Bis-quaternary aminosteroid
Presentation ●● 2 mg/mL solution ●● Lyophilized powder diluted in water to 2 mg/mL solution
Onset ●● 90–150 seconds ●● 2 minutes
Duration ●● 45–60 minutes ●● 20–30 minutes
Dose ●● Intubation: 0.05–0.1 mg/kg ●● Intubation: 0.08–0.1 mg/kg
●● Infusion 60 µg/kg/hour ●● Infusion: 50–80 µg/kg/hour
Effects
  Cardiovascular ●● Increase in heart rate ●● Slight increase in cardiac output and slight decrease
system ●● Increase in cardiac output in systemic vascular resistance
●● Increase in blood pressure (vagolytic)
Side effects ●● Rarely anaphylactoid reactions ●● Associated with critical illness polyneuropathy
●● Rarely anaphylactoid reactions
Metabolism ●● 30%–45% hepatic deacetylation ●● Hepatic deacetylation to active metabolites
followed by excretion in bile
 Pharmacology

Other Anaesthetic Drugs 192

Rocuronium and atracurium
●● Rocuronium is a medium-duration, non-depolarizing muscle relaxant that has rapid onset and can be
­rapidly reversed by sugammadex
●● Atracurium is a medium duration, non-depolarizing muscle relaxant that undergoes ester hydrolysis and
Hofmann degradation
Rocuronium Atracurium
Structure ●● Aminosteroid ●● Benzyl isoquinolinium ester (racemic mixture)
Presentation ●● 10 mg/mL solution ●● 10 mg/mL solution to be stored at 4°C–10°C
Onset ●● 1 minute ●● 90 seconds
Duration ●● 30–40 minutes ●● 35 minutes to 95% recovery of twitch height
Dose ●● Intubation: 0.6 mg/kg ●● Intubation: 0.5 mg/kg
●● Infusion: 300–600 µg/kg/hour ●● Infusion: 300–600 µg/kg/hour
Effects
  Cardiovascular ●● Slight increase in heart rate ●● Minimal effects
system ●● Slight increase in mean arterial
pressure
  Respiratory system ●● Occasional bronchospasm
Side effects ●● Rarely anaphylactoid reactions ●● Associated with critical illness polyneuropathy
●● Cutaneous flushing, hypotension and bronchospasm
may occur because of histamine release
Metabolism ●● None ●● Hofmann degradation to laudanosine and a
quaternary monoacrylate
●● Minor pathway: hydrolysis by non-specific plasma
esterases to quaternary alcohol and quaternary acid
Comments ●● Cisatracurium
■■ Isomer of atracurium that causes less histamine
and laudanosine release
■■ Similar duration
■■ Dose of 0.1–0.2 mg/kg
Sugammadex
Reversal agent that selectively chelates rocuronium or vecuronium to allow reversal from deeper block than is
possible with anticholinesterases. Can be used for rescue reversal of rocuronium but not vecuronium
Structure ●● Modified gamma-cyclodextrin
Presentation ●● Solution for injection of 100 mg/mL
Indications ●● Reversal of rocuronium- or vecuronium-induced neuromuscular blockade
Mechanism of action ●● Encapsulation of steroid portion of rocuronium/vecuronium within hydrophobic interior
●● Negatively charged carboxyl group of sugammadex binds to positively charged
nitrogen atom on rocuronium/vecuronium
●● The concentration gradient then favours movement of rocuronium/vecuronium away
from the effector site
Onset ●● 1.5 minutes if 16 mg/kg given in ’rescue reversal’ of rocuronium
●● 3 minutes if 4 mg/kg given for ’deep’ block with 1 to 2 post-tetanic counts
●● 2 minutes if 2 mg/kg for ’shallow’ block with reappearance of T2
Duration ●● Second dose of 4 mg/kg if required after rescue reversal. A delay of 24 hours is
recommended before using rocuronium or vecuronium again
Dose ●● See above
Effects ●● Minimal CVS, no respiratory effects
Side effects ●● Bitter or metallic taste
●● Bronchospasm
●● Reduces progesterone available from oral contraceptive pill (one missed day). Non-oral
hormonal contraception requires additional contraception for 1 week
Contraindications ●● Uncertain
Metabolism ●● Not metabolized; secreted by kidneys
Pregnancy ●● Use with caution; no information available
Paediatrics ●● 2 mg/kg for 2–17 year olds; not recommended in infants
Interactions ●● Toremifene or IV fusidic acid delays reversal of block
 Pharmacology

Other Anaesthetic Drugs 193

Suxamethonium
Suxamethonium chloride is a depolarizing muscle relaxant with the structure of two molecules of acetylcholine
joined together
Structure ●● Dicholine ester of succinic acid
Presentation ●● 50 mg/mL solution stored at 4°C
Indications ●● Rapid onset, short duration muscle relaxation
Mechanism of ●● Prolonged stimulation of acetylcholine receptors at NMJ
action
Onset ●● 30 seconds
Duration ●● 3–5 minutes
Dose ●● IV: 0.5–2 mg/kg, IM: up to 2.5 mg/kg, SL 2 mg/kg
Effects
Respiratory
  ●● Apnoea
system ●● Bradycardia with repeated doses
●● Fasciculations
●● Phase I block progressing to phase II block with repeated doses
  CNS ●● Increase in intracranial and intraocular pressure (usually avoided in penetrating eye injuries)
Gastrointestinal
  ●● Increase in intragastric pressure and decrease in lower oesophageal sphincter (LOS) pressure
tract ●● Increase in salivation and gastric secretion
  Miscellaneous ●● Transient hyperkalaemia
Side effects ●● Prolonged apnoea ●● Anaphylaxis ●● Sustained contraction in myotonia
●● Postoperative muscular pains ●● Masseter spasm ●● Resistance in myasthenia gravis
Contraindications ●● Family history of malignant ●● Hyperkalaemia ●● Duchenne muscular dystrophy
hyperpyrexia (MH) ●● Congenital myotonic
●● Low plasma cholinesterase disease
activity
Metabolism ●● Hydrolysed by plasma cholinesterase to succinylmonocholine and choline and then succinic
acid and choline
Suxamethonium (cont.)
Pregnancy ●● Mildly prolonged duration of action may occur
Paediatrics ●● Older than one year: 1 mg/kg
●● Younger than one year: 2 mg/kg
Comments ●● Hyperkalaemia increased substantially in burns/extensive muscle denervation
●● Potent trigger for MH
●● Generalized contractures in patients with myotonia

Suxamethonium apnoea
●● Suxamethonium is metabolized by plasma cholinesterase (also known as pseudocholinesterase)
●● Prolonged duration of action of suxamethonium will result from reduced enzyme activity because of
■■ inherited atypical plasma cholinesterase (see below)
■■ acquired deficiency of plasma cholinesterase activity (e.g. pregnancy, liver disease, renal disease, cardiac
failure, thyrotoxicosis and cancer)
■■ inhibition of plasma cholinesterase by drugs (e.g. metoclopramide, ketamine, OCP, lithium, lidocaine, ester
local anaesthetics, cytotoxic agents, edrophonium, neostigmine and trimethaphan)
●● Around 95% of people are homozygous for the normal genes
■■ Three most common abnormal alleles are atypical (dibucaine-resistant), silent (absent) and fluoride-resistant;
they result in prolongation of action of suxamethonium from 10 minutes to 4 hours
●● Dibucaine number is percentage inhibition of plasma cholinesterase by dibucaine, a local anaesthetic
■■ Less than the normal 75%–85% in people with abnormal variants of plasma cholinesterase gene
■■ Other agents such as fluoride and chloride may be used in similar tests
●● Initial phase I block becomes phase II block (also known as dual block) with repeated or large doses (e.g. 400 mg)

Phase I Phase II
Tetanus ●● Well sustained ●● Poorly sustained
●● Fade
Post-tetanic facilitation ●● No ●● Yes
Train of four ratio ●● >0.7 ●● <0.7
Effect of anticholinesterases ●● Block augmented ●● Block antagonised
Tachyphylaxis – ●● Yes
 Pharmacology

Other Anaesthetic Drugs 194

Local anaesthetics
Local anaesthetics are drugs that produce reversible blockade of neural transmission in auto-
nomic, sensory and motor fibres. They bind to fast sodium channels in the axon to prevent depo-
larization and action potential propagation

Characteristics
●● Poorly soluble weak bases with pKa >7.4 (i.e. predominantly ionized at neutral pH)
●● Consist of hydrophilic portion (usually tertiary amine) and hydrophobic portion (usually unsatu-
rated amine ring) linked by ester or amide
●● Modifications of chemical structure alter potency, rate of metabolism and duration of action

Amides (e.g. lignocaine, bupivacaine,

Esters (e.g. procaine, cocaine, amethocaine) ropivacaine)
●● Ester linkage –R–O–CO–R1 ●● Amide linkage –R–CO–NH2–R1
●● Unstable in solution ●● Stable in solution with long shelf-life
●● Rapidly hydrolysed by plasma cholinesterase ●● Broken down by metabolism N-dealkylation and
●● One of main breakdown products is para-aminobenzoate hydroxylation by liver microsomal enzymes
(PABA), which is associated with hypersensitivity reactions ●● Allergies are rare

Mechanism of action
●● Diffuses from site of injection to axon
●● Crosses axon membrane in unionized form (degree of ionization depends on pKa of LA and pH of
tissues; in acidosis, more LA in ionized form, so degree of penetration is less)
●● Within axon, LA dissociates into ionized form and binds to Na+ channels internally to block them
in open state
●● Smallest nerves blocked first
Local anaesthetics (cont.)
Functional characteristics of local anaesthetics
Speed of onset ●● pKa determines the degree of ionization at a particular pH (ionization)
●● drugs with low pKa are more unionized and cross the phospholipid membrane
quicker for a faster onset
Duration of ●● Related to
action ■■ lipid solubility – larger intermediate chains more soluble
■■ protein binding – increases duration of action
●● lignocaine 65% protein bound whereas bupivacaine 95% protein bound
●● bupivacaine has longer duration of action but also potentially more toxic
Potency ●● Aromatic ring structure and increased hydrocarbon length determine lipid
solubility of drug and hence potency
●● Ineffective in infected tissue due to acidity reducing unionized fraction that can
diffuse into nerve
Intrinsic ●● In general, local anaesthetics are vasodilators at low concentration and
vasodilator vasoconstrictors at high concentration
properties ●● Note: cocaine only vasoconstricts
Other factors ●● Patient variables – age, height, etc.
that affect the ●● Concentration of drug and dose given
onset/duration ●● Site of injection
−
of block ●● Additives given (vasoconstrictors, HCO3 , hyaluronidase, dextrose, etc.)
 Pharmacology

Other Anaesthetic Drugs 195

Local anaesthetic toxicity
Toxicity results from membrane-stabilizing effects of local anaesthetics (LAs) on other cells, especially in the
heart and CNS

Factors increasing systemic absorption

Total dose administered ●● Peak levels in plasma and rate of rise are important
●● ‘Safe’ doses are guides only
■■ lignocaine 3 mg/kg (7 mg/kg with adrenaline)
■■ bupivacaine/levobupivacaine 2 mg/kg
■■ prilocaine 6 mg/kg (8.5 mg/kg with adrenaline)
■■ ropivacaine 3.5 mg/kg
Site of injection ●● Affected by blood flow and tissue vascularity
●● Greatest absorption after intercostal block; least absorption after sciatic/femoral
blocks and local infiltration
Vasoconstrictor additives ●● Lowers maximal blood concentration
●● At clinical doses, all drugs exhibit some vasodilator activity (lignocaine more potent
vasodilator than bupivacaine)
Fraction of unbound (thus ●● Local anaesthetics mostly bound to a1-glycoprotein and albumin to lesser extent
active) drug in the plasma
Tissue binding and ●● Binding decreases as pH increases; acidosis leads to ion trapping and increased risk
metabolism of toxicity
●● Uptake by lungs reduces plasma levels after intravenous injection, which protects
heart and brain
Plasma clearance ●● Deficiencies in plasma cholinesterase may affect metabolism and thus duration of
action of esters
●● Hepatic dysfunction or reduced hepatic blood flow can reduce metabolism of amides
Chirality ●● Levobupivicocaine is less toxic than the racemic mixture
Fetal toxicity ●● Depends on all of above and expressed as umbilical blood:maternal blood:
bupivacaine = 0.3, prilocaine >1
Local anaesthetic toxicity (cont.)
Clinical features of LA toxicity
Subjective Objective
●● Circumoral tingling and paraesthesia ●● Muscle twitching
●● Light-headedness, dizziness, agitation, ●● Slurred speech
tremor ●● Loss of consciousness, coma
●● Difficulty in focusing, tinnitus ●● Convulsions
●● Respiratory arrest
●● Cardiac arrhythmias (leading to ventricular fibrillation,
especially with bupivacaine)

Management of severe LA toxicity ■■ Consider cardiopulmonary bypass

(AABGI Guidance) ■■ Start intralipid 20% infusion 1.5 mL ⋅ kg−1
as a bolus over 1 min (100 mL for a 70 kg
1. Recognition
patient)
■■ Sudden alteration in mental state, loss of
■■ Start iv infusion at 15 mL ⋅ kg−1 ⋅ hr−1 (1000 mL ⋅
consciousness, convulsions
hr −1 for a 70 kg patient)
■■ Cardiovascular collapse
■■ After 5 minutes if no response:
2. Immediate management
●● Give a maximum of two repeat boluses
■■ Stop injection of the LA
●● Double the infusion rate to 30 mL ⋅  kg−1 ⋅ hr−1
■■ Call for help
■■ Maximum cumulative dose of 12 mL ⋅ kg−1
■■ ABC, maintain airway with 100% oxygen
4. Follow-up
■■ IV access
■■ Transfer to ITU
■■ Control seizures with benzodiazepines,
■■ Exclude pancreatitis with regular follow-up/
thiopental or propofol
LFTs
3. Treatment – If circulatory arrest:
■■ Report cases to National Patient Safety
■■ Start CPR
Agency (NPSA)
■■ Manage arrhythmias (may be refractory to
treatment)
 Pharmacology

Cardiovascular System Drugs 196

Inotropes
Inotropes are drugs that increase myocardial contractility and thus cardiac output
●● They may be divided into three categories, Catecholamines (naturally occurring and synthetic)
and phosphodiesterase inhibitors.

Catecholamines ●● Act via stimulation of adenylate cyclase increasing cyclic adenosine monophosphate
(naturally occurring (cAMP) levels, which increases intracellular calcium and contraction force
and synthetic)
Naturally ●● Adrenaline
occurring ●● Noradrenaline
catecholamines ●● Dopamine
■■ acts on dopamine receptors via Gs and Gi proteins leading to increased/decreased
levels of cAMP
■■ dopamine receptors
●● central (D1, D2, D3) – located in basal ganglia, hypothalamus, chemoreceptor trigger
zone and spinal cord
●● peripheral (DA1, DA2) – presynaptic and postsynaptic found in heart, gut and kidneys
■■ β1 effects (increased contractility and heart rate) at medium dose (5–15 µg ⋅ kg ⋅ min-1)
■■ α effects (increased [SVR] and venous return) at high dose (>15 µg ⋅ kg ⋅ min-1)
■■ dilation of renal and mesenteric vessels via D1 receptors at low dose (<5 µg ⋅ kg ⋅ min-1)
Synthetic ●● Isoprenaline
catecholamines ■■ dose (0.02–0.2 µg ⋅ kg ⋅ min-1)
■■ unselective β-agonist increases heart rate and cardiac output
■■ peripheral and pulmonary vasodilation
■■ myocardial oxygen delivery may decrease with tachycardia, and arrhythmias are
common
Inotropes (cont.)
●● Dobutamine
■■ dose 2.5–10 µg ⋅ kg ⋅ min-1 infusion
■■ predominantly β1 effects, small amount of β2 effects; usually increases blood pressure
despite a small fall in systemic vascular resistance (β2)
■■ causes less tachycardia than other catecholamines
■■ may cause arrhythmias; avoid in patients with outflow obstruction
●● Dopexamine
■■ dose 0.5–6.0 µg ⋅ kg ⋅ min-1
■■ synthetic analogue of dopamine but more β2 effects and less D1 and D2 effects
■■ positive inotrope but with reduced afterload (β2 effects, which may reduce blood pressure)
■■ mesenteric and renal vasodilation with increased urinary output
■■ bronchodilation (β2)
●● Salbutamol
■■ dose 250 µg intravenous slowly or 3–20 µg ⋅ min-1 infusion
■■ β2 receptor agonist
■■ causes tachycardia and bronchodilation
■■ sometimes used in circulatory failure although not a direct inotrope
■■ tocolytic
Phosphodiesterase ●● Calcium
inhibitors & other ■■ intravenous Ca2+ salts improve blood pressure for a few minutes
inotropic agents ■■ only used as temporary measure in circulatory collapse secondary to increased levels
of K+ and Ca2+ channel antagonist overdose
●● Glucagon
■■ increases cAMP through G-proteins and stimulation of adenylate cyclase
■■ used in β-blocker overdose
●● Cardiac glycosides (e.g. digoxin)
■■ thought to increase Ca2+ intracellularly
■■ increase cardiac output and reduce heart rate; may cause vasoconstriction
●● Thyroxine (T4) and triiodothyronine (T3)
■■ positive inotropic and chronotropic effects via intracellular mechanisms
 Pharmacology

Cardiovascular System Drugs 197

Adrenaline and noradrenaline
Adrenaline Noradrenaline
Structure ●● Catecholamine ●● Catecholamine
Presentation ●● 0.1/1 mg ⋅ mL-1 solution ●● Metered dose inhaler ●● 2 mg/mL solution
Indications ●● Anaphylactic shock ●● Glaucoma ●● Hypotension secondary
●● Cardiac arrest ●● Croup to ↓ SVR (e.g. septic or
●● Bronchospasm ●● Local vasoconstrictor anaphylactic shock)
●● Low cardiac output ●● Prolong duration of ●● To maintain BP in raised
states action of local ICP
anaesthetics
Mechanism of ●● α- and β-adrenoceptor agonist ●● α-adrenergic agonist
action (with some β1-adrenergic
agonist activity)
Duration ●● Half-life (IV) 2–3 minutes; longer, due to vasocon- ●● Half-life 2.5 minutes
striction if SC
Dose ●● Anaphylaxis: 0.1 mg (1 mL of 1 in 10,000) IV or ●● Infusion: 0.03–1 µg ⋅ kg ⋅
1 mg (1 mL of 1 in 1000) IM bolus, repeated as min-1
required
●● Cardiac arrest: 1 mg IV
●● IV infusion: 0.01–2 µg ⋅ kg ⋅ min-1
●● Croup: 0.5 mg ⋅ kg-1 nebulized (5 mg maximum)
(repeat after 30 minutes)
Adrenaline and noradrenaline (cont.)
Adrenaline (cont.) Noradrenaline (cont.)
Effects ●● 0.01–0.03 µg ⋅ kg ⋅ min-1: b effects ●● Predominantly α effects
●● 0.03–0.15 µg ⋅ kg ⋅ min-1: increased α effects (lower dose has some
●● 0.15–0.3 µg ⋅ kg ⋅ min-1: α effects predominate β1 effects)
Cardiovascular ●● ↑ in SV, contractility, cardiac oxygen consumption, ●● Arterial and venous
system systemic vascular resistance, systolic blood pressure vasoconstriction
●● ↓ in diastolic blood pressure, ↑ in mean arterial ●● ↑ in systolic and
pressure diastolic blood pressure
Respiratory ●● Bronchodilation ●● Cardiac output may
system ●● ↑ in respiratory rate increase or decrease
●● ↑ in tidal volume ●● Bronchodilation
●● ↑ in minute volume
Caution ●● Monoamine oxidase (MAO) inhibitors ●● Monoamine oxidase
●● Halothane (arrhythmias) inhibitors
●● Extravasation
Side effects ●● Arrhythmias
●● Ventricular fibrillation
Metabolism ●● Catechol-O-methyl-transferase (COMT) in liver ●● Monoamine oxidase
(uptake-2) and catechol-​O-methyl-
●● Some by MAO within adrenergic neurones transferase
(uptake-1)
Paediatrics ●● 0.1–1.5 µg ⋅ kg ⋅ min-1 infusion ●● 0.1–1.5 µg ⋅ kg ⋅ min-1
infusion
 Pharmacology

Cardiovascular System Drugs 198

Phosphodiesterase III inhibitors
Phosphodiesterase III inhibitors selectively inhibit phosphodiesterase III isoenzyme
●● Used for their inotropic and vasodilator effects

Structure ●● Milrinone: bipyridine derivative

●● Enoximone: imidazolone derivative
Presentation ●● Milrinone: 1 mg/mL yellow solution
●● Enoximone: 5 mg/mL yellow solution
Indications ●● Congestive heart failure
●● During and after cardiopulmonary bypass
●● Low cardiac output states before heart transplant
Mechanism of ●● Positive inotrope and vasodilation
action ●● Inhibition of phosphodiesterase III prevents cyclic adenosine monophos-
phate (cAMP) degradation and consequently increases slow calcium
inward current during cardiac action potential
Onset ●● Enoximone: 10–30 minutes
Duration ●● Enoximone: 4–6 hours, (longer in patients with heart failure)
●● Milrinone: 2.7 hours
Phosphodiesterase III inhibitors (cont.)
Dose ●● Enoximone:
■■ intravenous bolus: 0.5–1 mg ⋅ kg-1 (maximum 3 mg ⋅ kg-1) every 3–6 hours
■■ infusion: 90 µg/kg/minute for 10–30 minutes and then 5–20 µg ⋅ kg ⋅ min-1
●● Milrinone:
■■ intravenous bolus: 50 µg ⋅ kg-1 over 10 minutes then 0.3–0.75 µg ⋅ kg ⋅ min-1
Effects ●● Increase in inotropy, stroke volume, cardiac output
●● Decrease in right atrial pressure, pulmonary capillary wedge pressure,
peripheral vascular resistance and systemic vascular resistance
●● Little effect on myocardial oxygen demand, heart rate and blood pressure
Side effects ●● Uncommonly: dysrhythmias, decreased blood pressure, headache and
gastrointestinal disturbances
Contraindications ●● Caution in hepatic and renal impairment
Metabolism ●● Enoximone: metabolized in liver to inactive sulphoxide form
●● Milrinone: 80% excreted unchanged
Comments ●● Non-specific phosphodiesterase inhibitors inhibit all five isoenzymes and
have other indications
■■ aminophylline – asthma
■■ caffeine – neonatal apnoea
 Pharmacology

Cardiovascular System Drugs 199

Alpha-antagonists
Phentolamine Phenoxybenzamine
Structure ●● Imidazolone ●● Tertiary amine
Presentation ●● 10 mg/mL yellow solution ●● 50 mg/mL solution
●● 10 mg tablets
Indications ●● Diagnosis and treatment of ●● Hypertensive crisis
phaeochromocytoma ●● Raynaud’s phenomenon
●● Treatment of high blood pressure ●● Preoperative treatment of
during anaesthesia phaeochromocytoma
●● LVF after myocardial infarction
Mechanism of ●● Competitive non-selective α-blocker ●● Irreversible competitive α-blocker
action
Onset ●● 1–2 minutes ●● 1 hour
Duration ●● 5–20 minutes ●● 3–4 days (until synthesis of new
receptors)
Dose ●● Intravenous: 1–5 mg ●● Oral: 10–60 mg/day
●● Intravenous: 10–40 mg over
1 hour
Alpha-antagonists (cont.)
Phentolamine (cont.) Phenoxybenzamine (cont.)
Effects
Cardiovascular ●● Decrease in systemic vascular ●● Decrease in systemic vascular
system resistance and blood pressure resistance and cardiac output
●● Reflex tachycardia ●● Decrease in blood pressure
●● Increase in cardiac output and ●● Tachycardia
coronary blood flow
●● Class I anti-arrhythmic
Gastrointestinal ●● Increase in secretions
system ●● Increase in motility
CNS ●● Sedation
Side effects ●● Orthostatic ●● Abdominal ●● Dizziness ●● Paralytic ileus
hypotension discomfort ●● Dry mouth ●● Impotence
●● Dizziness ●● Diarrhoea
Contraindications ●● Hypotension ●● History of cerebrovascular
●● History of myocardial infarction accident
●● Coronary insufficiency ●● History of recent myocardial
●● Angina infarction
Metabolism ●● 10% renally excreted unchanged ●● Deacetylation in liver

●● Prazosin and indoramin are highly selective α1 blockers used to treat hypertension
●● Yohimbine is selective α2 blocker that is not used clinically
●● Labetalol and carvedilol are combined α- and β-blockers
 Pharmacology

Cardiovascular System Drugs 200

Alpha agonists
Naturally occurring (α1 and α2 adrenergic receptors)
●● Adrenaline  ●  Noradrenaline

Synthetic α1 agonists
Phenylephrine Methoxamine
●● Direct acting sympathomimetic ●● Direct acting sympathomimetic
●● Rapid rise in systemic vascular resistance and blood pressure with reflex ●● Similar effects to phenylephrine
bradycardia ●● Discontinued in 2001
●● Used in hypotension (spinal anaesthesia and IV drugs)
●● Other uses
■■ nasal decongestant
■■ mydriatic agent
●● Dose: 50–100 µg boluses

Synthetic α2 agonists
Clonidine Dexmetomidine
●● Centrally acting α2-agonist (affinity is 200× that of α1-adrenoceptors). ●● Used for procedural and ITU
Stimulates presynaptic receptors causing suppression of catecholamine sedation by IV infusion
release (negative feedback) 0.7 μg ⋅ kg ⋅ hr−1, adjusted
●● Used as an antihypertensive (50–600 µg TDS PO) and for migraine prophylaxis according to response
●● Has analgesic and sedative actions; reduces MAC when given preoperatively ●● Cautions – heart block;
●● Used extradurally and intrathecally to prolong the duration of analgesia ischaemic heart disease,
●● Used to treat agitation in ITU hypotension, abrupt withdrawal
●● Can also be used for ADHD, withdrawal from alcohol and benzodiazepines
and sleep disorders
Alpha agonists (cont.)
Mixed α and β agonists
Ephedrine Metaraminol
●● Found naturally in plants or synthesized for medical use ●● Direct and indirect sympathomimetic
●● Actions (α1 but some β2 activity)
■■ direct and indirect sympathomimetic ●● Used in spinal/extradural-induced
■■ releases noradrenaline from nerve endings (prone to hypotension
tachyphylaxis as stores are depleted) ●● Dose: 0.5–1 mg boluses
■■ Inhibits MOA release (caution with MOA inhibitors)
●● Effects
■■ cardiovascular system – positive inotrope, chrono-
trope and increased blood pressure
■■ respiratory system – bronchodilation
■■ CNS – arousal and mydriasis
■■ maintains uteroplacental blood flow
 Pharmacology

Cardiovascular System Drugs 201

Antihypertensive drugs
Antihypertensives are drugs used to reduce blood pressure that are classified according to their
mechanism of action
Vasodilator drugs ●● Act on vascular smooth muscle
●● Used in hypertensive crises
●● Direct action (NHS)
■■ Nitrates (e.g. GTN)
■■ Hydralazine
■■ Sodium nitroprusside
●● Indirect action (AAAC)
■■ α-adrenoceptor antagonists
■■ Angiotensin II receptor antagonists
■■ Angiotensin-converting enzyme (ACE) inhibitors (also ↓ salt and water retention)
■■ Ca2+ channel blockers
Diuretics ●● Act on kidney to ↓ reduce ECF volume
●● May cause direct vasodilation
β-adrenergic ●● ↓ cardiac output
receptor antagonists ●● ↓ production of renin
Adrenergic blocking ●● Rarely used because of side effects
drugs ●● Guanethedine depletes nerve endings of noradrenaline (blocks uptake-1 and displaces
noradrenaline from its binding site)
●● Reserpine prevents storage and release of noradrenaline
Ganglion blocking ●● Nicotinic Ach receptor antagonists acting at autonomic ganglia
drugs (e.g. ●● Widespread side-effects from sympathetic blockade (hypotension, ↓ sweating) and
trimetaphan) parasympathetic blockade (constipation, urinary retention, impotence, dry mouth, blurring
of vision)
Centrally acting ●● ↓ Reduce sympathetic activity
drugs ●● Examples: clonidine, reserpine, a methyldopa
Antihypertensive drugs (cont.)
Anaesthetic ●● Spinal and extradural anaesthesia block sympathetic outflow
techniques
Anaesthetic agents ●● Inhalational – cause vasodilatation. Halothane ↓ baroreceptor activity, ↓ CO, ↓ sympathetic
activity
●● Intravenous – e.g. propofol (mechanism controversial)

Sites of action of antihypertensives

(Medulla–
vasomotor
Clinical nugget–treatment of hypertension
Baroreceptors centre) ●● Pharmacological treatment of hypertension in
(Halothane)
Centrally acting the community is important to avoid the serious
drugs consequences of chronic high blood pressure
Ganglion such as strokes, heart failure and renal disease
β-blockers Spinal/
blockers
epidural ●● Treatment will be in stages depending on the age
Adrenergic and ethnicity of the patient and tolerance of side
Heart
neurone effects (e.g. chronic cough with ACE inhibitors)
blockers ●● In patients <55, non-Afro-Caribbean, first line is
Vasodilators
ACE inhibitor or AR antagonist
Diuretics ●● Add in a Ca2+ -channel blocker (CCB) unless
Blood vessels
(ECF) there is evidence of fluid overload then choose
a thiazide-like diuretic
●● Older patients and Afro-Caribbean patients;
start with CCB. β-blockers are not normally used
for hypertension
 Pharmacology

Cardiovascular System Drugs 202

Glyceryl trinitrate (GTN)
Structure ● Organic nitrate ester
Presentation ●● Sublingual tablets  ●   Transdermal patches  ●  Oral spray  ●   Solution for injection
Indications ●● Reduce blood pressure  ●  Angina  ●   Left ventricular failure
Mechanism of ●● Produces nitric oxide, which vasodilates arteries and veins
action
Onset ●● 3 minutes sublingually
Duration ●● 30–60 minutes sublingually
Dose ●  300 µg sublingually (not enterally active)  ●   5 or 10 mg over 24 hours transdermally  
●  0.2–3 µg/kg/min intravenously
Effects
  Respiratory ●● Bronchodilation
system
  Cardiovascular ●  Venodilation  ●   Cardiac output and coronary blood flow unaffected  ●   Arterial dilatation with
system increasing dose  ●   ↓ systemic vascular resistance and systolic, diastolic, venous and pulmonary
artery pressures  ●   Heart rate unaltered in failure but reflex increased in normal state
CNS ●● ↑ intracranial pressure  ●  Headache
Side effects ●● Postural hypotension, tachycardia or bradycardia, headache, dizziness
●● Rapid injection may cause severe hypotension, sweating, apprehension, restlessness, muscle
twitching, retrosternal discomfort, palpitation, abdominal pain and syncope
●● Methaemoglobinaemia with prolonged use
Contraindications ●  Hypotension  ●  Constrictive pericarditis  ●  Hypovolaemia  ●  Mitral stenosis  ●  Hypertrophic
cardiomyopathy  ●  Marked anaemia  ●   Aortic stenosis  ●  Closed-angle glaucoma  ●  Cardiac
tamponade
Metabolism ●● Liver and red cell hydrolysis of ester bonds  ●   80% excreted renally
Comments ●● Absorbed by polyvinylchloride (PVC); polyethylene giving sets available
●● Explosive – patches should be removed before DC cardioversion
●● Caution; interaction with Viagra causes large drops in blood pressure
Sodium nitroprusside
Structure ●● Inorganic complex
Presentation ●● Powder for reconstitution in 5% dextrose
Indications ●● Hypertension  ●  Hypotensive anaesthesia  ●   Heart failure
Mechanism of ●● Binds to oxyhaemoglobin producing methaemoglobin, cyanide and nitric oxide, which
action vasodilates arteries and veins
Onset ●● 1–2 minutes
Duration ●● <10 minutes  ●   Plasma half-life about 2 minutes
Dose ●● 0.1–6 µg ⋅ kg ⋅ min−1 (maximum 8 µg ⋅ kg ⋅ min−1)
Effects
  Respiratory ●● Inhibits hypoxic pulmonary vasoconstriction
system
  Cardiovascular ●  Arterial vasodilatation leads to ↓ systemic vascular resistance and ↓ blood pressure 
system ●   Venous vasodilatation leads to ↓ preload  ●  Reflex tachycardia (not seen in patients with
heart failure) preserves cardiac output  ●   ↓ ventricular wall tension and myocardial oxygen
consumption  ●   Tachyphylaxis may occur
  CNS ●● Cerebral vasodilatation leads to ↑ intracranial pressure
  Endocrine ●● Increased levels of renin and catecholamine in plasma
Side effects ●  Nausea and vomiting  ●   Abdominal pain  ●  Retrosternal pain  ●  Restlessness  ●  Palpitations
●  Methaemoglobinaemia  ●  Dizziness  ●  Muscle twitching  ●  Cyanomethaemoglobinaemia
●  Headache
Toxicity ●● Cyanide ions cause uncoupling of oxidative phosphorylation, which causes metabolic
acidosis and increased mixed venous oxygen
Contraindications ●● Severe vitamin B12 deficiency  ●   Compensatory hypertension
Metabolism ●● Metabolized in liver via cyanide to thiocyanate, which is excreted by kidney
Pregnancy ●● Potential for accumulation of cyanide in fetus, so avoid prolonged use
Comments ●● Must be protected from decomposition by light
 Pharmacology

Cardiovascular System Drugs 203

Hydralazine
Structure ●● Phthalazine derivative
Presentation ●● Tablets  ●   White powder for dilution in water
Indications ●● Hypertension  ●  Hypotensive anaesthesia  ●   Congestive heart failure  ●  Pre-eclampsia
Mechanism of action ●● Interferes with calcium movements, which results in electromechanical decoupling
Onset ●● Intravenous: 15–20 minutes
Duration ●● 2–6 hours
Dose ●● Oral: 50–200 mg/day in divided doses  ●   Intravenous: 20–40 mg slowly
Effects
Cardiovascular ●● Vasodilator that acts predominantly on arterioles to ↓ systemic vascular resistance and
system hence blood pressure
●● Reflex tachycardia and ↑ cardiac output
CNS ●● ↑ cerebral blood flow
Renal system ●● Sodium retention and decreased volume of urine
Side effects ●  Systemic lupus erythematosus, particularly in slow acetylators and women  ●   Nausea and
vomiting   ●   ↓ urine output, fluid retention and oedema   ●   Peripheral neuropathy and blood
dyscrasias
Contraindications ●  Idiopathic SLE  ●  Myocardial insufficiency  ●  Severe tachycardia  ●  Porphyria  ●  High
output cardiac failure
Metabolism ●● Acetylation and oxidation followed by conjugation
●● Patients may be slow or fast acetylators
Pregnancy ●● Crosses placenta and may result in fetal tachycardia
●● Manufacturer advises avoid before third trimester
Comments ●  Oral bioavailability 25%–55%  ●   90% plasma protein bound  ●   Half-life 2–3 hours, but
<1 hour in fast acetylators
Nifedipine
Structure ●● Dihydropyridine
Presentation ●● Capsules  ●  Tablets  ●   Solution for intracoronary injection
Indications ●● Angina  ●  Hypertension  ●   Raynaud’s disease
Mechanism of action ●● Blocks calcium channels, which ↓ entry of calcium into cells and thus inhibits
contraction of smooth muscle
Onset ●● Orally: 15–30 minutes  ●   Sublingually: faster than oral
Duration ●● Elimination half-life 3–5 hours
Dose ●● 5–20 mg orally
Effects
Respiratory system ●● Inhibits hypoxic pulmonary vasoconstriction
Cardiovascular system ●● Myocardial and peripheral arterial dilatation leads to ↓ SVR which leads to ↓ BP, which
leads to reflex ↑ in heart rate, contractility and cardiac output
●● ↓ peripheral vascular resistance, ↓ left ventricular end diastolic and pulmonary artery
pressures
●● ↑ coronary blood flow
CNS ●● ↑ cerebral blood flow
Side effects ●● Headache  ●  Flushing  ●  Dizziness  ●  Gum hyperplasia  ●   Peripheral oedema
Contraindications ●  Cardiogenic shock  ●   Advanced aortic stenosis  ●   Within one month of myocardial
infarction  ●   Unstable or acute angina  ●  Porphyria
Metabolism ●● 95% metabolized in liver to renally excreted inactive metabolites
Pregnancy ●● May inhibit labour
Comments ●● May ↓ MAC by up to 20%
●● May ↑ effect of muscle relaxants
●● ↑ negative inotropic effect with volatile agents (both ↓ calcium release and entry into
myocardial cells)
 Pharmacology

Cardiovascular System Drugs 204

Beta blockers
Competitive antagonists at β adrenoceptors
●● May be selective for
■■ β1 receptors (cardioselective e.g. esmolol)
■■ β1 and β2 receptors (e.g. propanolol)
■■ α and β adrenoceptors (e.g. labetalol)
●● May be partial agonists at b adrenoceptors (i.e. demonstrate intrinsic sympathomimetic activity, e.g. pindolol)
●● These may be useful if profound bradycardias are a problem with other b-blockers

Uses Actions
●● Hypertension (only in selective cases, e.g. ●● Cardiovascular system
when evidence of sympathetic overactivity) ■■ bradycardia (↓ SA node automaticity, ↑ AV node conduction),
●● Heart failure which leads to ↑ coronary blood flow by ↑ diastolic filling time
●● Angina ■■ ↓ myocardial oxygen consumption
●● Dysrhythmias ■■ negative inotrope
●● Ischaemic heart disease and myocardial ■■ class II antiarrhythmic
infarction ■■ ↓ BP (↓ cardiac output, ↓ sympathetic activity, ↓ levels of renin)
●● Anxiety ■■ may precipitate cardiac failure (especially if used with other
●● Migraine negative inotropes)
●● Hyperthyroidism ●● Respiratory: bronchospasm (caution in asthma)
●● Glaucoma (topically) ●● Metabolic: masking of hypoglycaemia in patients with diabetes
●● Perioperatively ●● Renal: ↑ K+ / ↓ Na+ due to blocking of β1 receptor at Macula
■■ reduce hypertensive response to densa reducing release of renin
laryngoscopy/extubation ●● CNS: hallucinations, nightmares (especially lipid-soluble drugs,
■■ hypotensive anaesthesia e.g. metoprolol)
■■ treatment of hypertension, perioperative ●● Eye: reduces the production of aqueous humour, which leads to
ischaemia and dysrhythmias ↓ intraocular pressure (IOP) (e.g. timolol)
●● Other- exacerbation of Raynaud’s
Beta blockers (cont.)
Kinetics
●● Low lipid-solubility drugs (e.g. atenolol) have poor enteral absorption, minimal liver metabolism
and mostly unchanged excretion
●● Highly lipid-soluble drugs have opposite profile and thus need more frequent administration

Clinical nugget–β blockers peri-operatively

Most recent guidelines have supported the continuation of β blockers in patients who have
already been established on them during the peri-operative period of non-cardiac surgery.
Starting them anew just previous to surgery is associated with a reduction in cardiac events
and deaths but an overall increase in mortality. (POISE trial) There may be a case to start β
blockers in patients with intermediate or high risk of myocardial ischaemia, or with three of
the following risk factors (heart failure, CAD, diabetes, renal disease, CVA) but time should be
allowed to establish that there will be tolerance of the new medication.
 Pharmacology

Cardiovascular System Drugs 205

Drugs used in ischaemic heart disease
Acute coronary syndromes
●● Confirm diagnosis (ECG changes, troponin rise)
●● Combination anti-platelet therapy
■■ Aspirin 300 mg (may be self-administered) will halve the risk of vascular events including
death
■■ P2Y12 receptor antagonists – this is a surface protein found on platelets, being a chemorecep-
tor for ADP and is involved with platelet aggregation
■■ The choice of drug depends on the patient and the presentation. Combination with aspirin fur-
ther improves risk of cardiovascular events but benefit may be offset by increase risk in bleeding
●● Ticagrelor 180 mg (best overall outcomes)
●● Clopidogrel 300 mg (best if risk of bleeding)
●● Prasugrel 60 mg (if undergoing percutaneous coronary intervention [PCI])
●● Anti-coagulation therapy – continue for 8 days or until PCI
■■ Fondaparinux (s/c 2.5 mg o.d.) to patients who do not have a high bleeding risk or who are
going to have PCI within 24 hours
■■ Mode of action – synthetic pentasaccharide factor Xa inhibitor
■■ Low-molecular-weight heparin (LMWH) – slightly better than unfractionated heparin, but
both have benefits other than no anti-coagulation
●● β blockers – as long as no heart failure, bradycardia or hypotension
●● Thrombolytic therapy improves where PCI is unavailable. A bolus fibrin-specific drug should be
used as soon after diagnosis as possible
■■ Streptokinase or alteplase (tissue plasminogen activator) have equal efficacy and both
increase clot lysis
Drugs used in ischaemic heart disease (cont.)
Treatment after myocardial infarction
●● ACE inhibitor
●● Dual anti-platelet therapy
●● β blocker
●● Statin

Stable angina
●● Chest pain treatment – short-acting nitrate (vasodilator) which can cause light-headedness due
to ↓ venous return
●● Prevention: first line – β blocker/Ca channel blocker
●● If first-line therapy not tolerated then second-line therapy
■■ Long-acting nitrate
■■ Ivabradine (↓ HR by specific antagonism of ‘funny’ channel)
■■ Nicorandil (dual action: nitrate and K/ATP channel agonist causing vasodilation of coronary
arteries)
■■ Ranolozine (inhibition of late Na+ inward current → decrease in intracellular Ca2+ → reduced O2
cardiac demand)
 Pharmacology

Cardiovascular System Drugs 206

Antiarrhythmics
Vaughan-Williams classification classifies antiarrhythmics according to effects on cardiac action
potential
Class mechanism Site of action Drugs
I  N
 a+ channel blockade (decreased flux
in phase 0) and
A ●   Prolongs refractory period ●● Atria, ventricles and ●● Quinidine
accessory pathways ●● Procainamide
●● Diisopyramide
B  ●   Shortens refractory period ●● Ventricles only ●● Lignocaine
●● Mexiletine
●● Phenytoin
C ●   No effect on refractory period ●● Atria, ventricles and ●● Flecainide
accessory pathways ●● Propafenone
β adrenoceptor blockade
II  ●● Atrioventricular node ●● Propanolol
●● Sinoatrial node ●● Atenolol
●● Esmolol
III  K+ channel blockade ●● Atria, ventricles and ●● Amiodarone
accessory pathways ●● Sotalol
●● Bretylium
IV  Ca+ channel blockade ●● Atrioventricular node ●● Verapamil
●● Diltiazem

Adenosine and digoxin are not classified within this system

Antiarrhythmics (cont.)
Indications for antiarrhythmics Adenosine
●● Nucleoside comprising adenine and a pentose
Arrhythmia Drugs
sugar
Supraventricular ●● Digoxin ●● Inhibits atrioventricular node conduction and
tachycardia ●● Adenosine reduces contractility
●● Verapamil ●● Given by fast bolus (6 mg, 12 mg then 12 mg) into
●● β blockers large peripheral vein for treatment of supraventricu-
●● Quinidine lar tachycardia
Ventricular tachycardia ●● Lidocaine ●● May cause feeling of impending doom, dys-
●● Mexiletine pnoea, and bronchospasm and nausea
●● Contraindicated in asthma, second- and third-
Both supraventricular ●● Amiodarone
degree heart block and sick sinus syndrome
tachycardia and ●● Flecainide
ventricular tachycardia ●● Procainamide
●● Diisopyramide Amiodarone
●● Propafenone
●● Class III antiarrhythmic; prolongs phase 3 of the
●● Sotalol
cardiac action potential
Digoxin toxicity ●● Phenytoin ●● Slows conduction rate; prolongs refractory
●● Digoxin-specific period in SA and AV node
antibody ●● Part of the algorithm for VF or pulseless VT-300 mg IV
fragments followed by 900 mg infusion
●● Extensively metabolized in the liver; it has a very
long half life (weeks) and many drug interac-
tions (e.g. warfarin) by inhibiting cytochrome
P450
●● Side effects include corneal microdeposits, thy-
roid dysfunction, pulmonary pneumonitis; hepa-
totoxicity; peripheral neuropathy
 Pharmacology

Cardiovascular System Drugs 207

Digoxin
Structure ●● Glycoside  ●  Originally derived from foxglove
Presentation ●● 0.0625, 0.125 and 0.25 mg tablets  ●  0.05 mg ⋅ mL−1 elixir
●● 0.1–0.25 mg ⋅ mL−1 digoxin solution for injection
Indications ●  Atrial fibrillation (AF) and flutter with fast ventricular response  ●  No longer indicated for
heart failure except in select cases for symptom control but no improved mortality
Mechanism ●● In AF, ventricular rate is decreased by delaying conduction through AV node
of action ●● Digoxin works directly on heart, reducing the action of the Na+/K+ pump, ↑ intracellular Na+
and subsequently resulting in ↑ exchange of Na+ with extracellular Ca2+
●● ↑ Ca2+ increases excitability and inotropy
●● ↑ refractory period of the AV node and His bundle
●● An indirect effect ↑ acetylcholine release at cardiac muscarinic receptors, which also
prolongs the refractory period
Onset ●● Peak effect two hours after intravenous dose
Duration ●● Prolonged  ●  Large Vd and elimination half-life about 36 hours
Dose ●● Oral loading: 1–1.5 mg in divided doses over 24 hours or 250–500 µg once daily
●● Intravenous loading: 0.75–1 mg over at least two hours
●● Maintenance: 62.5–500 µg once daily  ●  Therapeutic range 1–2 µg ⋅ L−1
Effects ●● Increased contractility and automaticity  ●  Reduced heart rate
Side effects ●● Common (low therapeutic ratio) ●● Atrial and ventricular tachycardia
●● Arrhythmias ●● ECG changes: prolonged PR interval, ST
●● Premature ventricular contractions segment depression, flattened T waves and
●● Bigemini shortened QT interval
●● Atrioventricular block ●● Anorexia, nausea, diarrhoea and
●● Junctional rhythm abdominal pain
●● Visual disturbances of colour perception
and headaches
Digoxin (cont.)
Contraindications ●● Wolf-Parkinson-White syndrome ●● Ventricular fibrillation
●● Intermittent complete heart block ●● Ventricular tachycardia
●● Second degree atrioventricular block ●● Reduce dose in elderly and renal impairment
Metabolism ●● <10% metabolized by liver
●● 50%–70% excreted unchanged by kidney
Pregnancy ●● May need dose adjustment
Paediatrics ●● Licensed for use in heart failure and supraventricular arrhythmias
Comments ●● Intramuscular injection causes erratic absorption, pain and tissue necrosis
●● Verapamil, nifedipine, captopril, erythromycin, carbenoxolone, amiodarone and diazepam
↑ levels of digoxin in plasma
●● Antacids, cholestyramine, phenytoin and metoclopramide ↓ plasma levels
●● Toxic levels at DC cardioversion may cause severe ventricular arrhythmias, so recom-
mended to stop for 24 hours before cardioversion
Toxicity ●● Risk of toxicity increased by ●● Lignocaine or phenytoin are used to treat
■ hypokalaemia ventricular arrhythmias
■ hypernatraemia ●● Digoxin-specific antibody fragments (Fab)
■ hypercalcaemia are indicated if
■ hypomagnesaemia ■ plasma level >20 µg/L
■ acid–base disturbances ■ life-threatening arrhythmia
■ hypoxaemia ■ uncontrolled hyperkalaemia
■ renal failure ●● Re-exposure to Fab may cause
●● Toxicity may cause hyperkalaemia, hypersensitivity
which should be treated
●● Atropine and pacing may be needed
for bradycardia
 Pharmacology

Central Nervous System Drugs 208

Antidepressants
Antidepressants are drugs used to treat mood disorders and are classified as tricyclics, selec-
tive serotonin reuptake inhibitors (SSRIs), monamine oxidase inhibitors (MAOIs) and atypical
agents
●● Tricyclic overdose is relatively common and causes cardiovascular (sinus tachycardia, widened
QRS, arrhythmias, hypotension), central (excitation, seizures, depression) and anticholinergic
effects. Treatment is with gastric lavage, activated charcoal, supportive treatment, phenytoin (for
seizures and arrhythmias) and IV fluids for hypotension
●● SSRIs may affect platelet function. In combination with a MAOI or pethidine they may precipitate
serotonergic syndrome (agitation, hyperthermia, hyperreflexia and clonus) which can be fatal
●● MAOIs (e.g. phenelzine) may interact with pethidine or fentanyl to produce cerebral irritability,
hyperpyrexia and cardiovascular instability. Tyramine-rich foods and indirectly acting sympa-
thomimetics may cause a hypertension crisis. Pethidine and indirectly acting sympathomimetics
(e.g. ephedrine) should be avoided. Direct-acting agents only should be given if required but with
extreme caution as they may cause extreme hypertension. For elective cases, MAOIs would need
to be stopped 14 to 21 days prior to prevent these interactions; however this may cause relapse of
depression
Amitriptyline
Structure ●● Dibenzocycloheptadiene derivative  ●  Tricyclic
Presentation ●● Tablets  ●  Solution for injection
Indications ●● Depression  ●  Nocturnal enuresis  ●  Chronic pain
Mechanism of action ●● Blocks neuronal uptake of noradrenaline and serotonin, thus increasing their action in CNS
●● Antagonist at muscarinic cholinergic, alpha-1 adrenergic and H1 and H2 histaminergic
receptors
Onset ●● May take several weeks
Duration ●● Several days
Dose ●● Initially 75–150 mg/day  ●  Maintenance 50–100 mg/day maintenance
Effects
  Respiratory system ●● Respiratory depression in toxicity
  Cardiovascular system ●● Postural hypotension  ●  Sinus tachycardia  ●  Dysrhythmias
●● Prolonged PR and QT intervals
  CNS ●● Antidepressant  ●  Sedative
●● Fatigue may cause sedation and occasionally seizures in epileptics
Side effects ●● Anticholinergic: dry mouth, blurred vision, urinary retention and constipation
Contraindications ●● Recent MI  ●  Arrhythmias  ●  Severe liver disease
Metabolism ●● N-demethylation and hydroxylation then conjugation with glucuronide and sulphate
Paediatrics ●● 10–50 mg at night for nocturnal enuresis
Comments ●● Amitriptyline overdose can cause sinus tachycardia, prolonged QT interval and widened
QRS complex, ventricular arrhythmias, right bundle branch block, hypertension and
hypotension
●● Excitation, seizures and then depression occur
●● The anticholinergic effects may predominate
●● Treatment is supportive plus benzodiazepines or phenytoin for seizures
●● Inotropes should be avoided because they may precipitate arrhythmias
 Pharmacology

Central Nervous System Drugs 209

Phenytoin
Phenytoin is an anticonvulsant that is used to treat seizures, trigeminal neuralgia and arrhythmias following
tricyclic antidepressant poisoning
Structure ●● Hydantoin derivative
Presentation ●● Capsules, syrup and 50 mg/mL solution
Indications ●● Seizure prophylaxis and treatment  ●  Trigeminal neuralgia
●● Digoxin-induced arrhythmias  ●  Tricyclic antidepressant toxicity
Mechanism of action ●   Delays inward sodium and calcium flux and outward potassium flux during depolarization in excitable tissue,
which causes a membrane-stabilizing effect  ●  Raises seizure threshold
Onset ●● Intravenous: 10–30 minutes
Duration ●● 12–24 hours
Dose ●● Oral: 200–600 mg once daily  ●  Intravenous: 10–15 mg/kg loading then 100 mg three or four times daily
Effects
Cardiovascular
  ●  Class I antiarrhythmics  ●  Rapid intravenous infusion may cause hypotension, heart block, ventricular
system fibrillation or asystole
  CNS ●● Anticonvulsant
  Metabolic ●   Hypoglycaemia  ●  Hypocalcaemia  ●  Decreased secretion of antidiuretic hormone  ●  Disturbed liver
function tests
Side effects ●  Narrow therapeutic index  ●  Dose-dependent: nausea and vomiting, drowsiness, peripheral neuropathy,
behavioural disturbances, tremor, vertigo, slurred speech and ataxia  ●  Idiosyncratic: rash, gum hyperplasia,
acne, blood dyscrasias, systemic lupus erythematosus, hepatotoxicity and allergy
Contraindications ●● Porphyria
Metabolism ●● Hydroxylated and then conjugated to glucuronide by liver
●● 9% of population are slow hydroxylators
Pregnancy ●  Causes fetal mental retardation, craniofacial abnormalities, growth retardation and limb and cardiac
defects  ●  Possible neonatal vitamin K deficiency and bleeding
Paediatrics ●● 4–8 mg/kg oral
Comments ●   Induces hepatic enzymes reducing the effectiveness of benzodiazepines, pethidine, oral contraceptive pill and
warfarin  ●  Metronidazole, chloramphenicol and isoniazid may cause phenytoin toxicity  ●  Carbamazepine
and alcohol may induce metabolism of phenytoin reducing plasma levels
Carbamazepine and sodium valproate
Carbamazepine and sodium valproate are anticonvulsants that are also used in the treatment of trigeminal neuralgia
Carbamazepine Sodium valproate
Structure ●● Iminostilbene derivative ●● Salt of a carboxylic acid
Presentation ●● Tablets  ● Suppositories  ●  White syrup ●● Tablets  ● Syrup  ●  Ampoules for dilution with water
Indications ●● Epilepsy  ●  Trigeminal neuralgia ●● Primary generalized epilepsy
●● Bipolar disorder ●● Chronic neuropathic pain
Mechanism of action ●● Unknown  ● Anticonvulsant  ● Analgesic ●● Anticonvulsant thought to be through gamma-aminobu-
tyric acid (GABA) inhibition
Dose ●● 100–1600 mg/day in divided doses ●● Oral: 300–1250 mg twice daily
●● Intravenous: 400–2500 mg/day in divided doses
Effects
  Cardiovascular system ●● Antiarrhythmic, depresses AV conduction
  CNS ●● Raises seizure threshold ●● Anticonvulsant
  Genitourinary system ●● Antidiuretic
Side effects ●● Drowsiness ●● Hepatitis ●● Tremor ●● Acute pancreatitis
●● Ataxia ●● Rash ●● Nausea ●● Hair loss
●● Diplopia ●● Nausea and vomiting ●● Hepatic dysfunction ●● Thrombocytopenia
Contraindications ●● Porphyria  ●  AV conduction abnormalities ●   Porphyria  ●  Liver disease  ●  Family history of severe
●● Bone marrow depression hepatic dysfunction
Metabolism ●● Oxidation to active epoxide ●● Metabolized in liver by glucuronidation and oxidation to
●● Induces own metabolism active and inactive metabolites
Pregnancy ●● Risk of teratogenesis including neural tube ●   Risk of congenital malformations  ● Developmental
defects, possible neonatal vitamin K delay  ●  Neonatal bleeding  ●  Neonatal hepatotoxicity
deficiency and bleeding
Paediatrics ●● Licensed for use in children ●● Usually 10 mg ⋅ kg−1 maintenance
Comments ●● Induces hepatic enzymes
●● Reduces duration of action of vecuronium
●● Phenytoin levels may increase or decrease
 Pharmacology

Central Nervous System Drugs 210

Antiemetics
Antiemetics are those drugs used to prevent nausea and vomiting
●● Most drugs act centrally on the vomiting centre (VC) and chemoreceptor trigger zone (CTZ) but some (e.g. meto-
clopramide) have peripheral actions on the gastrointestinal tract
●● Antiemetic drugs include dopamine antagonists, ­anticholinergics, antihistamines, 5-HT3 antagonists, NK1 antago-
nists and miscellaneous drugs

Dopamine antagonists
Phenothiazines (e.g. chlorpromazine, prochlorperazine)
●● mainly used as antipsychotics but have a limited role as antiemetics
●● D2 receptor blockade at chemoreceptor trigger zone (CTZ) increases threshold for vomiting
●● chlorpromazine has antagonism at H1, α1, α2, and 5HT3 receptors
●● sedative and antipsychotic effects
●● impair central temperature regulatory mechanisms
●● well absorbed, very lipid soluble and highly protein bound
●● side effects include extrapyramidal reactions, anticholinergic effects, blood dyscrasias, gynaecomastia and
galactorrhoea, hypotension and neuroleptic malignant syndrome
Butyrophenones (e.g. domperidone, droperidol)
●● D2 antagonists at CTZ
●● also antagonize GABA
●● more sedating than phenothiazines
●● may cause neuroleptic malignant syndrome and extrapyramidal symptoms
Benzamides (e.g. metoclopramide) mechanism is threefold
●● antiemetic through D2 antagonism
●● prokinetic ↑ gastric emptying and ↓ oesophageal tone via peripheral cholinergic action
●● decreased sensitivity of visceral nerves to local emetics
●● used to treat chemotherapy-induced vomiting in high doses (thought to be due to central 5HT3 antagonism)
●● well absorbed but variable first-pass effect (bioavailability 30%–90%); conjugated in liver; 80% excreted in urine
●● side effects – extrapyramidal and dystonic reactions
●● may cause hypotension and tachycardia/bradycardia
●● increases prolactin
Anticholinergics
Atropine and hyoscine cross the blood–brain barrier and have antiemetic effects. Glycopyrrolate is
charged so does not cross the blood–brain barrier and therefore has no central effects

Antihistamines
See cyclizine

5-HT3 antagonists (e.g. ondansetron, granisetron)

●● Synthetic carbazoles
●● Antagonize central and peripheral 5HT3 receptors
●● Effective in postoperative nausea and vomiting, chemotherapy induced emesis
●● Ineffective in motion sickness
●● Side effects include headaches, flushing and constipation

Miscellaneous antiemetics
●● Steroids (e.g. dexamethasone) are useful for prophylaxis when given at the start of anaesthesia
but not effective for PONV
●● Canabinoids (e.g. nabilone) are used in chemotherapy and act on the vomiting centre
●● Benzodiazepines (e.g. lorazepam) are used in chemotherapy and may prevent anticipatory nausea
●● Propofol may reduce PONV if used for maintenance of anaesthesia which may be due to dopa-
mine 2 receptor antagonism
●● Neurokinin 1 (NK1) receptor antagonists (e.g. fosaprepitant) block substance P in the brainstem
and are used in chemotherapy
●● Acupuncture performed on the awake patient can prevent PONV
 Pharmacology

Miscellaneous Drugs 211

Cyclizine
Cyclizine is histamine-1 receptor antagonist used as an antiemetic. It has mild antimuscarinic action which
leads to its side effects of dry mouth, tachycardia and blurred vision

Structure ●● Piperazine derivative

Presentation ●● Solution  ●  Tablets  ●  Fixed-dose combinations with morphine, caffeine and dipipanone
Indications ●● Nausea and vomiting  ●  Motion sickness  ●  Vertigo  ●  Labyrinthine disorders
Mechanism of action ●● Antagonist of histamine at H1 receptors (antihistamine)
Onset ●● Minutes
Duration ●● 4–6 hours
Dose ●● 50 mg three times daily (0.5–1 mg/kg)
Effects
  Cardiovascular system ●● Mild anticholinergic effect and can produce tachycardia and hypotension due to
alpha-blockade
  CNS ●● Antiemetic  ●  Slight sedation
  Gastrointestinal system ●● Increase in lower oesophageal sphincter tone
Side effects ●● Anticholinergic: blurred vision, dry mouth, drowsiness and urinary retention
●● Tachycardia with rapid intravenous injection
Cautions ●● Prostatic hypertrophy  ●  Urinary retention  ●  Glaucoma
●  Pyloroduodenal Obstruction  ●  Hepatic disease  ●  Renal impairment
Metabolism ●● N-demethylation to norcyclizine
Comments ●● Antihistamines
■■ antagonists specifically at H1 receptors
■■ used to treat hay fever and allergic disorders
●● Chlorphenamine used with adrenaline to treat anaphylaxis
●● Alimemazine and promethazine more sedating than cyclizine and chlorphenamine
●● Non-sedating antihistamines (e.g. cetirizine, fexofenadine and loratadine) only cross
blood–brain barrier to small extent
Drugs acting on the uterus
3. Prostaglandins (E 2 , F2α and E1 analogue
Uterotonics [misoprostol])
1. Oxytocin (e.g. syntocinon/carbetocin)
■ ↑ myometrial calcium (increases myosin light
■ Nonapeptide – naturally occurring hormone in chain kinase activity and uterine contraction)
produced in the hypothalamus and stored in ■ Misoprostol 25 µg intravaginally for induction of
the posterior pituitary labour/rectally for PPH
■ ↑ intrauterine intracellular calcium, ↑ local pros- ■ PGF2α (hemabate) given IM/intramyometrially
taglandin production → uterine contraction 250 µg for uterine atony
■ Syntocinon 5 IU IV after caesarean delivery, infu- ■ Adverse effects
sions of 40 IU in 500 mL at 125 mL/hr for uterine atony ● Nausea and vomiting, diarrhoea, fever
■ Carbetocin 100 µg if risk of PPH ● PGF2α causes ↑ SVR and pulmonary vascular
■ Adverse effects resistance, bronchoconstriction, hypoxae-
● Vasodilatation – ↓ MAP, ↑ HR, ↓ SVR. Can mia; contraindicated in asthmatics, cardiac
cause maternal collapse disease and pulmonary hypertension
● Structurally similar to ADH so water and Na+
retention (in high doses)
2. Ergot Alkaloids (e.g. ergometrine) Tocolytics
Drugs that Inhibit uterine contractions and relax the
■ Indication – postpartum haemorrhage (PPH)
uterus
and uterine atony
●● β-adrenergic receptor agonists (ritodrine, salbuta-
■ Mechanism – partial agonist effects on uterine
mol, terbutaline)
α-adrenergic receptors
●● Calcium channel blockers (e.g. nifedipine)
■ Given 500 µg IM, repeated at 15–20 minutes
●● Oxytocin antagonists (e.g. atosiban)
■ Avoid IV:
●● Less widely used:
● Profound hypertension
■■ Magnesium sulphate
● Severe nausea and vomiting
■■ Prostaglandin synthetase inhibitors (e.g.
● Hypertensive crises (cerebral haemor-
indomethacin)
rhage, pulmonary oedema, retinal damage)
■■ Glyceryl trinitrate (GTN) IV
● Contraindicated in chronic hypertension,
pre-eclampsia, peripheral vascular disease
and ischaemic heart disease
■ Syntometrine = ergometrine 500 µg + oxytocin 5 IU
 Pharmacology

Miscellaneous Drugs 212

Anticholinesterases
Plasma cholinesterase (PChE, pseudocholinesterase)
●● Enzyme that hydrolyses ester bonds
●● Found in plasma, brain, liver and kidneys
●● Hydrolyses acetylcholine, suxamethonium, mivacurium, ester local anaesthetics, diamorphine,
aspirin and propanidid

Organophosphorus anticholinesterases
●● Used as insecticides and nerve gases (e.g. Novichok)
●● Irreversibly inhibit acetylcholinesterase and plasma cholinesterase by phosphorylation of esteratic
site
●● Inhibition lasts for weeks until new enzyme produced
●● Very lipid soluble, so are absorbed quickly through skin and readily cross blood–brain barrier
●● Ecothiopate eye drops are only clinically used organophosphorus anticholinesterases and have
been used to treat glaucoma
●● Ecothiopate has a quaternary ammonium group, which prevents it crossing blood–brain barrier
●● Toxicity causes
■■ nicotinic and muscarinic effects
■■ autonomic instability
■■ early central excitation with later depression, coma and apnoea
●● Treatment supportive, with atropine 2 mg intravenously or intramuscularly every 5–10 minutes as
needed until pupillary dilatation and tachycardia
●● Pralidoxime, a cholinesterase reactivator, may be used in moderate-to-severe poisoning; several
doses or infusion may be needed
Neostigmine
Neostigmine forms a carbamylated enzyme complex with cholinesterases. This slows the rate of hydrolysis of
acetylcholine by acetylcholinesterase, so that more acetylcholine is available at the neuromuscular junction
Structure ●● Quaternary amine
Presentation ●● Tablets  ●  Solution for injection
●● Fixed-dose combination of 2.5 mg neostigmine with 500 µg glycopyrrolate
Indications ●● Reversal of non-depolarizing neuromuscular block
●● Treatment of myasthenia gravis, urinary retention and paralytic ileus
Mechanism of action ●● Acetylcholinesterase inhibitor (anticholinesterase)
●● Binds to anionic and esteratic sites of acetylcholinesterase, which prevents hydrolysis
of acetylcholine which then accumulates
Onset ●● Within one minute  ●  Peak effect in 7–11 minutes
Duration ●● 20–60 minutes
Dose ●● 50 µg/kg intravenously for reversal of non-depolarizing neuromuscular blockade
Effects
  Respiratory system ●● Bronchoconstriction
  Cardiovascular system ●● Bradycardia
  CNS ●● Possible centrally mediated hypotension in high doses
●● Miosis
  Gastrointestinal system ●● ↑ salivation
●● ↑ Lower oesophageal tone
  Genitourinary system ●● Increased ureteric peristalsis
Side effects ●● Inhibits plasma cholinesterase to prolong duration of action of suxamethonium
Contraindications ●● Intestinal or urinary obstruction (linked with breakdown of gastrointestinal anastomosis)
Metabolism ●● Excreted mostly unchanged by kidney
●● Elimination half-life 50–90 minutes
Comments ●● Given intravenously with anticholinergic to antagonize cholinergic side effects
●● Highly ionized, so does not cross blood–brain barrier or placenta
●● Overdose of neostigmine may result in depolarizing neuromuscular blockade
 Pharmacology

Miscellaneous Drugs 213

Warfarin
Oral anticoagulants include warfarin, antiplatelets (e.g. aspirin), direct thrombin inhibitors (e.g. dabigatran),
and direct factor Xa inhibitors (e.g. rivaroxaban)

Structure ●● Coumarin derivative

Presentation ●● Tablets
Indications ●  Prophylaxis of embolization in DVT, PE, AF, TIAs, rheumatic heart disease and after prosthetic
heart valve insertion  ●  Treatment of DVT and PE
Mechanism of action ●● Inhibits conversion of oxidized to reduced vitamin K, which is necessary for production of
coagulation factors II, VII, IX and X
Onset ●● 18–72 hours after loading dose
Duration ●  Several days  ●  Effect can be reversed by giving vitamin K and waiting for the
production of new coagulation factors  ●  More rapid reversal of anticoagulation can be
achieved with coagulation factors or fresh frozen plasma (FFP)
Dose ●● Usually 3–9 mg/day titrated to target international normalized ratio (INR)
Effects ●● Anticoagulant only
Side effects ●● Haemorrhage  ●  Hypersensitivity  ●  Gastrointestinal upset
Contraindications ●● Peptic ulcer  ●  Severe hypertension  ●  Bacterial endocarditis
●● Caution with recent surgery, renal or hepatic dysfunction and breastfeeding
Metabolism ●● Metabolized by liver by oxidation or reduction followed by conjugation with glucuronide
Pregnancy ●● Contraindicated: crosses placenta and is teratogenic
Paediatrics ●● May be used in children
Comments ●  Can be substituted by intravenous or subcutaneous heparin or low molecular weight
heparin perioperatively  ●  Effect can be reduced by drugs that induce hepatic enzymes,
such as barbiturates, rifampicin and carbamazepine  ●  Increased effects can occur with
drugs that are highly protein bound, such as sulphonamides and non-steroidal anti-inflamma-
tory drugs  ●  Spinal and epidural anaesthesia contraindicated
Heparin
Warfarin and heparin are more effective in preventing venous than arterial thrombus
Structure ●● Mucopolysaccharide organic acid derived from bovine lung or porcine intestine
Presentation ●● 1000, 5000 or 25,000 U/mL of heparin sodium solution
●● 25,000 U/mL of heparin calcium solution
●● Various concentrations of low molecular weight heparins
Indications ●  Unstable angina  ●  Acute peripheral arterial occlusion  ●  Prevention of re-occlusion after
thrombolysis  ●  Prevention of clotting in extracorporeal circuits
●● Prophylaxis and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
Mechanism of action ●  Reversibly binds to antithrombin III to give 1000-fold increase in formation of inactive
antithrombin–thrombin complex
●● Inhibits factors IXa, Xa, XIa and XIIa  ●  Inhibits platelet aggregation by fibrin
Onset ●● Rapid
Duration ●● 4–6 hours
Dose ●  5000 U two or three times daily subcutaneously  ●  Intravenous infusion titrated to
activated partial thromboplastin time (aPTT)1.5–2.5 times control
Effects ●● Anticoagulant
●● Increases levels of free fatty acids in plasma
Side effects ●● Excessive bleeding  ●  Osteoporosis after prolonged use  ●  Skin necrosis
●● Thrombocytopenia and hyperkalaemia caused by aldosterone suppression
Contraindications ●● Haemophilia ●  Recent cerebral haemorrhage ●  Major trauma
●  Thrombocytopenia ●  Severe hypertension ●  Recent eye or CNS surgery
●  Peptic ulcer ●  Severe liver disease
Metabolism ●● Desulphated and depolymerized in the liver, kidneys and reticuloendothelial system
Pregnancy ●● Maternal osteoporosis after prolonged use
Paediatrics ●● 250 U/kg twice daily subcutaneously for DVT and PE
Comments ●● Spinal and epidural anaesthesia contra-indicated with treatment doses
●● Stopping infusion usually sufficient to stop haemorrhage
●● Reversed by specific antidote protamine
 Pharmacology

Miscellaneous Drugs 214

Oral drugs used in diabetes
The oral drugs used in diabetes are sulfonylureas, biguanides and other antidiabetics
Sulfonylureas include first generation (e.g. tolbutamide) and second generation (e.g. glibenclamide, gliclazide, glipi-
zide) drugs which increase insulin release from the pancreas. Cimetidine inhibits their metabolism increasing their effect.
Thiazides, corticosteroids and phenothiazines antagonise their effect
Metformin is the only biguanide available in the UK. It delays gut glucose uptake, increases peripheral insulin
sensitivity and inhibits renal and hepatic gluconeogenesis. It may cause severe lactic acidosis especially in renal
impairment or alcohol abusers
Acarbose delays intestinal glucose absorption, pioglitazone (a thiazolidinedione) improves insulin sensitivity and
meglitinides (e.g. repaglinide and metiglinide) increase insulin secretion by the pancreas

Perioperative management
●● If only missing one meal and for morning surgery omit morning oral therapy (except metformin, unless using con-
trast) and reduce the dose of insulin depending on the type
●● If only missing one meal and for afternoon surgery omit sulfonylureas gliptins and GLP-1 analogues. Give acarbose
and metformin as usual with a light meal. Use a reduced or normal dose of insulin depending on type
●● Variable rate insulin infusions (VRIIs) (not sliding scales) should be used when missing more than one meal. An
intraoperative blood glucose range of 6–10 mmol/L should be aimed for.

Intraoperative hypoglycaemia
●● For intraoperative blood glucose 4.0–6.0 mmol/L give 50 mL glucose 20% (10 g) IV. For hypoglycaemia
<4.0 mmol/L give a dose of 100 mL (20 g)

Intraoperative hyperglycaemia
●● If the blood glucose exceeds 12 mmol/L and insulin has been omitted, measure capillary blood ketone levels if
possible
●● If the capillary blood ketones are >3 mmol/L or there is significant ketonuria (>2+ on urine sticks) the patient should
be treated as having diabetic ketoacidosis with specialist help from the diabetes team. If not use a VRII
Insulin
Structure ●● Polypeptide hormone
Presentation ●● 100 U/mL solutions of recombinant human analogue insulin (formerly extracted from
bovine and porcine pancreas)
Indications ●● Diabetes mellitus  ●  Perioperative blood glucose control
●● Diabetic ketoacidosis  ●  Hyperkalaemia
●● To improve glucose utilisation during total parenteral nutrition
●● Provocation tests for growth hormone
Mechanism of action ●● Binds to insulin receptor to increase carbohydrate metabolism, protein synthesis and
lipogenesis
Duration of action ●● Short-acting (simple solution of insulin): 30–60 minutes IV, up to 8 hours SC
●● Medium- and long-acting solutions are complexed with zinc or protamine, or produced in
crystalline form to prolong duration of action to 16–35 hours
Dose ●● According to requirements
●● ‘Sliding scale’ perioperatively
Effects
 Carbohydrate ●  ↑ uptake of glucose by cells  ●  Promotes glycogen storage  ●  ↑ use of glucose for
metabolism energy
  Protein metabolism ●  ↑ uptake of amino acids  ●  ↑ protein synthesis  ●  Inhibits gluconeogenesis (conversion
of amino acids to glucose) 
  Lipid metabolism ●● Inhibits lipid breakdown  ●  ↑ fatty acid synthesis  ●  ↑ glycerol synthesis
Side effects ●  Hypoglycaemia from overdose  ●  Transient oedema  ●  Local reactions and fat
hypertrophy at injection site  ●  Rarely hypersensitivity reactions
Comments ●● Absorbed by polyvinylchloride (PVC)  ●  Long-term storage must be refrigerated
●● Longer-acting formulations consist of suspension with zinc or protamine
 Pharmacology

Miscellaneous Drugs 215

Antimicrobial drugs
●● Antibiotics are synthesized by microorganisms and kill or inhibit other microorganisms
●● Antibacterial drugs are drugs used to kill (bactericidal) or inhibit the growth and replication
of (bacteriostatic) microorganisms
●● Local guidelines and if necessary microbiologist advice should be followed for surgical
­prophylaxis and intensive care use of antimicrobials
Inhibition of cell wall ●● β lactams – b-lactam ring binds to bacterial transpeptidase/carboxypeptidase and
synthesis thus prevents crosslinkage of peptidoglycans, which weakens cell wall
■■ penicillins (mostly gram-positive action)
■■ cephalosporins (first-, second- and third-generation – mostly gram positive)
■■ carbapenems (e.g. imipenem – broad-spectrum gram positive and negative)
■■ monobactams (e.g. aztreonam – gram negative only)
●● Glycopeptides inhibit glycopeptide synthase and prevent peptidoglycan formation
for cell wall (e.g. vancomycin, teicoplanin – gram positive only)
Prevention of protein ●● Inhibition of the 50s subunit of bacterial ribosomes
synthesis in bacterial ■■ macrolides (e.g. erythromycin and clarithromycin – gram positive)
cell ■■ licosamides (e.g. clindomycin – gram positive only)
■■ Chloramphenicol (gram positive/negative and rickettsia)
●● Inhibition of 30s subunit of bacterial ribosomes
■■ aminoglycosides (e.g. gentamycin, neomycin – gram positive/negative)
■■ tetracyclines (gram positive/negative)
●● Formation of stable complex with elongation factor that is involved in translocation,
which blocks chain elongation
■■ fusidic acid
Inhibition of nucleic ●● Inhibition of DNA synthesis
acid synthesis ■■ metronidazole (anaerobes and protozoa)
●● Inhibition of a subunit of DNA gyrase and prevention of supercoiling of DNA
■■ quinolones (e.g. ciprofloxacin, nalidixic acid – gram positive/negative)
Antimicrobial drugs (cont.)
Inhibition of folic acid ●● Acts as false substrate (by mimicking folate)
synthesis ■■ sulphonamides (e.g. sulphamethoxazole, sulphadiazine)
●● Competitively inhibits bacterial dihydrofolate reductase
●● Trimethoprim (good gram positive and gram negative cover, except Pseudomonas)

Bactericidal Bacteriostatic
●● Penicillins ●● Erythromycin
●● Cephalosporins ●● Clindomycin
●● Carbapenems ●● Tetracyclines
●● Monobactams ●● Sulphonamides
●● Vancomycin/teicoplanin ●● Trimethoprim
●● Cotrimoxazole
(sulphonamide + trimethoprim)

Antifungals
●● Interfere with cell membrane integrity by attachment to sterols in fungal cell membranes, which
facilitates pore formation and leakage of molecules across cell membrane, for example macro-
lides (e.g. amphotericin) and nystatin, or
●● Inhibit enzymes involved in sterol synthesis in fungal cell membranes (e.g. fluconazole)

Antivirals
●● Viruses replicate using host cell enzymes, so they are difficult to target with antiviral drugs
●● Acyclovir inhibits nucleic acid synthesis and is used to treat herpes simplex and varicella zoster
●● Zidovudine is a nucleoside reverse transcriptase inhibitor used to treat HIV
 Pharmacology

Miscellaneous Drugs 216

Diuretics
Diuretics are drugs used to increase urine formation and output
Osmotic diuretics (e.g. ●● Increase renal blood flow by plasma expansion
mannitol, urea) ●● Filtered but not reabsorbed
●● Water drawn into renal tubule by osmotic effect
●● Short-term mannitol used to decrease intracranial pressure (ICP) by decreasing brain
bulk; transient increases in ICP due to cerebral oedema can occur initially if
blood–brain barrier disrupted
Loop diuretics (e.g. ●● Potent, short-acting natriuretics that act on ascending loop of Henle
frusemide, bumetamide) ●● Block Na+K+2Cl− co-transporter, which leads to ↑ excretion of filtered sodium
●● Used in acute cardiac failure (direct vasodilation)
●● Side effects: ↓ K+, hyperuricaemia, ↓ Mg2+ and hyperglycaemia
●● Risk of VIIIth cranial nerve palsy especially with concurrent use of aminoglycosides
Thiazide diuretics (e.g. ●● Blocks Na+Cl− transporter in proximal convoluted tubule (PCT) and proximal part of
bendrofluazide) the distal convoluted tubule (DCT)
●● Maximal effect occurs with small doses
●● Side effects include ↓ K+, ↓ Mg2+, hyperuricaemia, hyperglycaemia, and ↑ cholesterol
Potassium-sparing ●● Aldosterone antagonists (e.g. spironolactone)
diuretics ■■ competitively antagonize aldosterone and inhibit Na+ and Cl− reabsorption in DCT
■■ used in Conn’s syndrome and ascites
■■ may cause ↑ K+ in patients with diabetes and renal failure
●● Amiloride and triamterene
■■ inhibit sodium reabsorption in collecting duct causing natriuresis with increased
loss of Cl− and HCO3− and retention of K+ and H+
Carbonic ­anhydrase ●● Non-competitive inhibitor of carbonic anhydrase in PCT
inhibitors (e.g. ●● Prevents HCO3− reabsorption and H+ excretion, which thus prevents reabsorption of Na+
acetazolamide) ●● Causes hyperchloraemic metabolic acidosis
Diuretics (cont.)
Location of action of diuretics

K+ sparing
Bowman’s Thiazides
Carbonic
Capsule
anhydrase Osmotic
(200 µm)
inhibitors Aldosterone
Loop antagonists
DCT
JGA (5 mm)
PCT
(15 mm)

Collecting
duct (20 mm)
Loop of Henle
(15–25 cm)
 Pharmacology

Miscellaneous Drugs 217

Corticosteroids
Corticosteroid drugs have predominantly glucocorticoid effects, but have weak mineralocorti-
coid effects as well. Glucocorticoids have metabolic, anti-inflammatory and immunosuppres-
sive effects
Anti-inflammatory effects ●● In acute inflammation, glucocorticoids reduce production of tissue transudate
and cell oedema by
■■ stimulating production of lipocortin, which inhibits phospholipase A2 (and
thus formation of prostaglandins)
■■ preventing polymorphs and macrophages from reaching site of inflammation
●● Equivalent anti-inflammatory doses include
■ hydrocortisone 25 mg  ■  prednisolone 25 mg  ■  methylprednisolone 20 mg
■■ dexamethasone 4 mg
Immunosuppression ●● Glucocorticoids depress numbers of T lymphocytes, antibody production and
macrophage function
●● May predispose to infection (especially varicella zoster virus [VZV])
Side effects ●● Facilitation of gluconeogenesis, which leads to hyperglycaemia and glycosuria
●● Weak mineralocorticoid activity, which leads to salt and water retention,
decreased levels of K+ and increased blood pressure
●● Osteoporosis, skeletal muscle wasting (proximal myopathy)
●● Poor wound healing and growth suppression in children
●● ’Permissive action’ on vascular smooth muscle allows response to circulating
catecholamines
●● Adrenal suppression because of negative feedback effects on adrenocortico-
tropic hormone (ACTH); recovery may take months to recover; patients require
supplemental steroids for surgery
Corticosteroids (cont.)
Perioperative steroid
supplementation
●● If taking <10 mg prednisolone daily – no supplementation required
●● If taking >10 mg prednisolone daily
■■ 25 mg hydrocortisone (minor surgery)
■■ 25 mg perioperatively and 50–75 mg/day hydrocortisone for 48 hours
(moderate surgery)
■■ 25 mg perioperatively and 100–150 mg/kg/day hydrocortisone for 48–72 hours
(major surgery)

Drugs used in thyroid disease

Thyroid replacement therapy ●● T4 converted to more active T3 in cells
●● Both well absorbed enterally and highly bound to
●● Thyroxine (T4) used in hypothyroidism (caused by
albumin and thyroid binding globulin
hypothalamic, pituitary or thyroid disease)
●● Metabolism occurs in liver and excretion in bile
●● L-triiodothyronine (T 3) may be given intravenously in
hypothyroid coma (faster onset)

Treatments for hyperthyroidism

Carbimazole ●● Inhibits thyroid peroxidase and conversion of iodide to iodine, thus preventing synthesis of T3
and T4
●● Carbimazole is a prodrug that is rapidly converted to methimazole
●● Takes 1–2 weeks for full effect, as stored thyroid hormones not affected
●● Side effects include pruritus, arthralgia, rashes and agranulocytosis (rarely)

Propylthiouracil ●● Blocks iodination of tyrosine and partially blocks conversion of T4 to T3

●● Used in carbimazole intolerance

Iodides ●● Temporary inhibition of iodide binding and thus reduced hormone production
●● Reduces gland vascularity preoperatively

Propanolol ●● Reduces sympathetic effects of hyperthyroidism (negative inotrope and chronotrope)

●● Also blocks peripheral conversion of T4 to T3
 Pharmacology

Miscellaneous Drugs 218

Colloids
Suspension of particles in solvent, which ■■ haemaccel – 3.5% solution of polygeline
is unable to pass through semi-permeable in mixed salt solution with urea crosslinks
membrane ●● Dextrans
Historically used in preference to crystalloids ■■ different glucose polymer preparations
to treat shock as they remain intravascular for with varying average molecular weights
longer, but this is now controversial ■■ associated with renal dysfunction and
coagulopathy so not commonly used
Types
●● 4.5% or 20% albumin derived by fractionation Side effects
from human plasma and heat sterilized ●● Hypersensitivity reactions
■■ UK albumin is from the United States due to ●● Incidence of anaphylaxis
fears of prion protein transmission
■ albumin 1:30,000
■■ 4.5% albumin reflects normal plasma
■ hetastarch 1:16,000
●● Hydroxyethyl starch: 90% amylopectin ether-
■ gelofusine 1:13,000
ified with hydroxyethyl groups; hetastarch
■ haemaccel 1:2000
more etherified than pentastarch
■ dextran 70 1:4500
■■ HES solutions are classified as low, medium
and high molecular weight HES
■■ Large molecular weight HES remain intra-
vascularly for longer
●● Gelatin derivatives
■■ gelofusine – 4% succinylated gelatin in
saline prepared from bovine collagen
Crystalloids
Solution of small molecules that dissociate in water
into ions to form a true solution that may pass through
a semipermeable membrane
●● Do not readily pass through cell membranes
●● Used for intravascular volume expansion, for treat-
ment of dehydration, as maintenance fluid and
electrolytes, for priming of haemodialysis and car-
diopulmonary bypass machines, for acid–base bal-
ance and for dilution of drugs
●● Normal saline (0.9% NaCl) so called because iso-
tonic with physiological fluids
●● Dextrose solutions used to treat water depletion,
hypoglycaemia and (with insulin) hyperkalaemia
■■ glucose metabolized and water spreads
throughout all fluid compartments
●● Hartmann’s solution contains 29  mmol/L lactate
(metabolized to bicarbonate by liver)
●● Sodium bicarbonate (8.4% or 1.26%)
■■ may be used to treat severe metabolic acidosis
■■ may, however, worsen intracellular acidosis
(by increasing formation of carbon dioxide,
which diffuses into cells), reduce oxygen deliv-
ery (by shifting oxyhaemoglobin dissociation
curve to left) and cause hypernatraemia
●● Plasmalyte contains 27 mmol/L acetate and 23
mmol/L gluconate

Concentration of ions (mmol/L)

Crystalloid Na + K+ Ca2+ Cl− HCO− Osmolality pH

3

0.9% sodium chloride 154 0 0 154 0 300 5

5% dextrose 0 0 0 0 0 280 4

10% dextrose 0 0 0 0 0 560 4

4% dextrose, 0.18% saline 30 0 0 0 30 255 4.5

Hartmann’s 131 5 2 111 29 278 6

8.4% sodium bicarbonate 1000 0 0 0 1000 2000 8

Plasmalyte 140 5 0 98 0 295 7.4


Drugs that act on gastrointestinal tract
Drugs that reduce gastric acidity
●● Antacids (e.g. aluminium, magnesium and
sodium citrate)
■■ bases that react with gastric acid to form
salt and water
■■ used in treatment of dyspepsia and reflux
and preoperatively to reduce risk of acid
aspiration
■■ side effects may include salt and water
retention, alkalosis, belching, constipa-
tion or diarrhoea and lung damage if
aspirated (associated with particulate
magnesium trisilicate)
●● H2 receptor antagonists (e.g. ranitidine and
cimetidine)
■■ inhibit secretion of gastric acid
■■ cimetidine is enzyme inhibitor
■■ ranitidine is better absorbed and more
potent than cimetidine
●● Proton pump inhibitors
■■ lansoprazole and omeprazole irreversibly
inhibit Na+K+ATPase pump of parietal cell
■■ omeprazole is prodrug that inhibits cyto-
chrome P450
Pharmacology
Miscellaneous Drugs 219
Mucosal protectors
●● Chelates and complexes (e.g. bismuth che-
late and sucralfate)
■■ sucrulfate has cytoprotective action by for-
mation of mechanically protective barrier
■■ may reduce absorption of ciprofloxacin,
digoxin, phenytoin, H2 antagonists and
warfarin
●● Carbenoxolone
■■ probably acts by increasing gastric
mucous secretion
Antispasmodics
●● Anti-cholinergics (e.g. propantheline, hyo-
scine butyl-bromide and dicyclomine)
■■ used in irritable bowel syndrome and
diverticulitis
●● Direct-acting smooth muscle relaxants (e.g.
mebeverine and peppermint oil)
■■ cause direct gastric smooth muscle
relaxation
Drugs that act on gastrointestinal tract (cont.)
Prokinetics
●● Metoclopramide
■■ dopamine antagonist that increases gastric emptying and lower oesophageal sphincter
pressure
■■ also antiemetic
■■ may cause extrapyramidal effects such as occulogyric crisis
●● Domperidone
■■ also dopamine antagonist but does not cross blood–brain barrier, so less likely to cause extra-
pyramidal effects
■■ used in oesophageal reflux, gastric stasis and non-ulcer dyspepsia
●● Erythromycin
■■ agonist of the motilin receptor

Laxatives
●● Bulking agents
■■ for example, ispaghula husk, which absorbs and retains water to increase faecal mass
●● Faecal softeners
■■ for example, liquid paraffin
●● Osmotic laxatives
■■ for example, lactulose, which increases amount of water in large bowel
●● Stimulants
■■ for example, senna and docusate, which increase intestinal motility
 Pharmacology

Miscellaneous Drugs 220

Antiparkinsonian drugs
Parkinson’s disease results from basal ganglia dysfunction, with loss of dopamine in the stria-
tum and substantia nigra. Other neurotransmitters such as acetylcholine are also involved
Levodopa ●● Precursor of dopamine
●● 1% crosses blood–brain barrier (BBB) and converted to dopamine
●● Increases number of D2 receptors in brain
●● Dopamine itself does not cross BBB
●● Side effects include dyskinesias (up to 80%), oculogyric crises, arrhyth-
mias, orthostatic hypotension, behavioural difficulties and nausea and
vomiting (if given without a peripheral decarboxylase inhibitor)
Carbidopa or ●● Given with levodopa to decrease peripheral conversion to dopamine
benserazide by inhibition of dopa decarboxylase
●● Do not cross BBB
Domperidone ●● Dopamine antagonist given with levodopa
●  Crosses BBB slowly, so given to reduce peripheral effects of levodopa
●  Antiemetic and prokinetic
Selegiline ●● Selective monoamine oxidase B (MAOB) inhibitor, so has fewer
(mainly MAO–A–mediated) side effects of non-selective MAO inhibitors
and less severe drug interactions
Bromocriptine ●● D2 agonist
●● Side effect of inhibition of prolactin secretion
Certain acetylcholine ●● Benzhexol, benztropine, orphenadrine and procyclidine cross BBB and
antagonists decrease central acetylcholine activity
Respiratory stimulants
Doxapram
Analeptic (drug causing CNS stimulation) that stimulates respiration by action on peripheral
chemoreceptors
●● Used in postoperative respiratory depression and COPD
●● Increases tidal volume more than respiratory rate
●● Side effects
■■ vasomotor stimulation leads to hypertension and increased heart rate
■■ CNS – restlessness, dizziness, nausea, convulsions in high doses
●● Contraindicated in severe hypertension, coronary artery disease, thyrotoxicosis, asthma and
epilepsy

Aminophylline
Theophylline is a phosphodiesterase bronchodilator drug used in the treatment of asthma
●● Aminophylline is theophylline with added ethylenediamine which increases solubility so it can be
given intravenously
●● Used as a bronchodilator and occasionally as an inotrope, especially in paediatrics
●● Causes bronchodilation, increased contractility of the diaphragm, increased cardiac output,
diuresis and CNS stimulation
●● Side effects include arrhythmias, agitation, convulsions and GI disturbances
●● High risk of toxicity if given IV to a patient already on oral aminophylline due to low therapeutic
index
 Anatomy

Respiratory System 221

Anatomy of the larynx
Functions of the larynx are to protect the ●● Superior laryngeal nerve (X): Sensation above
tracheobronchial tree and lungs and allow the cords and cricothyroid muscle
coughing, speech and straining
Blood supply
Nerve supply Superior and inferior laryngeal arteries and veins
●● Recurrent laryngeal nerve (X): Sensation below
the cords and all muscles except cricothyroid Lymph node drainage
■■ Right more prone to damage in thyroid Upper and lower deep cervical nodes
surgery (relatively medial)
■■ Left more prone to damage from intra- Muscles of the larynx
thoracic pathology (lung/oesophagus/
lymph node malignancy) Type Muscle Actions
■■ Patterns of damage
Extrinsic Sternothyroid Depresses larynx
● Unilateral partial is the most common –
Thyrohyoid Elevates larynx
causes hoarseness Inferior constrictor Constricts glottis
● Bilateral partial transection may cause
total airway obstruction (abductors Intrinsic Cricothyroid Tenses VC
Thyroaretenoid Relaxes VC
affected > adductors)
Vocalis Relaxes VC
● Bilateral complete – cadaveric posi-
Thyroepiglottis Opens inlet
tion (midway between adduction/ Aryepiglottis Closes inlet
abduction) but may act as a valve Posterior cricoarytenoid Abducts VC
causing inspiratory stridor/dyspnoea/ Lateral and transverse Adducts VC
hoarseness Cricoarytenoid
Anatomy of the larynx (cont.)
Anatomy of the larynx

Epiglottis

Epiglottic tubercle
Vallecula
C3 Hyoid bone Epiglottis

Thyrohyoid
membrane

C4
Thyroid
cartilage
Aryepiglottic Vestibular fold
Arytenoid
cartilage fold
Cricothyroid Vocal cord
C6 membrane Cuneiform
cartilage
Cricoid
cartilage Corniculate
Glottic cartilage
opening
 Anatomy

Respiratory System 222

Anatomy of the nose
Functions of the nose Blood supply
●● Filter, warm, humidify air ●● Branches of the ophthalmic and maxillary
●● Olfactory organ arteries
●● Acts as a conduction channel for the para- ●● Septum – facial artery (superior labial branch)
nasal sinuses ●● Venous drainage via submucous plexus into
corresponding veins

Lateral wall of the nose

Ethmoid bone Frontal sinus

cribiform plate
+ olfactory • Vascular,delicate
organ of CNI Conchae • Covered with periosteum
• ↑Surface area for
humidification of gases
Sphenoid Superior
sinus concha Posterior ethmoid
sinus
Middle Frontal sinus
Eustacian concha opening
tube opening
Interior ethmoid
Maxillary Inferior concha sinus
ostium
Nasolacrimal duct
opening

Vestibule
Anatomy of the nose (cont.)
Nerve supply
●● Multiple branches of the ophthalmic (V1) and maxillary (V2) nerves (trigeminal) via the spheno-
palatine ganglion

Nasal intubation
Indications Contraindications

●● Maxillofacial/ENT surgery especially mandibular/ Base of skull fracture

maxillary fixation Nasal fracture
●● Paediatric ICU Nasal tumour/mass
●● Fibre-optic intubation Coagulopathy
■ Most direct route
■ Most comfortable if awake
 Anatomy

Respiratory System 223

Mediastinum
Thoracic area between the pleural sacs ●● Securing airway and ventilation may be challenging
●● Severe haemorrhage may occur requiring one-lung
Boundaries ventilation (OLV) and/or cardiopulmonary bypass
●● Anterior – sternum (CPB)
●● Posterior – vertebral column
Anatomy of mediastinum (transverse section at T4)
●● Inferior – diaphragm
●● Superior – structures of the neck
●● Divided into superior and inferior mediastinum via a
line connecting T4/5 and the angle of Louis
●● Inferior mediastinum further divided by the pericar-
dium into anterior, middle and posterior SVC

Arch of aor ta
Left phrenic
Contents nerve
Right phrenic nerve

●● Heart Trachea Right vagus

●● Great vessels Recurrent
Left vagus
●● Trachea laryngeal nerve
Oesophagus
●● Oesophagus Thoracic
duct
●● Nerves – vagus, phrenic, recurrent laryngeal nerves
and sympathetic trunk Body
●● Thymus, lymph nodes of T4

Anaesthetic considerations for

mediastinal mass
●● Mass can cause compression of any of mediatinal
contents (e.g. trachea, SVC obstruction, phrenic and (Reprinted from A to Z of Anaesthesia and Intensive
Xth CN) Care, Yentis et al., with permission from Elsevier.)
Diaphragm
The great muscle septum s­ eparating the thorax from the abdomen
●● Consists of a central tendon continuous with the pericardium surrounded by muscle (fourth costal
cartilage anteriorly to eighth rib posteriorly)
●● Provides up to 75% of respiratory function in quiet breathing (accessory muscles contribute more
when laboured)
●● Right is normally higher than left
●● Attachments
■■ Anterior/lateral – lower six ribs and costal cartilages
■■ Posterior – arcuate ligaments (median, lateral and medial) and right/left crura (from vertebral bod-
ies L1–L3 [right] and L1–L2 [left]) Posterior vagal trunk
Oesophagus
Anterior vagal trunk
■■ Cranial – xiphisternum
●● Nerve supply
■■ Motor – phrenic (C3–C5). Palsy →
L Phrenic nerve
raised hemidiaphragm (pierces dome)
■■ Sensory – phrenic (central part IVC R Phrenic nerve
Central
which is referred to the shoul- Left tendon Right
der), intercostals (peripheral) Aorta
Thoracic Azygos vein
●● Openings duct
■■ T8 – IVC, right phrenic nerve
■■ T10 – oesophagus, vagae
■■ T12 – aorta, thoracic duct, azy-
gos vein
Sympathetic trunk
 Anatomy

Respiratory System 224

Tracheobronchial tree
Trachea Main bronchi
●● Extends from C6 to T4/5 (carina) ●● Right main bronchus
●● 10 cm long, 2 cm diameter (adults) ■■ 2.5–3 cm long, wider and at an angle of
●● Relations: 25–30° from the midline
■■ Posteriorly ■■ inhaled foreign bodies pass more easily
● oesophagus and recurrent laryngeal ■■ divides into upper, middle and lower lobar
nerves bronchi which further divide into 3, 2 and 5
■■ Anteriorly segmental bronchi, respectively
● neck – thyroid isthmus ●● Left main bronchus
● thorax – brachiocephalic vessels ■■ 5 cm long at angle of 45°
■■ Laterally ■■ divides into upper and lower lobar bronchi
● neck – thyroid lobes, carotid sheath, (5 and 4 segmental bronchi, respectively)
inferior thyroid artery ●● Segmental bronchi → bronchi → respiratory
● thorax – common carotid and subcla- bronchioles → alveolar ducts → alveoli
vian arteries, aorta (left), vagus nerve,
azygous vein and mediastinal pleura Functions of the lungs
(right) ●● Gas exchange
●● Fibrous tissue reinforced by 15–20 U-shaped ●● Reservoir for blood (up to 900 mL)
cartilage rings, flattened posteriorly ●● Synthesis
●● Posterior smooth muscle fibres (longitudinal ■■ Surfactant
and transverse) ■■ Mucopolysaccharides
●● Lined with ciliated columnar epithelium and ■■ Collagen
mucous glands ■■ Prostaglandins
■■ Histamine
Tracheobronchial tree (cont.)
Functions of the lungs (cont.)
●● Metabolism Trachea
Left upper lobe

■■ Angiotensin t e Apical Posterior

gh b
■■ Bradykinin Ri er lo
p
up Apical
■■ Histamine Anterior
Posterior
●● Immune function
Anterior Superior

Nerve supply Lingular

lobe
Inferior
●● Sympathetic via cardiac plexus (T2–T4)
●● Parasympathetic via vagus Right Lateral Superior
middle basal
lobe Medial
Blood supply Medial Lateral basal
basal
●● Bronchial arteries (from aorta) Lateral basal Anterior
●● Intercostal arteries basal

●● Contribute to true (or anatomical) shunt with Posterior

basal
the thebesian veins of the heart, as bronchial Right lower lobe Left lower lobe
veins drain into the pulmonary veins
 Anatomy

Respiratory System 225

Thoracic inlet and first rib
Thoracic inlet contains:
• Trachea
• Oesophagus
• Vascular trunk
• Vagus nerves
Tubercle (articulates with • Thoracic duct
transverse process T1) • Phrenic nerves
Neck • Sympathetic chain

Head Scalenus anterior

(articulates (and phrenic nerve)
with T1)
Brachial
Scalenus plexus
medius
Subclavian Subclavian
Insertion vein artery
serratus 1st RIB
Shaft Scalenus
anterior
anterior
Groove for
subclavian
artery/brachial
plexus Sternum
Groove for Clavicle
subclavian vein
Intercostal space
The spaces between the ribs, filled with Intercostal nerve block
muscles, fibrous tissue, blood vessels, ●● Indications
nerves and lymphatics ■■ Rib fractures
■■ Chronic pain (herpes zoster, pancreatic)
●● Interconnects with sub-pleural and paravertebral
●● Standard monitoring, IV access, skilled assistant, etc.
spaces (affects LA spread)
●● Location – angle of the rib
●● Neurovascular bundle protected by running in the
●● Walk off rib inferior surface, advance 2–3 mm to enter
groove beneath each rib (within fascia)
groove
●● Blood supply is from 2 anterior and 1 posterior (sole
●● 3–4 mL LA with adrenaline
supply to lowest two spaces) intercostal arteries
●● Complications
which anastomose
■■ Pneumothorax
Subclavian artery internal thoracic arteries anterior intercostals ■■ High systemic absorption – risks overdose
Thoracic aorta (T3–11) Posterior intercostals ■■ Respiratory insufficiency if pre-existing phrenic
Superior intercostal artery nerve palsy

●● Nerve supply Intercostal space

Innermost
■■ Ventral rami of T1–11 thoracic nerves intercostals (incomplete muscle attaching
■■ Branches to inner surface of ribs)

● Rami communicantes (to/from sympathetic Vein Intercostal

Artery
trunk) Nerve
bundle
External intercostals
● Collateral (intercostal muscles, pleura) (Run obiquely forwards
and downwards) Internal intercostals
● Lateral cutaneous (anterior/lateral wall skin/ (Run obliquely backwards and downwards)
muscles)
● T1 and T2 are atypical (form part of bra-
chial plexus and intercostobrachial nerve,
respectively)
 Anatomy

Cardiovascular System 226

Structure of the heart and great vessels
Brachiocephalic artery
Left common carotid artery
Pulmonary valve Left subclavian artery

Superior vena cava

Aortic arch
Pulmonary trunk

Right pulmonary Left pulmonary

artery artery (branches)
(branches)
Ascending
Left
aorta
pulmonary veins
Right
pulmonary Left atrium
veins
Aortic valve
Left AV (mitral)
Right valve
atrium

Right AV
(tricuspid) Left
valve ventricle
Right ventricle

Inferior
vena cava
Endocardium
Apex
Blood high in oxygen Myocardium
Interventricular
Epicardium
Blood low in oxygen septum
Structure of the heart and great vessels (cont.)
Borders of the heart
●● Irregularly conical shaped and obliquely placed
within the mediastinum
●● Right border is the right atrium (RA)
●● Left border – left ventricle (LV) and part of the LA (left
atrium (LA; auricular appendage)
●● Inferior border – right ventricle (RV), lower part
RA and apex of LV
●● Anterior surface – mostly RV separated from the RA
by the atrioventricular (AV) groove and LV by the
interventricular groove
●● Diaphragmatic surface – RV and LV mostly, RA
where it receives the IVC
●● Posterior surface – LA with openings of the pul-
monary veins
Chambers of the heart – right side
●● RA – receives the superior vena cava (SVC) supe-
riorly, inferior vena cava (IVC) and coronary sinus
inferiorly (guarded by rudimentary valves) and
the anterior cardiac vein in the anterior part
●● Crista terminalis divides the ventricle
●● RA and RV communicate via the tricuspid valve
(medial, anterior and inferior cusps)
●● Pulmonary valve between RV and pulmonary
trunk also is tricuspid (posterior, L and R anterior)
●● Infundibuloventricular crest lies between the
AV and pulmonary orifices separating the inflow
and outflow tracts of the RV
●● Papillary muscles project into the lumen and
attach to the tricuspid valve via chordae tendineae
●● The moderator band crosses the cavity from
septum to anterior wall. Conveys the R AV bundle
to the ventricular muscle
Chambers of the heart – left side
●● LA smaller than the RA but with thicker walls
●● Four pulmonary veins empty into the posterior wall
●● Mitral valve between LA and LV is bicuspid (large
anterior and smaller posterior cusp) attached to
pupillary muscles via chordae tendineae
●● Aortic valve is tricuspid (three semilunar cusps –
R and L posterior and anterior)
●● Immediately above the cusps are the dilated
aortic sinuses feeding the coronary arteries
Nerve supply
●● Vagus (cardio-inhibitor)
●● Cervical and upper thoracic sympathetic gan-
glia (cardio-accelerator)
●● Transmitted to the heart via the superficial and
deep cardiac plexuses
 Anatomy

Nervous System 227

Bones of the skull Anatomy

Parietal bone Frontal bone

Sphenoid bone

Temporal bone
Lacrimal bone
Nasal bone
Occipital bone
Maxilla

Zygoma Mandible
Base of the skull
Cribiform plate
• CN I
Optic canal
• Opthalmic artery
Frontal air sinuses • CN II

Ethmoid air sinuses Superior orbital fissure

• Superior + inferior opthalmic
veins
Furamen rotundum • CNs III, IV, V1, VI
• CN V2
Foramen ovale
Foramen spinosum • Otic ganglion
• Middle meningeal artery • CN V3
• CN V3 (middle meningeal • Accessory meningeal artery
branch) • Lesser petrosal nerve
Foramen lacerum • Emissary veins
• Internal carotid artery
• Artery + nerve of Internal acoustic meatus
pterygoid canal • Labyrinthine artery
• CNs VII and VIII
Stylomastoid foramen
Jugular foramen
• Stylomastoid artery
• CN VII • Inferior petrosal sinus
Hypoglossal canal Foramen magnum
• Sigmoid sinus
• Hypoglossal nerve • Anterior + posterior
• CNs IX, X, and XI
spinal arteries
• Vertibral arteries
• Medulla oblongata
 Anatomy

Nervous System 228

Cerebral arterial supply
Arterial supply Cerebral circulation
Anterior communicating
Anterior cerebral => Superior/medial hemisphere

Internal carotid => Each supply 1/3rd cerebral supply

Middle cerebral => Lateral hemisphere,

Posterior communicating lateral temporal, basal ganglia
Posterior cerebral => Occipital + temporal
lobes
Form the ‘Circle of Willis’ Superior cerebellar
MCA = Commonly affected in CVA Pontine
Labyrinthine
Anterior inferior cerebellar
Basilar

Posterior inferior cerebellar

Posterior spinal

Vertebral

Anterior spinal
Venous drainage of head and neck
Deep structures Cerebral hemisphere/ Eye
cerebellum

R+L internal cerebral

vein

Cavemous sinus
Great cerebral vein Superior sagittal sinus (either side pituitary
(falx cerebri) fossa)
Inferior sagittal sinus
(falx cerebri) Superior petrosal
sinus
Confluence of
sinuses Inferior petrosal sinus

Transverse sinus
(tentorum cerebelli)

Sigmoid sinus
Jugular foramen

External Internal jugular External

jugular vein Anterior vein Anterior jugular vein
jugular vein jugular vein

Right subclavian vein Left subclavian vein

Brachiocephalic trunk

Superior vena cava

 Anatomy

Nervous System 229

Epidural and paravertebral space
The potential space surrounding the
dural sac within the vertebral canal
●● Extends from foramen magnum to the sacral
hiatus
●● Contents – spinal nerves, epidural fat, con-
nective tissue, lymphatics, valveless epidural
venous plexus
●● Transverse width varies from 1 mm (cervical)
to 6 mm (lumbar)
●● Segmented and discontinuous (connective
tissue layers) in the lumbar region, more con-
tinuous in the thoracic region
●● Communicates freely with the paravertebral
space through the intervertebral foraminae
●● Ligamentum flavum consists of two ligaments
which are triangular in shape and meet in the
midline connecting the laminae of adjacent
vertebrae
Paravertebral space
Boundaries
●● Medially – vertebral bodies
●● Anterolaterally – parietal pleura
●● Posteriorly – superior costotransverse ligament
Lumbar paravertebral block
●● Lateral/prone position
●● 8 cm needle inserted perpendicular to the
skin 3–5 cm lateral to L4 spinous processes to
hit the transverse process
●● Walk off transverse process in a cephalad
direction
●● Advance 1–2 cm (may use a loss of resistance
[LOR] technique)
●● Insert 5 mL LA
●● Complications – extradural, subarachnoid
and IV injection

Dural sac
●● Comprises dura and arachnoid membranes,
subarachnoid space (CSF), spinal nerves
(cauda equine and filum terminale)
●● 0.3–0.5 mm thickness
Epidural and paravertebral space (cont.)
Relationships of epidural space Structures passed through
Epidural
to reach the epidural space
Vertebral
space body + intervertebral discs Posterior Ligamentum
longitudinal flavum
Subcutaneous
ligament tissue
Pedicles
Skin
+ periosteum
Dural sac
Intervertebral
foraminae

E
P S
Spinous I
Ligamentum process P
D A
Transverse flavum U C
process Lamina R E
Spinous A
+ periosteum L
process

Interspinous
ligament
Supraspinous
ligament
 Anatomy

Nervous System 230

Cutaneous nerves of upper limb
Cutaneous nerves of upper limb
Anterior Posterior

Supraclavicular
(C3-4)
Upper lateral cutaneous
nerve of the arm
(C5, C6 – axilliary)
Lower lateral Intercostobrachial
cutaneous (T2)
nerve of arm
(C5-6) Post. cutaneous Post. cutaneous
Medial cutaneous N. of arm N. of forearm
nerve of arm
(C8-T2)
Lateral cutaneous Lateral curaneous
nerve of arm Medial cutaneous nerve of arm
(C5, C6) nerve of forearm (C5, C6)
(C8-T1)

Radial Radial
(C6-8) Ulnar (C6-8)
(C8-T1)
Ulnar
(C8-T1)

Median
(C5-8)
Median
(C5-8)
Cutaneous nerves of lower limb
Anterior Posterior
Genitofemoral
(L1–2)

Subcostal Subcostal
(T12) Ilioinguinal (T12)
(L1)

Lat. femoral
cutaneous
(L2–3) Lat. femoral cutaneous
(L2–3)

Obturatur
(L2–4)

Ant.
femoral
cutaneous Posterior femoral
(L2–4) nerve of thigh
(S1–3)

Common
peroneal
(L4–S2) Common peroneal
Saphenous (L4–S2)
(L3–4)

Superficial
peroneal Sural (S1–2)
(L4–S1)
Sural Tibial (calcaneal branch)
(S1–2) (S1–2)
Tibial (medial and lateral
plantar branches)
(L4–5)

Deep peroneal
(L4–5)
 Anatomy

Nervous System 231

Brachial plexus
‘BBC’
• Biceps
• Rhomboids • Brachialis
Dorsal • Levator scapulae • Coracobrachialis
scapular nerve Suprascapular nerve Lat. pectoral Pectoralis • Lat. cutaneous
major nerve of forearm
Upper Lateral Musculocutaneous
C5
Lateral root of • Deltoid + overlying skin
• Teres minor
median nerve Axillary
• Upper cutaneous
C6 nerve of arm
• ‘Loaf’ muscles
• Medial skin forearm
Middle Posterior Median
C7 • Lateral fingers, skin

• Triceps
Lower + upper subscapular
• Supinator
C8 • Subscapularis • Exensor muscles forearm
Radial
Thoracodorsal nerve • Brachioradialis
• Lat dorsi Medial root of • Skin of posterior arm
Lower Medial median nerve Ulnar
T1
• Flexorcarpi ulnaris
• Medial 2 bellies of flexor
Medial pectoral N Medial cutaneous digitorum profundus
• Pectoraus major/Minor nerves of arm + • Most of small muscles of hand
forearm • Skin-palmar medial 1½ fingers
• Dorsal medial 2½
Long thoracic nerve (Post.
aspects 5,6,7)
Serratus anterior

Roots Trunks Divisions Cords Branches

‘Really Tired Drink Coffee Black’

(Each trunk divides into anterior (A) and posterior (P) divisions)
Stellate ganglion
●● Peripheral SNS arises from the intermediolat- ●● Horner’s syndrome
eral column of the spinal cord ■■ meiosis (paralysis of dilator pupillae)
●● Efferent fibres exit through the ventral roots from ■■ ptosis (paralysis of sympathetic supply to
T1-L2 and travel through the white rami commu- levator palpebrae)
nicantes to enter the sympathetic chain ■■ unilateral vasodilatation and anhidrosis
●● Sympathetic chain is 22 paired ganglia that lie (blockage of sympathetic outflow to the face)
along each side of the anterolateral vertebral ●● Indications for stellate ganglion block include:
column within a fascial plane to synapse in gan- ■■ refractory angina pectoris
glia within the sympathetic chain or in peripheral ■■ complex regional pain syndromes in the arm
ganglia ■■ acute/chronic postherpetic neuralgia
●● In 80%, the first thoracic and inferior cervical ■■ vascular insufficiency in the arm
ganglia are fused to form the stellate ganglion,
which is oval-shaped and approximately 1 inch
Vertebral
long and 0.5 inches wide artery
●● Lies anterior to the neck of the first rib and C7
transverse process and anteromedial to the ver-
tebral artery C7
●● Posterior to the common carotid artery, internal
Stellate
jugular vein (IJV), phrenic nerve and dome of
C8 ganglion
pleural
●● Medially is the vertebral column, oesophagus First
rib
and trachea
Longus
Significance TI
colli muscle

●● Diffusion of local anaesthetic to the stellate gan-

glion during a brachial plexus block may pro- Brachial
duce sympathetic blockade of the head and plexus
neck
 Anatomy

Nervous System 232

Anatomy of the vagus nerve

Three nuclei in the medulla:

1 Dorsal (visceromotor)
2 Nuclei ambiguus (motor)
3 Nucleus tractus solitaris (sensory)

(Between the olive and inferior cerebellar peduncle)

Jugular foramen (with CN Lateral

Medial
IX and XI)

Internal jugular vein

Internal
carotid artery
Carotid sheath

Neck

Thorax
Anatomy of the vagus nerve (cont.)
Right vagus Left vagus
Aortic
Right rec. Left rec.
laryngeal arch
laryngeal
nerve
nerve
Right subclavian
artery
SVC Pulmonary
plexus

Anterior
vagal trunk

Right
main
bronchus
Cardiac, Diaphragm
pulmonary,
oesophageal
Motor to Sensory to Secretomotor to
plexi
Posterior
vagal trunk ●● Bronchial muscles ●● Dura ●● Gastrointestinal
●● Gastrointestinal ●● Respiratory tract tract
tract ●● External auditory meatus ●● Respiratory
Diaphragm
●● Larynx ●● Gastrointestinal tract tract
●● Myocardium ●● Myocardium
●● Epiglottis

Trigeminal nerve
●● Provides the sensory supply to the face, nose,
mouth and part of the scalp, and motor sup-
ply to the muscles of mastication
●● Arises by a motor root (single nucleus) and
sensory root (three nuclei) beside the pons
●● Sensory root carries the trigeminal ganglion
(lies in a depression in the petrous temporal
bone) which divides into ophthalmic (V1),
maxillary (V2) and mandibular (V3) divisions
●● Motor root forms part of the mandibular
division
Ophthalmic division (V1)
●● Crosses cavernous sinus and enters the orbit
via the superior orbital fissure
●● Branches (all sensory)
■■ Frontal
● Further divides into supraorbital and
supratrochlear – frontal scalp sensation
■■ Lacrimal
● Supplies eyelid and facial skin
● Parasympathetic fibres (originally from
CN V11) to the lacrimal gland
Anatomy
Nervous System 233
■■ Nasociliary
● Continues as infratrochlear nerve
● Sensory to skin next to medial canthus
● Carries long ciliary nerves (sensory
from cornea, and sympathetic to dila-
tor pupillae)
Maxillary division (V2)
●● Exits skull through the foramen rotundum
●● Crosses the pterygopalatine fossa
●● Carries the sphenopalatine ganglion (para-
sympathetic to lacrimal gland)
●● Branches (all sensory):
■■ Greater and lesser palatine (soft/hard
palate)
■■ Sphenopalatine (nasal cavity and hard
palate)
■■ Posterior, middle and anterior superior
dental nerves
■■ Infraorbital (via infraorbital foramen) –
lower eyelid, cheek, upper lip
■■ Zygomatic – skin of temple and over
cheekbones
Trigeminal nerve (cont.)
Mandibular division (V3)
●● Largest division and is both motor/sensory
●● Leaves skull through foramen ovale
●● Branches
■■ Inferior alveolar → mental nerve (sen-
sory to skin of lower chin and lip) and mylo-
hyoid nerve (motor)
■■ Lingual (sensory from tongue along with
chorda tympani)
■■ Auriculotemporal (sensory from temple
skin and over the tragus, parasympathetic
to parotid gland)
■■ Buccal (sensory from face, motor to mas-
seter and temporalis muscles)
Local anaesthesia to the face
●● Supraorbital/supratrochlear – local infiltration
above the supraorbital ridge
●● Infratrochlear – infiltrate 1 cm above inner
canthus along medial orbital wall
●● Infraorbital – 1.5 cm below the inferior orbital
margin
●● Mental nerve – mid-mandibular point in line
with the pupil
●● Zygomatic – subcutaneous infiltration over
branches
●● Auriculotemporal – block over posterior
aspect of zygoma
Trigeminal neuralgia
Intermittent, spasmodic, unilateral severe pain
in one of the divisions of the trigeminal nerve
●● Causes are unknown – putative aetiology
includes central (spontaneous neuronal dis-
charge from the pons) or peripheral (com-
pression of neurones in the posterior fossa or
due to demyelination disorders)
●● Pharmacological treatment
■■ Carbamazepine (∼90% success) – moni-
tor FBC
■■ Phenytoin (∼60% success)
■■ Baclofen – GABAB analogue
■■ Gabapentin
●● Surgical treatment
■■ Radiofrequency ablation of trigeminal
ganglion under x-ray guidance through
foramen ovale
■■ Chemical ablation of trigeminal ganglion
(1–2 mL 1% lidocaine)
■■ Decompression of nerves in the posterior
fossa
 Anatomy

Nervous System 234

Anatomy of the orbit
Pyramidal shaped space in the skull contain- ●● Superior orbital fissure – lacrimal, frontal,
ing the eye, extra-ocular muscles, optic nerve trochlear, oculomotor, nasociliary and abdu-
and orbital vessels cent nerves and ophthalmic veins
●● Inferior orbital fissure – trigeminal nerve
Relations of orbit (maxillary branch)
●● Superior
■■ Wall = frontal and sphenoid bones The eye
■■ Frontal air sinuses, meninges and frontal lobe ●● The globe is high and lateral in the orbit (nee-
●● Inferior dle access is usually medially/inferolaterally)
■■ Wall = maxilla, zygomatic and palatine ●● Conjunctiva – clear membrane covering the
bones sclera
■■ Maxillary air sinus ●● Tenon’s fascia – thin fibrous layer beneath
●● Medial conjunctiva that completely covers the sclera
■■ Wall = ethmoid, maxilla, lacrimal, sphe- ●● Sclera – fibrous layer around eye (except cornea)
noid bones ●● Cornea – clear transparent frontal covering
■■ Nasal cavity, ethmoid and sphenoid sinuses of eye
●● Lateral ●● Choroid – vascular layer between sclera and
■■ Wall = zygomatic and sphenoid bones retina
■■ Temporal fossa, middle cranial fossa, ●● Retina – light sensitive inner layer
meninges and temporal lobe ●● Anterior chamber – between cornea and iris,
contains aqueous humour
Openings of orbit and structures ●● Posterior chamber – area behind iris and in
front of lens
passing through them ●● Vitreous humour – transparent gelatinous
●● Optic canal – optic nerve, ophthalmic artery material between lens and retina
Anatomy of the orbit (cont.)
Innervation Blood supply
●● Extraocular muscles; LR6SO4O3 ●● Ophthalmic artery – branch of internal carotid
●● Sensory – trigeminal (V) nerve (ophthalmic ●● Superior and inferior ophthalmic veins
and maxillary branches)

Section through the eye Extrinsic muscles of eye, nerves through

superior orbital fissure
Cornea Posterior
Aqueous humour chamber Superior orbital
(Anterior chamber) fissure
Iris Superior
Frontal oblique
Conjunctiva
Lens Lacrimal Central
Suspensory artery of reti
IV (Trochlear)
ligaments (→sup. oblique) Optic nerve
Choroid
III (Occulomotor) Opthalmic
Sclera (→All others) artery
Retina
IV (Abducens) Fibrous ring
(→Lat rectus)
Optic nerve
Vitreous Inferior
Nasociliary oblique
Central body
artery of retina Fovea III (Occulomotor)
centralis
 Anatomy

Nervous System 235

Cranial nerves
12 paired nerves numbered according to their attachments to the brain in a rostral-caudal direction
●● Olfactory and optic nerves arise directly from the brain, the remainder from the brainstem

Brainstem
Cranial nerve Fibres Structures innervated Functions nucleus

I Olfactory Sensory Olfactory epithelium (via Olfaction ………………………

olfactory bulb)
II Optic Sensory Retina Vision ………………………

III Oculomotor Motor Superior/middle/inferior Movement of eye Oculomotor

rectus, inferior oblique, ball nucleus
levator palpebrae
Parasympathetic Pupillary constrictor, ciliary Pupillary constriction Oculomotor
muscle of eyeball; both via and nucleus
the ciliary ganglion accommodation
IV Trochlear Motor Superior oblique Movement of eyeball Trochlear nucleus
V Trigeminal Sensory Face, scalp, cornea, nasal General sensation Trigeminal sensory
and oral cavities, cranial nucleus
dura mater
Motor Muscles of mastication Opening/closing Trigeminal motor
mouth nucleus
Tensor tympani muscle Tension of tympanic Trigeminal motor
membrane nucleus
Cranial nerves (cont.)
VI Abducens Motor Lateral rectus Movement of eyeball Abducens nucleus
VII Facial Sensory Anterior two-thirds of Taste Nucleus solitarius
tongue
Motor Muscles of facial Facial movement Facial motor
expression nucleus
Stapedius muscle Tension of ossicles Facial motor
nucleus
Parasympathetic Salivary and lacrimal Salivation and Superior salivatory
glands via submandibular lacrimation nucleus
and pterygopalatine
ganglia
VlII Sensory Cochlea Hearing Cochlear nucleus
Vestibulocochlear Vestibular apparatus Proprioception of Vestibular nucleus
head, balance
IX Sensory Eustachian tube, middle General Sensation Trigeminal sensory
Glossopharyngeal ear nucleus
Carotid body and sinus Chemo/
baroreception
Pharynx, posterior 1/3 of Taste Nucleus solitarius
tongue
Motor Stylopharyngeus Swallowing
Parasympathetic Salivary glands via the otic Salivation Inferior salivatory
ganglion nucleus
 Anatomy

Nervous System 236

Cranial nerves (cont.)
X Vagus Sensory Pharynx, larynx, oesopha- General sensation Trigeminal sensory
gus; external ear nucleus
Aortic bodies and arch Chemo/
baroreception
Thoracic and abdominal Visceral sensation Nucleus solitarius
viscera
Motor Soft palate, larynx, pharynx, Speech, swallowing Nucleus
upper oesophagus ambiguus
Parasympathetic Cardiovascular, respiratory Control of these Dorsal motor
and gastrointestinal systems nucleus of vagus
systems
XI Accessory Motor Sternomastoid, trapezius Movement of head Nucleus
and shoulders ambiguus, cranial
nerves
XII Hypoglossal Motor Intrinsic and extrinsic Movement of tongue Hypoglossal
muscles of tongue nucleus
Internal jugular vein (IJV)
●● Originates from the sigmoid sinus at the jugu- ●● TPN
lar foramen ●● Massive air embolism
●● Terminates at the subclavian vein behind the ●● Haemofiltration
sternoclavicular joint ●● Pacing

Relationships to IJV Technique

●● NICE guidelines stipulate that all IJV line inser-
Anteriorly Posteriorly Medially Superficially tions should now be performed under ultra-
Internal C1–C8 Internal Carotid
sound guidance
Carotid transverse carotid, sheath fascia ●● Asepsis, Seldinger technique
Artery processes common SCM muscle
(initially) Prevertebral carotid Platysma
Complications of insertion
CN X fascia arteries Subcutaneous ●● Carotid puncture/cannulation
Sympathetic CN’s IX, tissue ●● Embolism (air or debris)
chain X, XI, XII Skin ●● Nerve injuries (phrenic, brachial plexus, sym-
Pleura pathetic chain)
Thoracic ●● Tracheal/oesophageal puncture
duct (L) ●● Extravasation
●● Thoracic duct puncture (chylothorax)
Central line insertion ●● Arrhythmias
●● Haemothorax
Indications
●● Pneumothorax
●● Targeted fluid balance ●● Late complications
●● Anticipated CVS instability ■■ Infection (local and systemic)
●● Difficult peripheral IV access ■■ Thrombus
●● Drug administration – long term, inotropes,
chemotherapy
 Anatomy

Vertebral Column 237

Sacral anatomy and caudals
Caudal ●● Can use ultrasound guidance
●● Insert needle/cannula through hiatus (slightly
●● LA into the sacral canal (continuation of the
cranially) until a ‘click’ felt (sacrococcy-
epidural space) to block the sacral/lumbar
geal membrane). Redirect cranially <2 cm
nerve roots
(beware aberrant dura)
●● Useful to supplement GA (especially in chil-
●● Aspirate for blood and inject LA – there should
dren) for prevention of post-operative pain
be very little resistance
below umbilicus and for chronic back pain
●● Doses: 20–30 mL 0.25%–0.50% bupivacaine
●● High failure rate in adults due to variable
(adults) or in children (0.25% bupivacaine;
anatomy
●● Technique (see diagram) 0.125% provides less motor blockade)
■■ 0.5 mL/kg for sacral block
■■ Full monitoring, skilled assistant, emer-
■■ 1.0 mL/kg for inguinal block
gency drugs, IV access etc
■■ 1.25 mL/kg for lower abdominal
■■ Lateral position with legs drawn to chest

L5

Anterior + posterior
sacral foramina Median sacral crest +
(contain sacral spinal tubercle processes
llium
lliu

nerve roots)
m

Intermediate Contents of sacral canal

sacral crest – Dura, filum terminate (to S3)
– Epidural space
Sacral hiatus covered by Cornu (formerly S5 – Sacral venous plexus
sacrococcygeal membrane articular process) – Sacral nerves
(where laminae of the 5th sacral – Lymphatics
vertebrae have not fused) Coccyx – Areolar connective tissue
Cross section of the neck at C6

Anterior jugular
vein Sternomastoid muscle

Pretracheal
Trachea
Carotid sheath Investing Fascia
Cricoid cart
(IJV, carotid artery
+ vagus nerve) Prevertebral
Oesophagus
External jugular
vein C6

Vertebral
artery Sympathetic
Phrenic
nerve chain
Thyroid Scalene Brachial
gland muscles Recurrent plexus
laryngeal
nerve
 Anatomy

Vertebral Column 238

Vertebrae
The vertebral column consists of 7 cervical, 12 thoracic, 5 lumbar, 5 sacral (fused) and 3–5
coccygeal (fused) vertebrae
●● Two primary concave curves (thoracic and pelvic) and two compensatory convex curves (cervical
and lumbar)
●● All vertebrae connected via ligaments and fibrocartilagenous discs
●● Each consists of an anterior body and posterior arch (encloses the vertebral foramen which form
the vertebral canal)
●● Each arch has two laminae, two pedicles and seven processes (one spinous, four articular and
two transverse)
●● Cervical vertebrae
■■ C1 has no body or spine and an anterior arch (articulates with odontoid peg of C2)
■■ C2–C6 have bifid spinous processes
■■ C7 has a prominent single spinous process
■■ Each has the additional foramen transversarium (vertebral arteries)
●● Thoracic vertebrae
■■ Heart-shaped bodies, articulating with ribs via the costal facets
■■ Large transverse processes (articulate with rib tubercles)
■■ Long downsloping spinous processes
●● Lumbar vertebrae
■■ Kidney-shaped bodies
■■ Thick transverse processes
■■ Horizontal spines
Vertebrae (cont.)
Diagram of generic vertebra

Spinous
process

Lamina Vertebral foramen

Transverse
process
Pedicle

Superior
articular Body
process

Interior
articular
process Inferior vertebral
notch

Spinous
process
 Anatomy

Surface Anatomy 239

Antecubital fossa
Antecubital fossa Main venous drainage of arm

Biceps Brachial
tendon artery Axillary
Radial Median vein
nerve Deltopectoral
nerve
triangle
Lateral Medial Brachial
epicondyle epicondyle vein
Cephalic
vein Basilic vein

or
at
on s
Br

Pr tere Median
ac

Antecubital
hio

cubital vein
ra

fossa
Ulnar
dia
lis

nerve
Median vein
of forearm
Boundaries
Medial – Lateral border of Pronator teres
Floor – Brachialis (mainly) Dorsal venous
Lateral – Medial border of brachioradialis
Supinator network of hand
Superior – Line joining humeral epicondyles
Roof – Skin
Subcutaneous tissue
Superficial fascia
Contents:
• Lateral cutaneous nerve of forearm
• Medial cutaneous nerve of forearm
• Median cubital vein
• Deep fascia (reinforced by bicipital aponeurosis)
Axilla
● Area underlying the glenohumeral joint at the ●● Contents
junction of the upper limb and thorax ■■ Axillary artery – main artery to the upper
●● Overall shape is that of a four-sided pyramid limb
with a base and an opening at the apex ● Three parts, all related to pectoralis
●● Borders minor (medial, posterior and lateral).
Only the medial and posterior parts
Anterior Border pass through the axilla
Pectoralis major and minor
■■ Axillary vein – drains the arm via the
cephalic and basilic veins
■■ Brachial plexus – plexus of spinal nerves
Medial Border forming the peripheral nerves of the upper
Serratus anterior and thoracic wall
Lateral Border limb
Intertubecular sulcus
■■ Biceps brachii and coracobrachialis –
tendons attaching to the coracoid process
Posterior Border
of the scapula
Sacpularis, teres major, latissimus ■■ Axillary lymph nodes
dorsi
 Anatomy

Surface Anatomy 240

Abdominal wall Superficial fascia

●● Five paired muscles Skin

Fatty
Membranous
(scarpa’s)
●● External oblique originates from the inferior eight ribs Aponeurosis (campers)

■■ Inferomedial path (‘down and in‘)

■■ Ends in a thick aponeurosis with internal oblique
and transversus abdominis to form the rectus Recris abdominis

sheath
■■ Inferiorly the aponeurosis forms the inguinal Transrersalis fascia
canal Parietal
peritoneum
●● Internal oblique arises from the iliac crest, inguinal

inas
e
ligament and thoracolumbar fascia

que
bliqu

dom
Tap block
Internal obli
■■ Superiomedial path (‘up and in’) to the lower ribs

External o

Transrtrsus ab
and linea alba Visceral peritoneum
●● Transversus abdominis – deepest originating from
the inguinal ligament, iliac crest, lower six ribs and
thoracolumbar fascia
■■ Horizontal path anterior to posterior
●● Vertical muscles within the rectus sheath sepa-
rated by the linea alba – rectus abdominis and
pyramidalis Erector
spinae

Sensory supply at

L
.D
or Vertebrae
s i.
●● Anterior rami of spinal nerves T7-L1 as the intercostal
nerves (T7-T11), subcostal nerve (T12) and ilioingui-
nal nerve (L1)
●● Transverse abdominis plane block (TAP) block per-
formed by injecting local anaesthetic between the
internal oblique and transversus abdominis muscles ●● Ilioinguinal (L1) and iliohypogastric nerves (T12
●● Nerves divide into lateral and anterior branches and L1) supply skin overlying the hypogastrium, geni-
where they pierce the rectus sheath and supply the talia and upper gluteal region
anterior abdominal wall skin
Femoral triangle and lumbar plexus
N A V Y
Inguinal ligament

Ant. sup. Pubic

iliac spine tubercle T12

IIioinguinal +
L1
(m

rd s
iliohypogastric
Sa al bo

bo gu
Lateral Medial
ed

)
er
ial lon
(L1)
r to rde
i
riu

ed tor
Genitofemoral (L1, L2)
s r)

(m duc
Lymphatics,
Ad

lymph nodes
L2 Lateral cutaneous
(within femoral
nerve of the thigh
canal)
(L2, L3 posterior
divisions)
Femoral L3
nerve
(below fascia iliaca)
not in femoral sheath Femoral within femoral L4
Femoral artery vein sheath
(mid-inguinal point) Obturator Femoral nerve
Roof: Skin Floor: Laterally – iliopsoas nerve (L2, 3, 4
Subcutaneous tissue Medially – pectineus (L2, 3, 4 posterior
Superfical fascia adductor longus anterior divisions)
divisions)
Deep fascia (fascia lata)
 Anatomy

Surface Anatomy 241

Sacral plexus and sciatic nerve
L4

L5

S1

S2

S3

S4

Perineal Posterior cutaneous

Pelvic splanchnic branch N. of thigh
(parasympathetic) of S4
Perforating cutaneous Sciatic nerve
nerve (L4–S3)
Pudendal nerve

Posterior Anterior division

division

Superior gluteal (L4, L5, S1) Nerve to obturator internus (L5, S1, S2)

Interior gluteal (L5, S1, S2) Nerve to quadratus femoris (L4, L5, S1)
Common peroneal nerve Tibial nerve
↓ ↓
Dorsiflexion/eversion of foot ‘TP’ – Tibial → plantar flexion/inversion of foot
Popliteal fossa Cross-section through the ankle
Popliteal Extensor
artery hallucis longus
Dorsalis pedis
artery
Tibial nerve Saphenous Deep peroneal
nerve nerve
Semimembranosus Biceps
semitendinosus femoris Long Superficial
saphenous vein peroneal
nerve
Medial Lateral Medial
malleolus Lateral
malleolus
Common Posterior
peroneal tibial artery Sural nerve
nerve
Tibial Achilles
nerve tendon

2 heads of
gastrocnemius Popliteal vein
 Anatomy

Surface Anatomy 242

Lower limb blocks
Ankle blocks
●● Tibial nerve (L5–S3)
■■ Supplies anterior and medial sole
■■ Inject 5–10 mL LA at the level of the medial malleolus lateral to the posterior tibial artery
●● Sural nerve (L5–S2)
■■ Supplies posterior sole and heel, lateral side of the foot and posterior lower leg
■■ Inject 5–10 mL LA in a ‘fan’ from the Achilles tendon to the lateral malleolus
●● Saphenous nerve (L3–L4)
■■ Supplies medial side of ankle joint
■■ Infiltrate 10 mL subcutaneously above the medial malleolus
●● Deep peroneal nerve (L4–S2)
■■ Supplies the skin between the first and second toe
■■ Inject 3 mL LA between the anterior tibial and extensor hallucis longus tendons (lateral to dor-
salis pedis artery)
●● Superficial peroneal nerve (L4–S2)
■■ Supplies the dorsum of the foot
■■ Infiltrate 6–7 mL LA from lateral malleolus to the anterior tibia
●● Ultrasound may be used to identify nerves and vessels
Lower limb blocks (cont.)
Femoral nerve block (3-in-1) ●● 10–15 mL LA for a femoral block, 20–30 mL for
●● Nerve stimulator (50 mm needle)/ultrasound a  3-in-one block (applying digital pressure
guided below injection → rostral spread (classically
●● Aim the needle at 45° cephalad, depth 3–4 cm femoral, lateral cutaneous nerve of thigh and
●● Should feel 2 ‘pops’ (fascia lata/fascia iliaca) obturator nerves although unlikely to block
●● If using a nerve stimulator – look for a patellar obturator))
twitch at 0.5 mA
½
ASIS
½
1cm
1cm
PT

Femoral
artery

Fascia iliaca block ●● Use ultrasound or draw a line from the ASIS to
●● Hip/anterior thigh and knee surgery the PT. Needle insertion point is 1 cm caudal
●● Fascia iliaca lies anterior to the iliacus muscle to where lateral and middle thirds meet
within the pelvis ●● 2 fascial ‘pops’ will be felt (fascia lata and fas-
●● Femoral and lateral cutaneous nerve of the cia iliaca)
thigh lie below it ●● Aspirate and inject approximately 20–30 mis LA

/3 rd
1

ASIS 2
/3 rds
1 cm

PT