You are on page 1of 11


Neurons have two characteristic structural and functional features: an excitable membrane, and synapses. Excitability means the ability of neurons to generate and
propagate sterotypic electrical impulses (action potentials). This is a feature which is also shared with muscle and some endocrine cells but it is most highly developed
in neurons. The action potential is the primary means of communication in the nervous system. Synapses are specialised points of communication that allow neurons
to communicate with each other. Neurons are organised such that dendrites collect input from other neurons, primarily through synapses, whereas axons transmit
output from the cell body or soma to other neruons. The soma (body) contains the nucleus and the protein synthesis machinery for the cell.
Resting membrane potential is a fundamental and essential property of all cells. The membrane potential is an electrical gradient that results from the

differences in concentrations of charged organic and inorganic ions across the cell membrane. For most mammalian cells the resting membrane potential is negative
to the outside, usually -60 to -70 mV. The predominant ions involved are organic anions and K+ inside the cell and Na+ and Cl- on the outside. This ions have two driving
forces, the concentration gradient and the electrical gradient. The distribution of ions across the cell will equal equilibrium when these two forces are balanced. This
relationship was first described by Nernst in 1888. It is represented by the Nerst equation, E = (RT/zF)ln([ionoutside]/[ioninside] where E is the Nerst potential, R is the gas
constant, T is the temperature in Kelvins, z is the valence of the ion and F is faradays constant. This can be simplified, if the ion is single valence (K, Cl, Na) then the first
part of the equation can be simplified to 58. Therefore it is possible to calculate the Nernst potential for these important ions. Epotassium = 58Log10(4/140) = -90,
Echloride = -58Log10(116/4) = -85, Esodium = 58Log10(145/12) = 65. This introduces a new concept which is selective permiability. The Nerst potential for potassium and
chloride is similar to the resting membrane potential, and this is consistent with the fact that the cell membrane is highly permiable to these ions. The sodium potential
is vastly different to the RMP and it follows that the cell membrane is not permiable to this ion (otherwise the RMP would beome more positive). Two key elements
establish and maintain the membrane potenial; cell membrane channels which are selectively permiable to ions and cell membrane pumps which actively transport
charged particles against electrochemical gradients. There is a slight permiability to sodium but the Na.K.ATPase pump ensures that the RMP does not become more +



Skeletal motor, joint position

Touch, Pressure
Muscle spindle, motor
Pain, temp, touch
Preganglionic autonomic

voltage (m)






is obscured
by B peak

Vm (mV)






threshold value

Potassium Flux

Sodium Flux


Action potentials. All animal cells have a resting potential, ion pumps and a membrane which can act to conduct an electrical
signal. What distinguishes neruons (and to a less extent muscles and endocrine cells) is their excitability. Excitability is the ability of
a cell to generate and propagate a large, rapid potenial change in response to a relatively small trigger stimulus. The central
phenomenon of excitability is is the action potential. The actional potential is a very rapid, sterotyped event, a coordinated
sequence of several processes which leads to a propagation of signal along the axon without decrement which unlike passive
conduction is self regenerating. The actional potential has several characteristics that are important for its information carrying
behaviour. The first of these characteristics is threshold behaviour, which states that at a certain point (threshold) sodium channels
initiate a postive feedback mechanism which is self sustaining and regenerative. The second charateristic is all or none behaviour
and is closely realted to the threshold characteristic. It states that a signal will continue undiminished as long as there are sodium
channels to propagate it. The final characteristic is a refractory period. This is a short period of time following propagation where
there cannot be an immediate repolarisation. A consequence is that if two signals are travelling towards each other they will be
unable to pass and cancel each other out, terminating both signals. The action potential depends on voltage gated ion channels
that respond to changes in membrane potential by opening or closing. Although there are many channels involved in the
generation of the action potential there are only two key participants, the sodium channels and the potassium channels. Phase one
is characterised by an influx of sodium ions until the neuron reaches the threshold value which is variable based on the RMP, the
recent activity and the rate of depolarisation but often is assumed to be -55 mV. Following threshold value being reached there is a
poitive feedback mechanism which leads to the all or nothing event where sodium rushes into the cell (Phase 2). Shortly following
the initiation of the action potential potassium channels (delayed rectifier) permit a potassium efflux (as there is now a large
difference in the Nerst potential for potassium, this, coupled with the closing of the sodium channels leads to a rapid repolarisation
(Phase 3). Phase 4 represents an overshoot before a return to the RMP.


Time (ms)

Axonal conduction repeats the same events as described above. The inward sodium current depolarises

the membrane, and this is propagated along the membrane. Unlike a normal electrical signal which decays, an
action protential maintains its size and shape and will conduct unchanged along a neuron for a theoretically
indefinite distance. Whilst the size of the action potential is contast, the rate of transfer varies greatly according
to the characteristics of the axon. ,Channel opening speed, ECF composition and temperature all increase
conduction speed. The most important factors however in terms of conduction velocities is axon diameter and
the presence of myelin. Myelin is a tight spiral wrapping of glial cells around an axon, which is usually evenly
spaced with nodes of Ranvier. These are characterised by a high concentration of sodium channels, action
potentials will skip along the axon from node to node, increasing velocity. The relative conduction velocities
are used to classify nerve axons. Myelinated A fibres are the fastest and these are further subclassified
according to their width (and therefore conduction velocity) into four subcategories. B fibres are present in the
autonomic nervous system. Unmyelinated C fibres are the slowest fibres and have the smallest diameters.
Perpiheral nerves contain a mixture of these fibres and nerve conduction studies will demonstate this by
recording a serious of peaks in the compound action potential which is shown in the adjacent diagram.

time (ms)
A synapse is the anatomical site where nerve cells communicate with other nerves, muscle and glands. There are
two types which have been identified, either a chemical or electrical synapse. In electrical synapses, the
membranes of the presynaptic and postsynaptic neurons come close together, and gap junctions form between
the cells. Like the intercellular junctions in other tissues, these junctions form low-resistance bridges through which
ions can pass with relative ease. Electrical synapses may be found at the dendritic sites of contact that synchronise
neuronal activity, but are generally quite rare in mammalian cells. Synaptic transmission usually occurs via chemical
neurotransmitters. At chemical synapses, a synaptic cleft separates the terminal of the presynaptic cell from the
postsynaptic cell. An impulse in the presynaptic axon causes secretion of a chemical that diffuses across the
synaptic cleft and binds to receptors on the surface of the postsynaptic cell. This triggers events that open or close
channels in the membrane of the postsynaptic cell.

1. Action potential

2. Calcium

3. Release of
from vesicles

K+ K+
Cl- Cl- Cl-

Na+ Na+


5. Potassium efflux 4. Neurotransmitter 5. Sodium influx

or chloride influx post synaptic receptors
inhibitory or excitatory

Neurotransmitters are chemical mediators that are released into the synaptic cleft in response to the arrival of an action potential at the nerve ending. The release of

all neurotransmitters is voltage dependent and requires the influx of calcium ions into the presynaptic terminals(see also full AI on neurotransmitters). Neurotransmitters
may be excitatory or inhibitory, depending on the configurational change produced in the protein receptor by its interaction with the neurotransmitter. At the inhibitory
synapses, a neurotransmitter increases the permeability of postsynaptic receptors to potassium and chloride ions. Receptors responding to inhibitory neurotransmitters
are associated with protein channels that are too small to allow the passage of larger hydrated sodium ions. The predominant outward diffusion of potassium ions
increases the negativity of the resting transmembrane potential, and the neuron is hyperpolarized. This is called a inhibitory post synaptic potential or IPSP. The permeability changes evoked by excitatory neurotransmitters allow sodium influx and thereby decrease the negativity of the resting transmembrane potential, bringing it nearer
threshold potential. This is known as the excitatory post synaptic potential or EPSP. Glutamate (major excitatory amino acid neurotransmitter in the CNS; glutamate
receptors [includes N-methyl-D-aspartate receptors] are ligand-gated ion channels.) -Aminobutyric acid (GABA) (major inhibitory neurotransmitter in the CNS; when two
molecules of GABA bind to the receptor, the chloride ion channel opens and allows chloride ions to flow into the neuron causing it to become hyperpolarized.) Acetylcholine (excitatory neurotransmitter that interacts with muscarinic and nicotinic receptors in the CNS; contrasts with the inhibitory effects [increased potassium permeability]
on the peripheral parasympathetic nervous system.) Dopamine (high concentrations are present, especially in the basal ganglia; most likely it is an inhibitory neurotransmitter.) Noradrenaline (neurons responding to noradrenaline send predominantly inhibitory impulses.) Glycine (principal inhibitory neurotransmitter in the spinal cord.)
Substance P (excitatory neurotransmitter presumed to be released by terminals of pain fibers that synapse in the substantia gelatinosa of the spinal cord.) Endorphins
(excitatory neurotransmitters for descending pathways that inhibit the transmission of pain.) Serotonin (inhibitory neurotransmitter exerting profound effects on mood
and behavior.)

Christopher Andersen 2012


Ascending sensory pathways The afferent nerve fibres enter the CNS via
the spinal cord dorsal roots, the trigeminal and the vagus verve roots. After
entering the spinal cord they ascend within the spinal cord to their final destination which is usually designated by the suffix There are six in total, only two are
shown here the others being spino-reticuluar, -mesencephalic, -limbic, and
Spinothalamic is shown here in blue. It mainly
conveys pain pathways as well as cold, warmth and
some touch. Importantly following synapse in the
dorsal horn they cross over to the contralateral side
and ascend in the aterior (ventral) and lateral
spinothalmic tracts.
Dorsal colums are shown in green and transmit non
noxious fine touch, proprioception and vibration on
the ipsilateral side. The dorsal column is divided into
two fasciculus, the gracilis which is medial and
carries the information from the toes up to T6 and
the cuneatus immediately adjacent laterally which
carries information from T6 and above.
Spinal cord
dorsal horn
dorsal root

Descending motor pathways from the cerebral cortex excite the spinal
cord neurons both directly and indirectly. There are six descending motor
pathways, two from the cerebral cortex (cortospinal and corticobulbar), and four
from the brainstem (the rubrospinal, vestibulospinal, tectospinal and reticulospinal). The corticospinal tract (aka pyramidal tract) is the most important motor
pathway and is shown here in purple. It originates in the motor cortex, travels
through the internal capsule then crosses over to
the contralateral side in the pyramids of the medulla
into two main tracts the antero (ventral) and lateral.
It synapses in the ventral horn, then travels out
through the ventral root to the effector organ.
The rubrospinal, vestibulospinal and reticulospinal
tracts form the extrapyramidal tracts. They are
important in postural tone and direct voluntary
movement. The rubrospinal is shown here in red. It
should be noted that the lateral vestibularspinal
tract arises in the lateral vestibular nucleus and
remains on the ipsilateral side during its course
through the spinal cord.
Spinal cord
ventral horn

ventral root

Cerebrospinal fluid is a specialised extracellular fluid located in the ventricles, the spinal cord central canal and the


Arachnoid villi (valve)

subarachnoid space that bathes the brain and the spinal cord. It has a total volume of 150mL in a male adult and is formed
in two different places, the choroid plexus (70%) and the endothelial cells lining the brain capillaries (30%). The formation
occurs by both passive filtration and active transport. This occurs at a rate of around 500mL/day, which equates to a
turnover of 3-4 times per day. Its formation is dependent on the cerebral perfusion pressure, with the arterial pressure
being most significant (production is unchanged with a modest increase in ICP). Under most conditions it assumed that
4th Ventricle
the formation of CSF is constant. CSF is absorbed in the arachnoid villi and granulations and these act as valves with CSF
escaping to the venous system but not backflowing, as the pressure increases the valves open wider. Whilst it is isotonic
with plasma their compositions differ, CSF having minimal large components due to filtration, with negligable albumin,
globulin and fibrinogen. It has increased Cl-, and Na+. CSF also has increased CO2 with a pCO2 of 50, leading to a pH of
7.32. CSF has less of the other major cations with less K+, Ca++ and Mg++. It has a number of important functions. Firstly it
provides mechanical protection for the brain by making it bouyant and reducing its effective weight from 1400g to 50g. This prevents the brain from injury due to
changes in position or due to acceleration and deceleration. The second function is maintaining a constant ionic environment and preventing sudden fluxes in ion
composition. The CSF is also very important in acid base regulation, this is especially the case in terms of primary respiratory disorders. CO2, which diffuses across the
membrane, changes to H+ and HCO3- and acts on the central chemoceptors to adjust the respiratory rate. The CSF provides intracerebral transport for important
substances such as amino acids and sugars. Finally it protects the brain by physically buffering increases in ICP by translocating to the extracranial space. CSF Flow is
determined by the pressure in the lateral ventricle (normally 15cm H2O) and cilia direct flow towards the fourth ventricle. It exits the brain via two foramens, the
Foramen of Luschka and Foramen Magendie.

Cerebral blood flow At rest the brain receives around 750ml of flow which equates to approximately 15% of total CO. It has a high myocardial consumption of 3-3.5

ml O2 /min/100g which when calculated using the weight of the brain (1400g) results in around 50 ml of oxygen which is 20% total consumption (remembering that
total oxygen consumption is around 250ml/min). As always flow = pressure/resistance. In this setting it is the cerebral blood flow (CBF) = cerebral perfusion pressure
(CPP) / cerebrovascular resistance (CVR). The CPP is normally MAP - CVP, however in pathological states where there is raised ICP a starling resistor model is set up. In this
setting ICP>CVP and therefore the CPP = MAP -ICP. Extrinsic nerve and hormonal control have little influence on CBF. The cerebral circulation demonstrates a very well
controlled autoregulation normally within the range of 50-150mmHg. It should be noted that in chronic hypertension this may be reset. The mechanism of autoregulation has not been fully elucidated, however it is believed to by primarily due to myogenic stretch factors. Local metabolic factors are significant also, but primarily from
a regional cerebral flow perspective and may include adenosine, NO, H+. The exceptions to this are arterial PCO2 which demonstrates an almost linear relationship with
CBF from 20mmHg-80mmHg, and to a lesser extent O2 which when to oxygen content drops significantly (associated with a PaO2 of less than 50mmHg which is on the
steep part of the dissociation curve) there is an increase in CBF. Above this point oxygen saturations have little influence.

cerebral blood volume (5-8%). Intracranial pressure is determined by the total volume of each because the cranial vault is not distensible.
The normal intracranial pressure is between 5-15mmHg. The Monroe-Kellie hypothesis states that for ICP to remain normal, an increase in
any one of the volumes must be matched by a decrease in another. Brain tissue volume comprises mainly of ECF and ICF, CSF volume is
determined primarily by the ration of production to absorption, and CBV is the sum of the arterial and venous blood volumes. The
relationship between volume and pressure in the brain can be represented on an elastance curve (change in pressure/change in volume)
which is the iverse of compliance. Initially CSF is displaced and this acts as a physical buffer to pressure changes but eventually there is a
sharp rise in pressure with ongoing increases in volume.

slope = elastance
Intracranial Pressure

Intracranial pressure The intracranial space contains three compartments: brain tissue (80-85%), cerebrospinal Fluid (7-10%) and





Volume (mL)

Sleep is an essential, readily reversible physiological state characterised by unconsciousness, reduced muscle tone, analgesia, amnesia, respiratory and autonomic
disturbances and dreaming. There are two main states of sleep, non rapid eye movement (NREM) sleep and REM sleep. NREM sleep is also known as slow wave sleep.
It is a deep restful sleep and is characterised by decreases in peripheral vascular tone, blood pressure, respiratory rate, and metabolic rate. Slow wave sleep is brought
about by the inhibition of the midline pontine and medullary nuclei (raphe nuclei). NREM sleep is divided into four stages. During progression through the stages
the EEG becomes more synchronised and slows and the person becomes more difficult to rouse (stage 4 is the most difficult). REM sleep (paradoxical or stage 5) is
distinct from slow wave sleep because the brain becomes quite active, skeletal muscle contractions occur and the EEG resembles rapid low-voltage, irregular
(desynchronised) activity which is similar to alert humans. REM sleep lasts for 5-30 minutes and occurs at approximately 90 min intervals. This period of sleep is
characterised by decreased muscle tone, irregular heart rate and respiration and increased barin metabolism by up to 20%. Natural sleep and anaesthesia are share
many similarities, but they are clearly distinct. Both are characterised by unconsciousness, analgesia, amnesia, and atonia (in REM sleep). The EEG in sleep is
characterised by predictble rhythmic variations generated endogenously. The effects of anaesthetics on the EEG are agent and dose dependent, but can resemble
the patterns observed during different stages of sleep. Natural sleep is characterised by autonomic variability, whereas most anaesthetics produce autonomic
stability even in the face of painful stimuli. Finally in contrast to anaesthesia natural sleep is characterised by easy arousability and spontaneous movements.
Christopher Andersen 2012


Electroencephalopathy is the recording of the spontaneous electrical activity of the brain. The electroencephalogram EEG records the summed electrical activity
caused by dendritic postsynaptic potentials located in the superficial layer of the pyramidal cells in the outer cortex. The activity recorded at an individual scalp
electrode represents averaged synaptic electrical activity within 20-25mm of the recording electrode. The signal is generated by something called a differential
amplifier and the noise is removed by common mode rejection which basically subtracts the one signal from another removing the shared signals. Analysis is often a
visual assessment of the relative frequencies, amplitude and symmetry which is an extremely important component of analysis, activity is usually symmetric about the
midsagittal line.. There are three basic types of activity; continuous and rhythmical, transient and background activity. The frequency spectrum of the EEG is usually
described in four bands, delta waves are the slowest 0-3 Hz, theta waves are 4-7 Hz, alpha waves, typical of an awake patient with eyes closed are 8-12 Hz, Beta waves
are the fastest and representative of an awake and alert patient or someone in REM and are 13-30 Hz. More complex computation methods are also available often
employing fourier analysis. The EEG is affected by both drugs and pathophysiological states. It is the former property that leads EEG to be used in anaesthesia to assess
levels of sedation. Most general anaesthetics produce EEG excitation initially followed by progressive slowing. Deep sedation is often characterised by a shift in activity
to the frontal regions, reduced variability, burst suppression or a silent EEG. Opiates do not appear to produce an initial excitement phase but produce a steady decline
in EEG frequency, maintenance of amplitude in the delta range and without producing burst suppression or electrical silence. In addition to anaesthesia the EEG is
affected by a range of physiological variables. Hypoxaemia, hypotension, hypocarbia, hypoglycaemia and ischaemia cause slowing and flattening of the the EEG.
Hypercarbia produces excitation up to a point when the EEG becomes flat. Hypothermia produces slowing below 35 degrees and electrical silence at 7-20 degrees. The
EEG is also dependent on age, with an adult pattern emerging at 10-15 years of age. Generalised encephalopathies of metabolic or infective origin present as a
generalised excess of slow wave activity. Focal slow wave activity may be suggestive of a focal lesion such as a tumour. An abnormal discharge of high voltage is
suggestive of a epileptiform disturbance.
Normal EEG in alert adult patient

Generalised metabolic encephalopathy

Generalised tonic clonic seizure

Demonstrates normal alpha waves

in the posterior electrodes (will
move frontal if patient closes eyes).

Slow wave (theta and beta) activty

across all leads

Across all leads with high amplitude

and frequency

Focal epileptic discharges

Spike and wave activity that is

occurring in the right parietal region

Evoked Potentials Whereas the EEG is the measurement of spontaneous electrical activity in the cerebral cortex, evoked potentials EPs are produced in response to
a deliberate stimulus involving specific neuronal tracts. They may be physiologic in nature such as light flashes to the eyes as in visual evoked potentials or nonphysiologic such as electrical pulses delivered to peripheral nerves in somatosensory evoked potentials. Because the the amplitude of sensory EPs is so small a technique
known as signal averaging is used to resolve EPs from much greater EEG and ECG activity. Signal averaging involves repeatedly stimulating the nervous system and
measuring the response during the period of stimulated neural activity. The waveforms are analysed for the amplitude (peak to trough) and the latency (delay from
stimulus to wave appearance) of the characteristic waves. The waveforms are described as P (postive) or N (negative) by their latency after stimulation. Evoked
potentials are classified according to the sensory pathway stimulated, visual-EPs, auditory-EP, braintem auditory EP, somatosensory EP, and motor EPs.
Nerve conduction studies Recording of the electrical response of a muscle to stimulation of its motor nerve at two or more points along its course permits
conduction velocity to be determined in the fastest-conducting motor fibers between the points of stimulation. The latency and amplitude of the electrical response
of muscle (i.e., of the compound muscle action potential) to stimulation of its motor nerve at a distal site are also compared with values defined in normal subjects.
Sensory nerve conduction studies are performed by determining the conduction velocity and amplitude of action potentials in sensory fibers when these fibers are
stimulated at one point and the responses are recorded at another point along the course of the nerve. In adults, conduction velocity in the arms is normally between
50 and 70 m/s, and in the legs is between 40 and 60 m/s. A loss of myelination or a reduction in diameter of axons will lead to an increase in latency.
Lumbar puncture is usually performed with the patient in the lateral of the sitting position.
Whichever position is chosen, the patient should be asked to flex their lumbar spine to a
maximal amount, thereby widening the spaces between the spinous processes. The line that
joins the top of the illiac crests (the intercristal line) usually passes through the body of the 4th
lumbar vertebrae and is therefore a useful landmark. The space above this line is usually the
3rd/4th interspace, immediately below this is the 4th/5th interspace. The interspace is important
as the spinal needle should not be entered at a level which it may enter the spinal cord. In the
adult, the spinal cord usually ends at the level of the 1st -2nd lumbar vertebra and divides into
the cauda equina. Lumbar puncture is normally performed midline, although an alternative in
the setting of a calcified supraspinus and interspinus ligament is a lateral or paramedian
approach. After infiltration with local anaesthetic the spinal needle passes through the following
structures shown in the diagram adjacent; the skin, subcutaneous tissue, the supraspinus
ligament, the interspinus ligament, the ligamentum flavum and finally the dura mater. This last
structure is classically described as producing a pop as the needle enters the space.
The epidural (also known as the extradural or peridural) space in the spinal canal is that part






not occupied by the dura and its contents. It extends from the foramen magnum to end by
fusion of its lining membranes as the sacrococcygeal membrane. It contains fat, nerves roots,
blood vessels and lymphatics. The posterior aspect of the space is limited by the laminae and
overlying ligamentum flavum, laterally by the pedicles of the vertebral arches and the intervertebral spaces. The anterior structures are the bodies of the vertebrae, the intervertebral discs and
the posterior longitudinal ligament. The epidural space can be entered by a needle passed
either between the spinal laminae or via the sacral hiatus. The spinal canal is roughly triangular
in cross section therefore the space is deepest in the midline posteriorly. In the lumbar region
the distance between the laminae to the posterior aspect of the dura is about 5mm.
Sacral hiatus
epidural approach

Christopher Andersen 2012







To be accepted as a neurotransmitter, a candidate chemical must (1) be present in higher concentration in the synaptic area than in
other areas (ie, must be localized in appropriate areas), (2) be released by electrical or chemical stimulation via a calcium-dependent mechanism, and (3) must exhibit synaptic
mimicry ie produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse. Below are the major neurotransmitters.

Glutamate is the main excitatory transmitter in the brain and spinal cord, and it has been calculated that it is the transmitter responsible for 75% of the excitatory transmission in the brain. Synthesis: Glutamate is formed by reductive amination of the Krebs cycle
intermediate -ketoglutarate in the cytoplasm. Receptors: Glutamate receptors are of two types: metabotropic receptors and ionotropic
receptors. The metabotropic receptors are G protein-coupled receptors that increase intracellular IP3 and DAG levels or decrease
intracellular cAMP levels. The ionotropic receptors are ligand-gated ion channels that resemble nicotinic cholinergic receptors and GABA
and glycine receptors. There are three general subtypes, the kainate receptors, AMPA receptors, and NMDA receptors. The all three allow
Na and K flux, and NMDA also allows significant Ca flux. Fate: Glutamate is removed from the synaptic cleft by active transport into
neurons and astrocytes. This uptake is important because persistant excitation by glutamate is an excitotoxin which may kill cells by
overstimulating them.



GABA is the major inhibitory mediator in the brain, including being responsible for presynaptic inhibition. Synthesis GABA, which exists

as gamma-aminobutyrate in the body fluids, is formed by decarboxylation of glutamate. The enzyme that catalyzes this reaction is
glutamate decarboxylase (GAD), which is present in nerve endings in many parts of the brain. Receptors: The GABAA and GABAC receptors
are ion channels made up of five subunits surrounding a pore, and allow the influx of Cl-. The GABAB receptors are metabotropic and are
coupled to heterotrimeric G proteins that increase conductance in K+ channels, inhibit adenylyl cyclase, and inhibit Ca2+ influx. Fate:
GABA is metabolized primarily by transamination to succinic semialdehyde and thence to succinate in the citric acid cycle. GABA
transaminase (GABA-T) is the enzyme that catalyzes the transamination.

Glycine has both excitatory and inhibitory effects in the CNS. When it binds to NMDA receptors, it makes them more sensitive.







However, glycine is also responsible in part for direct inhibition, primarily in the brain stem and spinal cord. Like GABA, it acts by
increasing Cl- conductance.

Acetylcholine is a major neurotransmitter in the peripheral nervous system, and it is also present in the brain. Fibers that release ACh
are called cholinergic fibers. Acetylcholine is the transmitter at the neuromuscular junction, in autonomic ganglia, and in postganglionic
parasympathetic nerve-target organ junctions and some postganglionic sympathetic nerve-target junctions. It is also found within the
brain, including the basal forebrain complex and pontomesencephalic cholinergic complex. These systems may be involved in
regulation of sleep-wake states, learning, and memory (hence anticholinesterases in dementia). Synthesis: from choline and acetyl
coenzyme A in the cytoplasm of synaptic terminals and stored in synaptic vesicles. Receptors are separated into two main groups, the
muscarinic and the nicotinic. Nicotinic receptors are ligand gated ion channels which are located in skeletal muscle, on postganglionic
neurons in both the SNS and PNS, on adrenal chromaffin cells and within the CNS where they are important in memory and learning.
Muscarinic receptors are GPCR that inhibit adenylyl cyclase activity. They are located on the heart where they are inhibitory, and in the
smooth muscle and the glands where there are excitatory and are blocked by atropine. Fate: After it is released and activates receptors
on the postsynaptic membrane, the concentration of ACh at the postsynaptic membrane is reduced (thereby stopping receptor
activation) by the enzyme acetylcholinesterase. This enzyme is located on the pre- and postsynaptic membranes and rapidly destroys
ACh, releasing choline. The choline is then transported back into the axon terminals where it is reused in the synthesis of new ACh. The
ACh concentration at the receptors is also reduced by simple diffusion away from the site and eventual breakdown of the molecule by
an enzyme in the blood.
Serotonin (5-hydroxytryptamine; 5-HT) In general, serotonin has an excitatory effect on pathways that are involved in the control of
muscles, and an inhibitory effect on pathways that mediate sensations. The activity of serotonergic neurons is lowest or absent during
sleep and highest during states of alert wakefulness. In addition to their contributions to motor activity and sleep, serotonergic
pathways also function in the regulation of food intake, reproductive behavior, and emotional states such as mood and anxiety.
Synthesis: formed in the body by hydroxylation and decarboxylation of the essential amino acid tryptophan. Receptors: serotonin
receptors are diverse in both distribution and function. They are found throughout the brain and peripherally on platelets and smooth
muscle and the gut. They are both pre and post synaptic. They may be GPCR with a range of second messengers including andenylyl
cyclase and phospholipase C or ligand gated channels. Fate: After release from serotonergic neurons, much of the released serotonin
is recaptured by an active reuptake mechanism and inactivated by monoamine oxidase (MAO).




HO CH2 CH2 N (CH3)3


CH3 C O CH2 CH2 N (CH3)3


axons project to all parts of the brain, including the cerebral cortex and the spinal cord. Histamine is also found in cells in the gastric
mucosa and in heparin-containing cells called mast cells that are plentiful in the anterior and posterior lobes of the pituitary gland as well
as at body surfaces. Histamine is formed by decarboxylation of the amino acid histidine. The function of this diffuse histaminergic system
is unknown, but evidence links brain histamine to arousal, sexual behavior, blood pressure, drinking, pain thresholds, and regulation of
the secretion of several anterior pituitary hormones.


Dopamine Dopaminergic neurons are located in several brain regions including the nigrostriatal system, which projects from the

substantia nigra to the striatum and is involved in motor control, and the mesocortical system, which arises primarily in the ventral
tegmental area. The mesocortical system projects to the nucleus accumbens and limbic subcortical areas, and it is involved in reward
behavior and addiction. Synthesis: Dopamine is formed by hydroxylation and decarboxylation of the amino acid tyrosine. Some of the
tyrosine is formed from phenylalanine, but most is of dietary origin. Tyrosine is transported into catecholamine-secreting neurons and
adrenal medullary cells by a concentrating mechanism. It is converted to dopa and then to dopamine in the cytoplasm of the cells by
tyrosine hydroxylase and dopa decarboxylase. The dopamine then enters the granulated vesicles (where it is converted to norad). The
rate-limiting step in synthesis is the conversion of tyrosine to dopa. Tyrosine hydroxylase, which catalyzes this step, is subject to
feedback inhibition by dopamine and noradrenaline, thus providing internal control of the synthetic process. Storage: is granulated
vesicles Receptors: There are five known dopamine receptors which are GPCR which either upregulate or down regulate cAMP. Fate:
Dopamine is metabolized to inactive compounds by MAO (oxidisation) and COMT (methylation) in a manner analogous to the
inactivation of norepinephrine.



Histamine Histaminergic neurons have their cell bodies in the tuberomammillary nucleus of the posterior hypothalamus, and their





rate limiting


amino acid



dopamine beta

Noradrenaline The chemical transmitter present at most sympathetic postganglionic endings is noradrenaline.

In the CNS,
noradrenergic neurons are located in the locus ceruleus and other medullary and pontine nuclei. From the locus ceruleus, the axons of
the noradrenergic neurons form the locus ceruleus system. They descend into the spinal cord, enter the cerebellum, and ascend to
innervate the paraventricular, supraoptic, and periventricular nuclei of the hypothalamus, the thalamus, the basal telencephalon, and
the entire neocortex Synthesis is from dopamine (as described above) which it is converted to noradrenaline by dopamine -hydroxylase (DBH). which occurs in neurons and the adrenal medulla. Storage: is granulated vesicles Receptors: are the alpha receptors 1
(increases IP3 and DAG) and 2 (decreases cAMP) and the beta receptors 1 to 3 which all increase cAMP. Fate: metabolized to inactive
compounds by MAO (oxidisation) and COMT (methylation).




Adrenaline Is very similar to noradrenaline in most of its actions, as it uses the same receptors, although it is mostly released from

the adrenal medulla not at symptathetic nerve endings. It is released from neurons throughout the brain and like norad is plays
essential roles in states of consciousness, mood, motivation, directed attention, movement, blood-pressure regulation, and hormone
release. Synthesis: is from norad phenylethanolamine -N- methyltransferase (PNMT) which occurs in neurons and the adrenal medulla.
Storage: is granulated vesicles Receptors: are the alpha receptors 1 (increases IP3 and DAG) and 2 (decreases cAMP) and the beta
receptors 1 to 3 which all increase cAMP. Fate: metabolized to inactive compounds by MAO (oxidisation) and COMT (methylation).

Christopher Andersen 2012





Antipsychotic medications Classification of antipsychotics is usually based on whether they are older first generation medications with significantly more
extra-pyramidal symptoms or newer generation so-called atypical or second generation antipsychotics. Other terms used are neuroleptics which have strong
experimental and clinical evidence of antogonism of D2 dopamine (DA) receptors and are characterised in particular by the supression of spontaneous movements
and complex behaviours, although this classification has fallen out of favour in recent times. Pharmaceutical aspects Antipsychotics are avaiable in tablet form
although their unpredictable patents of oral absorption make this problematic with some of the agents. Some of the agents are available as wafers for sublingual
administration. Other options include IV formulations and IM depots which are preparations of esters of antipsychotics drugs, or incorporated into carbohydrate
microspheres, which are absorbed and eliminated much slower than oral and IV formulations. Pharmacodynamic properties The common activity of both
first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) appears to be post-synaptic blockade of brain dopamine D2 receptors. The
exception, aripiprazole, is a D2 partial agonist. Several lines of evidence support the role of these receptors in the activity of antipsychotics, including a correlation
between receptor binding and clinical potency. SGAs differ from older medications in that serotonin 5HT2 receptor binding can exceed their affinity for dopamine D2
receptors, whereas first-generation generally do not. Largely for that reason, 5HT2 activity has been suggested as one basis for the lower risk of extrapyramidal side
effects of many of the atypical drugs compared to FGAs, particularly the high-potency agents. The antipsychotic drugs affect all levels of the CNS. Theories on the
actions of antipsychotic agents are based on their ability to antagonize the actions of DA as a neurotransmitter in the basal ganglia and limbic portions of the
forebrain. The beneficial effects of antipsychotics relate to their demonstrated efficacy in reducing the symptoms of psychoses such as disordered thought processes
(including hallucinations and delusions), disorganised or irrational behavours and varying degrees of altered mood. Other beneficial effects of these drugs include
anti emetic properties and release of prolactin (which may also a side effect). Pharmacokinetic properties Most antipsychotic drugs are highly lipophilic, highly
membrane- or protein-bound, and accumulate in the brain, lung, and other tissues with a rich blood supply. They also enter the fetal circulation and breast milk. It is
virtually impossible to remove these agents by dialysis. Elimination half-lives with respect to total concentrations in plasma are typically 2040 hours. Biological
effects of single doses of most antipsychotics usually persist for at least 24 hours, permitting once-daily dosing once the patient has adjusted to initial side effects.
The antipsychotic drugs are metabolized largely by hepatic CYPs and by glucuronidation, sulfation, and other conjugation processes. Hydrophilic metabolites of
these drugs are excreted in the urine and to some extent in the bile. Most oxidized metabolites of antipsychotic drugs are biologically inactive. Loss of efficacy with
prolonged treatment is not known to occur with antipsychotic agents, but some tolerance to sedative effects of antipsychotics usually develops over days or weeks.
Side effects are extensive and serious. Neurological side effects can be divided into four acute effects (acute dystonia, akathisia, parkinsonism and neuroleptic
malignant syndrome) and two delayed (tarditive dyskinesia and perioral tremor). Cardiovascular effects include postural hypotension (probably due to baroreceptor
impairment) and long QT syndrome. Metabolic effects include weight gain and metabolic syndromes, Haem side effects include blood dyscrasias. Endocrine include
increased prolactin secretion.
Antidepressant medications

Classification Antidepressant medications may be classified into five major groups. The older generation drugs are the monoamine
inhibitors (phenelzine) and the tricyclic antidepressants (amitriptyline). Newer agents include the SSRIs (paroxetine) and SNRIs (venlafaxine). A fifth group including other
drugs such as mirtazepine is sometimes added but is not considered here. Pharamaceutical aspects all antidepressants are only available in oral form with the exception
of amitriptyline and a related tricyclic imipramine. Pharmacodynamic The amine hypothesis of mood postulates that brain amines, particularly noradrenaline (NA) and
serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the hypothesis, a functional decrease in the activity of such
amines is thought to result in depression; a functional increase of activity results in mood elevation. The amine hypothesis is largely based on studies showing that many
drugs capable of alleviating symptoms of major depressive disorders enhance the actions of the central nervous system (CNS) neurotransmitters 5-HT and NA. Difficulties
with this hypothesis include the facts that (1) postmortem studies do not reveal any decreases in the brain levels of NA or 5-HT in patients suffering from depression; (2)
although antidepressant drugs may cause changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects; (3) most antidepressants ultimately cause a downregulation of amine receptors. The acute effect of tricyclic drugs is to inhibit the reuptake mechanisms (transporters) responsible for the
termination of the synaptic actions of both NA and 5-HT in the brain. This presumably results in potentiation of their neurotransmitter actions at postsynaptic receptors,
they also demonstate alpha adrenergic effects, muscarininc effects and histamine blocking which leads to many of its side effects. MAOIs decrease NA, dopamine and
5-HT breakdown in the presynapse neuron. SSRIs demonstrate more selective blocking of reuptake at the presynaptic cleft. SRNIs cause blocking of reuptake of both NA
and 5 HT. Pharmaocokinetic MAOIs are notable for their prolonged duration of action >1 week, although they are usually dosed daily. The TCAs are well absorbed orally
but may undergo first-pass metabolism. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required before their
elimination; plasma half-lives of 8-36 h usually permit once-daily dosing. Both amitriptyline and imipramine form active metabolites, nortriptyline and desipramine,
respectively. SSRIs are generally very well absorbed orally (up to 100%) lipid soluble, highly protien bound, have large volumes of distribution, half lives which allow daily
dosing and metabolised hepatically to inactive metabolites (fluoxetine is the exception with an active metabolite which last several days and allows weekly dosing).
SNRIs are variable in their pharmacokinetics, venlafaxine is well absorbed with a high first pass metabolism leading to a bioavailability of 45%, it has a large volume of
distribution, a relatively short half life, but an active metabolite which prolongs duration of action. Side effects MAOIs induce sedation and can casue severe orthostatic
hypotension. SSRIs and SNRIs have less side effects and but may cause nausea, vomitting and sexual dysfunction. Tricyclic antidepressants routinely produce adverse
autonomic responses, in part related to their relatively potent antimuscarinic effects, including dry mouth constipation, dizziness, tachycardia, palpitations, blurred
vision,and urinary retention. Cardiovascular effects include orthostatic hypotension, sinus tachycardia, and variable prolongation of cardiac conduction times with the
potential for arrhythmias, particularly with overdoses. Weakness, fatigue and weight gain are also common. Overdosage with TCAs or MAOIs can be life threatening with
initial excitatory responses seizures, myoclonus and dystonia rapidly progressing towards coma with associated respiratory depression, urinary retention, and cardiac
arrythmias. Treatment is gastric lavage and activated charcoal, supportive management (usually ICU/intubation) and phenytoin or lignocaine to treat the arrhythmias.
Anticonvulsant medications
K Channels

Na+ Channel

Inactivation of sodium channels

Prototype: Phenytoin (also Carbemazepine)
Indications: partial/tonic clonic not
absence seizures
Pharmacodynamics: neuron hyperpolarisation via Na Channels
Pharmaceutical: Oral but Fosphenytoin is a
water soluble form for IV preparations
Pharmacokinetics: t1/2 6-24 hrs -non linear
metabolism (first order to zero order with
increasing concentration). Extensive
protien binding >95%, increased levels
when competition for binding.
Side effects: cardiac arrythmias, hirsutism
in females, gingival hyperplasia, SIADH,
skin rash, rarely steven-johnson or SLE

Christopher Andersen 2012

GABA related effects

Prototype: Diazepam - benzodiazepines
(also gabapentin, barbituates)
Indications: status epilepticus, anxiolytic,
Pharmacodynamics: neuron hyperpolarisation via GABAA Receptor sensitisation
Pharmaceutical: Oral and IV
Pharmacokinetics: t1/2 1-2 days with
prolonged active metabolite (60hrs). v high
lipid solubility and protien binding. Effect
reduced by rapid redistribution. Tolerance
and physiological dependence develops.
Side effects: sedation, synergistic
respiratory depression with other agents,
lethargy, ataxia, decreased coordination.

Ca2+ Channel

Inactivation of Ca2+ channels

Prototype: Valproic acid best known,
(ethosuximide is actual prototype)
Indications: partial/tonic clonic and
absence seizures
Pharmacodynamics: neuron hyperpolarisation via Ca Channels (also Na Channels)
Pharmaceutical: Oral enteric coated
Pharmacokinetics: absorbed rapidly and
completely, highly protien bound, diffusion
and carrer transport to CSF, hepatic metab,
active metabolites, t1/2 15 hours, urine
Side effects: commonly; anorexia, nausea,
vomitting, occasionally; sedation, ataxia,
tremor. rarely; fulminant hepatitis.


Other processes of hyperpolarisation

Prototype: Levetiracetam (others include
Indications: refractory epilepsy, bipolar
Pharmacodynamics: unknown, possibly
?K Channels, ?NMDA, ?Na Channels
Pharmaceutical: Oral and IV
Pharmacokinetics: rapid and complete
absorption, 100% bioavailability, Vd is near
total body water, minimal protien binding,
t1/2 6-8 hrs minimal metabolism, inactive
metabolites. Urine excretion mostly
unchanged (66%)
Side effects: somnolence, asthenia,
dizziness, agitation, nausea

Parkinsons disease pharmacology Parkinsonism has four cardinal features: bradykinesia (slowness and poverty of movement), muscular rigidity, resting tremor
(which usually abates during voluntary movement), and an impairment of postural balance leading to disturbances of gait and falling. The pathological hallmark of PD
is a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta (SNpc) that provide dopaminergic innervation to the striatum (caudate and
putamen). Ultimately leading to decreased excitation of the motor cortex and inhibition of the thalamus. Drugs in common clinical use that may cause parkinsonism
include antipsychotics such as haloperidol and thorazine and antiemetics such as prochloperazine and metoclopramide. Strategies of drug treatment of parkinsonism
involve increasing dopamine activity in the brain, decreasing muscarinic cholinergic activity in the brain, or both. Although several dopamine receptor subtypes are
present in the substantia nigra, the benefits of most antiparkinson drugs appear to depend on activation of the D2 receptor subtype.
Levodopa Because dopamine has low bioavailability and does not readily cross the blood-brain barrier, its precursor, L-dopa (levodopa), is used. Pharmaceutical:
Levodopa is usually given with carbidopa, a drug that does not cross the blood-brain barrier but inhibits dopa decarboxylase in peripheral tissues. With this combination, the plasma half-life is prolonged, lower doses of levodopa are effective, and there are fewer peripheral side effects. Pharmacodynamics: By increasing the
concentration of dopamine in the CNS many of the symptoms of PD are temporarily alleviated, although this may be at the cost of dyskinesias when the concentration
is high and rapid return of PD symptoms when the concentration lowers limiting the effectiveness. Pharmacokinetics: Bioavailibility is around 75% via active transport in the small bowel, competition for binding sites means there is
absorption is slowed if ingested with a meal. Levodopa enters the brain via an L-amino acid transporter (LAT) and is
converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (dopa decarboxylase), which is present
in many body tissues, including the brain. It has a half life of 1-3 hours and requires frequent dosing. Side effects in
addtion to the dyskinesias are hallucinations and confusion, and orthstatic hypotension.
Bromocriptine An ergot alkaloid. bromocriptine acts as a partial agonist at dopamine D2 receptors in the brain. The
drug increases the functional activity of dopamine neurotransmitter pathways, including those involved in
extrapyramidal functions. Bromocriptine has been used as an individual drug, in combinations with levodopa (and
with anticholinergic drugs), and in patients who are refractory to or cannot tolerate levodopa. Common adverse
effects include anorexia, nausea and vomiting, dyskinesias, and postural hypotension. Behavioural effects, which
occur more commonly with bromocriptine than with newer dopamine agonists, include confusion, hallucinations,
and delusions. Ergot-related effects include erythromelalgia and pulmonary infiltrates. Use of bromocriptine in
patients with Parkinson's disease has declined with the introduction of non-ergot dopamine receptor agonists such
as pramipexole.
Monoamine oxidase inhibitors Selegine is a selective inhibitors of monoamine oxidase type B at lower doses, the
form of the enzyme that metabolizes dopamine. It demonstrates modest benefit and may be useful in early disease
or in combination with levodopa. Adverse effects and interactions of monoamine oxidase inhibitors include
insomnia, mood changes, dyskinesias, gastrointestinal distress, and hypotension.
Catechol-O-Methyltransferase (COMT) Inhibitors Entacapone and tolcapone are inhibitors of COMT, the enzyme in
both the CNS and peripheral tissues. The drugs are used individually as adjuncts to levodopa-carbidopa, decreasing
fluctuations, improving response, and prolonging "on-time." Tolcapone is taken 3 times daily, entacapone 5 times
daily. A formulation combining levodopa, carbidopa, and entacapone is available, simplifying the drug regimen.
Adverse effects related partly to increased levels of levodopa include dyskinesias, gastrointestinal distress, and
postural hypotension. Levodopa dose reductions may be needed for the first few days of COMT inhibitor use. Other
side effects include sleep disturbances and orange discoloration of the urine.

Parasympathetic agonists (cholinomimetics) are drugs that mimic acetylcholine by directly or indirectly activating the receptors with which acetylcholine

interacts. Cholinergic agonists can act at nicotinic receptors, muscarinic receptors or both. They are usually classified by whether they act directly on the receptor or
indirectly by inhibiting cholinesterases and therefore prolonging the action of acetylcholine. Direct acting cholinomimetics comprise a group of choline esters
(including acetylcholine, methacholine) and a second group of naturally occurring alkaloids (muscarine, pilocarpine, nicotine) and the depolarising neuromuscular
blockers such as suxamethonium (see neuromuscular junction page). The with the exception of the DNMBs, direct acting cholinomimetics have limited uses beyond
topical application to produce miosis and for diagnostic purposes in the case of methacholine. The indirect agents however are used commonly in a critical care
setting for the reversal of non depolarising neuromuscular blocking agents and in the treatment of myasthenia gravis and increasingly for the percieved CNS benefits
in the treatment of dementia. The indirect cholinomimetics (anticholinesterase) include the prototype neostigmine as well as edrophonium, physostigmine, donepezil
(for dementia) and the organophosphates (which are irreversible and cause poisoning). The anticholinesterase drugs are ionised water soluble agents that inhibit
acteylcholinesterase at the synaptic cleft. In the paralysed patient these agents reverse the nondepolarising blockade at the nicotinic ACh receptor. Because anticholinesterase drugs activate muscarinic receptors, the co-administration of a muscarinic receptor antagonist such as atropine or gylcopyrrolate can reduce the side
effects of bradycardia, bronchospasm or intestinal spasm. Neostigmine is a quaternary amine. When used in theatres it is delivered IV but is also available in oral form.
It is poorly absorbed from the gut and has a low oral bioavailability. It is minimally protien bound, has a low volume of distribution and is partially metabolised in the
liver. It does not cross the BBB. More than 50% is excreted in the urine unchanged (therefore caution is required in renal impairment).

Parasympathetic antagonists (anticholinergics) Anticholinergic drugs (atropine, scopolamine, glycopyrrolate) competitively inhibit the action of ACh by

reversibly binding to cholinergic postganglionic receptors. They are selective for muscarinic receptors at the doses normally employed clinically. Atropine and
scopolamine (hyoscine hydrobromide) are naturally occuring tertiary amines derived from the belladona plant. They are able to cross the BBB. Their anticholinergic
activity is primarily due to the L enantiomer although they are presented as racemic mixtures. Low doses of atropine (2mcg/kg) act centrally and may augment vagal
outflow, decreasing heart rate. At normal clinical doses (15-70mcg/kg) atropine also acts on peripheral muscarinic receptors blocking the action of the vagal nerve
and increasing the heart rate and pupil size whilst decreasing secretory gland activity. A limitation to the use of atropine and scopolamine is an infrequent side effect
called central anticholinergic syndrome which consists of agitation, disorientation, delerium, hallucinations and restlessness but may present as increased somnolence and is a differential for delayed wakening from anaesthesia. As a quarternary amine, glycopyrrolate does not cross the BBB and therefore does not exert CNS
effects. It is however, more potent and longer acting at peripheral muscarinic receptors than atropine. It is used to decrease secretions and treat vagally mediated
bradycardia, and to inhibit cardiac muscarinic side effects when anticholinesterase agents are used to reverse the effects of muscle relaxants. Ipatropium, a derivative
of methylatropine is an inhaled anticholinergic that is utilised for its bronchodilating effects via blockade of M3 muscarinic receptors located on smooth muscle in
the airway.



Sedation Mydrasis

Heart rate

GI tone


tertiary amine

crosses BBB








tertiary amine

crosses BBB








quaternary amine

peripheral only







Christopher Andersen 2012


Duration (IV)

Definition of Pain an unpleasent sensory and emotional experience associated with actual or potential tissue damage, or describes in terms of such damage
Ascending Pain Pathways
Cortex there are multiple

projections to the cortex and

the significance is unknown.
The main regions are the
somatosensory areas I and II


Thalamus lateral projections


are more involved in discrimination

and the medial projections in the
affective-motivational aspects of

Substantia Gelatinosa
(Rexed Laminae I and II)

Spinal Cord 2 main pathways

usually projects contralaterally to

the spinothalmic (discrimination)
or spinoparabrachial pathway
(affective regions), although some
pain pathways are ipsilateral

Primary afferent

Nociceptor may be
either a cutaneous receptor
which has both A and C
fibres or deep tissue which
is predominantly C fibres.

Basic pain pathways Physiological pain occurs when a noxious stimulus activates peripheral
nociceptors and is recognised as a potentially harmful stimulus. The pathophysiological processes
which include inflammation and nerve damage following injury or ischaemia, result in an altered
response and are therefore termed pathophysiological pain. Nociceptors are widespread in the skin,
muscle, connective tissues, blood vessels and viscera. They respond to mechanical, thermal, and
chemical stimuli. The main molecular events that control the excitability of of a primary neuron include
the opening and closing of voltage gated sodium or potassium channels. Primary afferent nociceptors
are pseudounipolar, with the cell body located in the dorsal root ganglion. The two main cutaneous
neuron types associated with noxious stimulation are the A fibres which are small myelinated fibres
responsible for localisation and sharp focussed pain responses more so in the cutaneous setting and
the C fibres which are slow unmyelinated fibres associate with dull diffuse pain and are found in higher
relative numbers on the viscera. In addition to having a preponderance of C fibres, the primary afferent
fibres in the deep tissues may elict repsonses such as sweating, increased blood presure and increased
respiratory rate.

Peripheral sensitisation is an excitatory modulation of the pain response in peripheral tissues. Part of

the inflammatory response is the release of intracellular contents from damaged cells such as
macrophages, lymphocytes and mast cells. Nociceptive stimulation also results in a neurogenic inflammatory response with the release of substance P, deurokinin A and calcitonin gene related peptide (CGRP)
from the peripheral terminals of nociceptor afferent fibres. The result is a reduction in the threshold for
firing of the afferent nerve and the so called peripheral sensitisation. Clinically this results in increased
sensitivity to both noxious and non-noxious pain (eg pressing a swollen inflammed tissue causes more
Central sensitisation beyond the primary area of hyperalgesia there is a secondary area of hyperalgesia where the threshold is not decreased. This region is explained by central sensitisation mechanisms
caused in the dorsal horn of the spinal cord which cause an excitatory modulation of the pain response.
These mechanisms include wind-up which is mediated by NMDA receptors and refers to a phenomenon
when repeated stimulus winds-up the neurons and may lead to a sustained response. There is also a
widening of receptor fields and this may be witnessed by the convergent (wide dynamic response WDR)
neurons in lamina V now sending pain signals to non noxious stimuli. The final mechanism disussed here is
long term potentiation, which relates to the increased efficacy of pathways that are repeatedly activated,
potentiating responses in the long term and implicated in chronic pain syndromes. The concept of central
sensitisation is fundamental to practice of pre-emptive analgesia which seeks to prevent these secondary
responses. Preventive analgesia is the persistence of analgesic treatment efficacy beyond its expected
duration. In clinical practice, preventive analgesia appears to be the most relevant and holds the most
hope for minimising chronic pain after surgery or trauma, possibly because it decreases central sensitisation and windup.
Pain Signal





A - fibre


Descending Pain Pathways


Spinal Modulation

Supraspinal Modulation

Primarily from the thalamus

and the periaqueductal grey
PAG of the midbrain and RVM
this projects inferiorly via
neurotramsitters such as
opiods, serotonin, alpha
adrenoceptors and norad

Characterised in terms of the Gate

Theory which is located in the substantia
gelatinosa, and the central sensitisation
mechanisms of wind up the activation of
wide dynamic range (convergent) neurons
in lamina V and long term potentiation LTP.

Grey PAG


Peripheral Modulation

is characterised by preipheral
sensitisation caused by a soup of
inflammatory mediators released
by afferent nerves (substance P and
CGRP) which and locally released
mediators decrease the signaling

Gate theory and central modulation was proposed as an explanation for modulation of the pain response. It is believed to
occur in the substantia gelatinosa. In this theory the information which arrives from the primary afferent nerve is modulated by an
inhibitory signal produced by an additional neuron. Essentially the A fibres are believed to augment this response and therefore
reduce pain signalling. The C Fibres are believed to reduce inhibition and therefore increase the pain signalling. It is possible to take
this concept further as some texts do and intergrate the supraspinal modulation as well, which would also influence the inhibitory
neuron through mediators such as opiods, alpha adrenoceptors, serotonin and noradrenaline.

SG = Substantia

Eicosanoids arachidonate metabolites, including prostaglandins, prostacyclin, thromboxane A2, leukotrienes, lipoxins, and
hepoxylinsare not stored but are produced by most cells when a variety of physical, chemical, and hormonal stimuli activate acyl
hydrolases that make arachidonate available. Prostaglandins (PGs), leukotrienes (LTs), and related compounds are called
eicosanoids, from the Greek eikosi (twenty). Precursor essential fatty acids contain 20 carbons and three, four, or five double
bonds. The production of protaglandins and leukotrienes occurs in a stepwise process which has several therapeutic targets and is
shown adjacent. Eicosanoids and PAF lipids contribute to inflammation, smooth muscle tone, hemostasis, thrombosis, parturition,
and gastrointestinal (GI) secretion. PGE2 Hyperalgesia, vasodilation, production gastric mucus, gastric acid, fever. PGI2 Hyperalgesia,
vasodilation, inhibit platelet aggregation, gastric mucus, renin release, natiuresis. TXA2 Platelet aggregation, vasocontriction. PGF2
Bronchoconstriction, unterine contraction. PGD2 Vasodilation, bronchoconstriction. Several classes of drugs, most notably aspirin,
the traditional nonsteroidal anti-inflammatory agents (NSAIDs), and the specific inhibitors of cyclooxygenase-2 (COX-2), such as the
coxibs, owe their principal therapeutic effects to blockade of eicosanoid formation.

Cell membrane phospholipids

glucocorticosteroids X
Arachidonic Acid
cycloxygenase (1 and 2)
NSAIDs & Aspirin
Prostaglandin H2 (PGH2)
Prostacyclin PGI2


Classification scheme for analgesics

Opioid Analgesics

Non Opioid Analgesics


Semi synthetic




Partial agonist

Complex Analgesic


Christopher Andersen 2012




Non selective
COX -2 selective

NMDA antagonists - Ketamine

Alpha2 Agonists - Clonidine
Antidepressants - Amitryptaline
Gases and Vapours
Substance P depletors
Hormones / Steroids

Opiates are drugs derived from the the opium plant, Papaver somniferum which contains morphine, codiene, thebaine and many other alkaloids. An opioid is a much
more general term which referes to all substances which bind opioid receptors. Opioids exert both peripheral and central anlagesic actions and they act on pain without
interfering with objective sensations such as touch and temperature. As noted on the previous page pain is made up of two components, fast and slow pain. The fast pain
is carried in through the neospinothalamic pathways and conducts well-localised objective aspects of painful sensations. Slow pain is transmitted rostrally more slowly
becuase of extensive synaptic interactions in the brainstem and limbic structures. It is poorly localised and responsible for the hurt or suffering associated with pain.
Opioid drugs specifically target slow pain. Patients will often report that the pain is still there but the hurt is gone.
Opioid receptors are members of the family of G protien coupled receptors. There are three major classes of opioid receptors , , and .

In general the opioid

receptors are inhibitory, acting primarily through the Gi and Go classes of G Protien. They inhibit andenylyl cyclase (, , and ) and can also stimulate K+ channel activity
( and ) and inibit Ca2+ channel activity (). They are present on both pre and post synaptic terminals. Although they share their ability to elict spinal and supraspinal
analgesia, their pharmacologic properties differ. Most of the clinically used opioids including methadone and the fentanyl series are relatively selective for receptors,
reflecting their similarity to morphine. The effects include analgesia, constipation and respiratory depression. Studies involving the use of the opioid antagonist
naloxonazine and the potent morphine metabolite morphine-6-glucuronide (M6G) have revealed at least three distinct subtypes of the receptor. The receptor are
divided into two known subtypes have similar effects to receptor but there are no agents acting on receptors available clinically. There are three subtypes.
Although several of the highly selective 1 produced analgesic effects the accompanying side effects have prevented their development. These side effects include a
significant diuretic action, psychotomimetic effects and dysphoria. The utilisation of the receptor is limited to the mixed agonist/antagonist drugs.

Endogenous opioid peptides

Pharmacologically endogenous peptides share many characteristics including the ability to produce analgesia. They are stored in
vesicles and upon release bind to the G Protien coupled opioid recptors. Endorphins exert their effects at all three receptors. The recently discovered endomorphins have
uniquely high selectivity for receptors. The receptors are highly selective for enkephalins. Dysnorphins are endogenous ligands for the K receptors. Regional
differences exist in the distribution of the various opioid peptides within the CNS. The enkaphalins are widely distributed, implying a wide range of actions beyond simple
analgesia. In contrast the -endorphin is limited to the pituitary and arcuate region of the hypothalamus, although these areas have
extensive projections. Although it unclear whether they act as classic neurotransmitters, they appear to inhibitory modulation at many
sites peripherally, spinally and supraspinally.
Piperidine ring
Structure activity relationship The most opioids have the general phenanthrene structure composed of a three ring nucleus, an
additional piperidine ring and a tertiary amine (red). Most of the substitution and variability occurs at the coloured areas. In particular
codiene is a morphine prodrug and this involves the removal of a methyl group at position 3 (coloured in blue) and replacement with
the hydroxyl group shown. This occurs via CYP2D6 and absence of this reduces codiene effect.

Therapeutic and adverse effects of opioids



Miosis - caused by excitatory action on parasympathetic nerve innervating the pupil

Nausea and vomiting produced by morphine-like drugs are caused by direct

Nervous System

Cough Morphine and related opioids also depress the cough reflex, at least partly

Respiratory system - caused by two mechanisms, direct inhibition of the

respiratory centre and indirectly by decreased consciousness

Stomach Morphine and other mu agonists usually decrease gastric acid secretion
and decrease motility prolonging digestion times

Cardiovascular system In the supine patient, therapeutic doses of morphine-like

opioids have no major effect on blood pressure or cardiac rate and rhythm. Such doses do produce
peripheral vasodilation, reduced peripheral resistance, and an inhibition of baroreceptor reflexes.
Therefore, when supine patients assume the upright position, orthostatic hypotension and fainting
may occur, although this is usually only in combination with pre-existing instability.

stimulation of the chemoreceptor trigger zone in the area postrema of the medulla.
by direct action on a cough center in the medulla.

Biliary tract After the subcutaneous injection of 10 mg morphine sulfate, the sphincter
of Oddi constricts, and the pressure in the common bile duct may rise more than tenfold within
15 minutes; this effect may persist for 2 hours or more.
Small Intestine Morphine diminishes biliary, pancreatic, and intestinal secretions
and delays digestion of food in the small intestine.
Large Intestine Propulsive peristaltic waves in the colon are diminished or abolished
after administration of morphine, and tone is increased to the point of spasm.

Urinary may cause urinary retention

produces analgesia and modulation of the pain response in

peripheral, spinal and supraspinal locations. May produce both euphoria and dysphoria. Decreases
Level of consciousness and may cause confusion. Can induce psychosis.

Musculoskeletal system may cause muscle rigidity which can impair respiratory function by
decreasing chest wall compliance.
Skin Therapeutic doses of morphine cause dilation of cutaneous blood vessels. The skin of the face,
neck, and upper thorax frequently becomes flushed. These changes may be due in part to the
release of histamine and may be responsible for the sweating and pruritus that occasionally follow
the systemic administration of morphine.

Time to 50% decrease (mins)

Routes of administration The lipid solubility of opioids largely determines the speed of onset and duration of intrathecal analgesia; hydrophilic drugs (eg morphine)
have a slower onset of action and longer halflives in cerebrospinal fluid with greater dorsal horn bioavailability and greater cephalad migration compared with lipophilic
opioids. Because of the hydrophilic nature of morphine, there is rostral spread of the drug in cerebrospinal fluid (CSF), and side effects, especially respiratory depression,
can emerge up to 24 hours later as the opioid reaches supraspinal respiratory control centers.The behaviour of epidural opioids is also governed largely by their lipid
solubility. The greater sequestration of lipid soluble opioids into epidural fat and slow rerelease back into the epidural space means that elimination from the epidural
space is prolonged, resulting in relatively smaller fractions of drug reaching the cerebrospinal fluid. Lipophilic opioids (eg fentanyl) have a faster onset but shorter duration
of action compared with hydrophilic drugs (eg morphine). Transdermal routes of administration are also determined by lipid solubility (hence the use of fentanyl patches).
There is a significant first pass metabolism with morphine (60-70%), therefore is often delivered via SC, IM or buccally.

Comparative pharmacology The duration of effect is dependent on the mechanism of administration, rate of



clearance, active metabolites and lipid solubility. Highly lipid soluble opioids rapidly cross the BBB and therefore have
higher potency, but because they rapidly distribute they often have a rapid offset in action (bolus fentanyl). Low lipid
soluble drugs like morphine have a longer duration of action.
The pKa determines the % ionised at physiological pH and therefore drugs such as alfentanil with a low pKa is mostly
non-ionised at 7.4 therefore are able to cross the BBB quickly as well increasing the speed of onset.


Fentanyl has similar pharmacokinetics to

thiopentone, it is rapidly distributed to tissues due
to its high lipid solubility but it has a slow
clearance. As a result it has a short duration of action if given as a bolus (redistribution), but repeat
dosing leads to a markedly higher duration of action due to an increased context sensitive half time.


Infusion duration (mins)


Remifentanil has a unique metabolic and pharmacokinetic profile. It undergoes rapid methyl ester
hydrolysis by tissue and plasma esterases (not plasma cholinesterase) to relatively inactive metabolites,
as a result its effect is terminated by metabolic clearance rather than redistribution. This results in a
rapid reduction in plasma concentration even during prolonged infusions and this is independent of
age, weight, sex, hepatic or renal function.
Dose equivalence is shown adjacent. Morphine is three times as potent IV compared to PO due to
bioavailability. Oxycodone and methadone and equipotent. Codiene is 10-15 times weaker. Tramadol is
10 times weaker. It should be noted that there is significant inter and intra-patient variability and
changing agents when a patient is tolerant to one opioid they may be less tolerant to another
regardless of equivalence.

Christopher Andersen 2012

(pH = 7.4)





























VdSS (l/kg)






Relative lipid


Equivalent dose
10mg morphine











0.5-1.0 mg



NSAIDs classification can be based on their cycloxygenase selectivity, on whether their enzyme inhibition is irreversible or reversible (aspirin versus others) or based

on their chemical structure. With regards to the last method the following categories are noted; salicylates (aspirin), arylproprionic acid (ibuprofen, naproxen),
arlyacetic acids (diclofenac, ketorolac) and oxicams (meloxicam, piroxicam). The route of administration for NSAIDs is usually oral, there is rapid absorption through the
small bowel (some are administered IV such as ketorolac, tenoxicam and parecoxib). NSAIDs are highly protien bound and have low volumes of distribution. The effects
of highly protien bound drugs (such as warfarin) may become potentiated as they become displaced. Characteristically these drugs are metabolised in the liver and
excreted in an inactive form in the urine and bile. Cycloxygenase exists as two isonzymes COX-1 and COX-2. COX-1 (the constitutive form) is responsible for the
production of prostaglandins that control renal blood flow and form the protective gastric mucosal barrier. In addition COX-1 mediates the synthesis of thromboxane.
A variant of COX-1 which has been called COX-3 exists centrally and is possibly the mechanism by which paracetamol reduces pain and pyrexia. COX-2 (the inducible
form) is produced in response to tissue damage and facilitates the inflammatory response. COX-2 aslo mediates the production of prostacyclin (PGI2) in vascular
endothelium. As a result COX-2 inhibitors may alter delicate thromboxane/prostacyclin balance in favour of platelet aggregation, vasocontriction and thromboembolism.

Aspirin is the acetylated derivative of salicylic acid, which is produced from the glycoside salicin obtained from willow bark. Aspirin is



most commonly used for its analgesic, antipyretic and anti-inflammatory effects. It is most effective in low intensity somatic pain,
rather than severe visceral pain. Aspirin also rapidly reduces body temperature in febrile patients. Bacterial pyrogens cause the release
of the inflammatory cytokines IL-1 and TNF-alpha increasing central PGE2 production by COX-3. Aspirin inhibits COX-3 as well as COX-1
and COX-2, decreases prostaglandin synthesis in the hypothalamus, and thus reduces body temperature. The anti-inflammatory effects
of aspirin are due to the decreased synthesis of prostaglandins, particularly by COX-2, although relatively high doses are usually
required. Aspirin irreversibly acetylates COX-1 in platelets, decreasing thromboxane synthesis and reducing their adhesiveness and
aggregation, so that the bleeding time is prolonged. A new generation of platelets must be formed from megakaryocytes before normal thromboxane production is
restored. In adults, acute overdosage with aspirin leads to an increase in metabolism and a rise in O2 consumption and CO2 production, due to an uncoupling of oxidative
phosphorylation. In addition, there are complex effects on acidbase balance. Toxic doses of aspirin produce a CSF acidosis, causing stimulation of the respiratory centre
and increased ventilation, with a rise in pH and a fall in PaCO2 . Terminally, an acidotic state due to respiratory and metabolic changes may occur. This is a common
presentation of severe aspirin overdosage.

Paracetamol has analgesic and antipyretic effects that are similar to aspirin, but little or no antiinflammatory activity. It is
generally accepted that it has little effect on extracerebral COX-1 or COX-2, although it inhibits central COX-3. Consequently, it
prevents the enhanced synthesis of prostaglandin E2 in the hypothalamus during pyrexia, and thus reduces elevated body
temperature. It has similar effects to aspirin on non-specific pain. Paracetamol is also synergistic with opioid medications,
reducing the overall opioid requirement by 20-30%.
At normal therapeutic dosages, primarily hepatic metabolism to sulfate and glucuronide conjugates, while a small
amount is metabolized by CYP2E1 to a highly reactive intermediate, N-acetyl-p-benzoquinoneimine (NAPQI),
which is conjugated rapidly with glutathione and inactivated to nontoxic cysteine and mercapturic acid
conjugates. At toxic doses (as little as 4 g daily) glutathione conjugation becomes insufficient to meet the
metabolic demand causing an increase in NAPQI concentrations, which may cause hepatic cell necrosis.


Conjugation with
-SH groups


The aim of treatment is to replenish glutathione and enact supportive management. The use of activated charcoal
may be indicated in some patients. It is useful to plot the serum paracetamol levels against a nomogram to help
predict likelhood of hepatocellular damage and help guide therapy. The standard therapy is N-acetylcystiene
infusions which most toxicologists agree replaces glutathione, therefore reducing hepatocellular damage. ALT is
generally to most sensitive marker of liver damage. Renal damage may also be prominent.

NMDA Antagonists The activation by excitatory amino acids (glutamate) of spinal cord dorsal horn N-methyl-D-aspartate (NMDA) receptors is essential for
development of central sensitisation after tissue damage. The anaesthetic ketamine is a potent NMDA receptor antagonist, and relatively low dose ketamine given
by subcutaneous or continuous infusion produces significant pain relief. A notable advantage of ketamine is that it is effective for both nociceptive and neuropathic
pain, which presents as a burning stinging pain with allodynia and dysesthesias. It may be of particular benefit with pain of a mixed nociceptive/neuropathic nature
such as cancer patients and burn victims. As discussed previously the side effects of this drug such as hallucinations limit its use.
2 Adrenoceptor Agonists clonidine and dexmedetomidine have been shown to provide effective analgesia after a variety of surgical procedures. Their use has
concentrated on the spinal or epidural administration of clonidine to take advantage of the known attentuating effect of stimulating spinal 2 receptors on pain
perception. In particular agents such as clonidine may reduce wind-up via inhibitory actions at wide dynamic range nerurones. In general 2 agonists are useful only as
adjuncts to conventional opioid analgesics because of side effects of sedation, hypotension, and bradycardia, which can be marked. Clonidine is also useful in opioid
withdrawal states and the treatment of complex regional pain syndromes.
Anticonvulsants are useful for the alleviation of neuropathic pain. Drugs used include carbamazepine, phenytoin, sodium valproate, and the newer agents such as

gabapentin. Suggested mechainsms of action include frequency dependent block of sodium channels, calcium channel blockade, and potentiation of GABA inhibition
of spinal nociceptive pathways through either increased release of reduced breakdown. The frequent adverse events have limited their use. One meta-analysis has
shown that in patients with trigeminal neuralgia the NNT with carbamazepiene is only 2.6, but the number needed to harm is a 3.4! Common side effects include
sedation, rashes, nausea, anorexia, dizziness, confusion, and ataxia. More serious side effects include blood dyscrasias, sub acute hepatic impairment, renal failure and
Stevens-Johnson syndrome. The newer agents such a gabapentin have a an improved safety profile but still precipitate the serious adverse events.

Tricyclic antidepressants are used to relieve neuropathic pain. All potentiate noradrenergic activity by inhibiting noradrenaline reuptake at nerve endings,
probably in descending modulatory inhibitory pain pathways. The anti-depressants have similar NNT and NNH profiles to the anticonvulsants and are again effective
for the treatment of neuropathic pain but are beset by poor side effect profiles, mostly related to the vagolytic effect. Some tricyclic side effects are transitory such as a
dry mouth and sedation, but others are more serious including postural hypotension, urinary retention, narrow angle glaucoma, paralytic illeus, and cardiac
arrythmias. SSRIs have safer side effect profile, have not demonstrated efficacy in the treatment of neuropathic pain. SNRIs may be effective in some forms of
neuropathic pain such as diabetic neuropathy.

A wide variety of pain conditions, both acute and chronic, may be accompanied by painful muscle spasm. Antispasmodics can be useful in treating
this aspect of the patient's symptoms, but their action may be more the result of sedation rather than muscle relaxation. Baclofen is the most commonly used drug in
this class. These medications may also cause CNS depression and should be used cautiously when combined with other CNS depressant medications.

Lignocaine The 5% lidocaine patch has shown efficacy and excellent tolerability in trials involving patients with postherpetic neuralgia and allodynia and in patients
with allodynia due to different types of peripheral neuropathic pain. Lidocaine gel (5%), which is less expensive than the patch, has also shown efficacy in patients with
postherpetic neuralgia and allodynia. Topical lidocaine is most appropriate for patients with well localized neuropathic pain. Although it can be used as monotherapy, it
is often used as an adjunct to systemic medication.
Substance P Depletor (Capsaicin) is an alkaloid derived from chili peppers; repeated application is thought to deplete substance P from primary afferent

neurons. Capsaicin is available as a cream (0.025% or 0.075%), and as a high concentration patch (8%). A systematic review found that capsaicin had moderate to poor
efficacy for relief of chronic musculoskeletal or neuropathic pain, but might be useful as an adjunctive therapy or for patients unresponsive to other treatments.
Capsaicin has been used in patients with post herpetic neuralgia, HIV neuropathy, and diabetic neuropathy.

Christopher Andersen 2012

Physiochemical characteristics and clinical relevance Local anaesthetics are weak bases and exist predomi-



nantly in the ionised form at neutral pH as their pKa exceeds 7.4. They fall into two groupings ester or amide, which
describes the linkage between aromatic lipophilic group and the hydrophilic amide group that each possess. Individual
structures confer different physiochemical and clinical characteristics. Potency is closely correlated to lipid solubility
(more so in vitro - but still significantly in vivo). The duration of action is closely associated with the extent of protien
binding. Local anaesthetics with limited protien binding have a short duration of action and conversely those with more
lipophilic end
hydrophilic end
extensive protien binding have a longer duration of action. The onset of action is closely related to the pKa. Local
anaesthetics are weak bases and exist mainly in the ionised form at normal pH. Those with a high pKa have a greater fraction present in the ionised form, which is
unable to penetrate the phospholipid membrane, resulting in a slow onset of action. Conversely, a low pKa reflects a higher proportion in the un-ionised form and
therefore a faster onset of action as more is available to cross the phospholipid membrane. A cororally of this characteristic is the decreased efficacy of local anaesthetics in bacterially infected tissues which, due to CO2 production are acidic and therfore exacerbates the difference between pKa and pH (in addition there is increased
vasodilation and blood flow which decreases the anaesthetic efficacy). The intrinsic vasodilator activity varies between drugs and influences both the potency and the
duration of action. In general local anaesthetics cause vasodilation in low concentrations (lignocaine>bupivacaine>ropivacaine) and vasoconstriction in higher doses.

Local anaesthetic toxicity can be caused by excessive amounts of the drug (max doses shown below), by rapid absorption and/or by impaired metabolism (such
as patients with cardiac failure and liver disease). Perhaps more commonly it is seen after accidental intravascular injection. Systemic toxicity of local anaesthetics is
concentration dependent, with CNS toxicity occuring a lower concentrations than cardiac toxicity.

Lignocaine blood
concentration g/mL





Therapeutic range

Mild CNS excitation

Severe CNS excitation

CNS Inhibition

Cardiac depression

antiarrhythmic effects

altered sound perception
circumoral numbeness

muscle twitching

central cardiorespiratory

impaired cardiac conduction

decreased contractility
cardiac arrest

More potent local anaesthetics, such as bupivacaine and ropivacaine also produce systemic toxicity but at lower levels. Bupivacaine has extremely high potency at
cardiac Na+ channels such that the cardaic symptoms occur prior to CNS symptoms. It appears that the R (+) enantiomer of local anaesthetics has greater affinity for the
cardiac Na+ channels which has lead to the development of S (-) enantiomer drugs levobupivacaine and ropivacaine. Other toxicity issues include anaphylaxis which is
gerenally rare, transient neurological syndrome associated with intrathecal lignocaine and methemoglobinaemia which is associated with prilocaine.

Prevention and management Prevention involves ensuring the patient is not overdosed by using the reference values, using with caution in patients with
congestive cardiac failure and liver failure, and being aware of the vascularity and risk of direct intravascular injection. Management of the situation if toxicity is
suspected, involves stopping the injection immediately and prepare to treat the reaction. Aggressive resuscitation is indicated in most cases following ACLS protocols.
Benzodiazepines are the drugs of choice for seizure control. Phenytoin is not effective and should be avoided. Propofol can be used to control seizures but has the risk
of potentiating cardiovascular toxicity. In severe reactions, monitor the cardiovascular system (CVS) and support the patient with intravenous fluids and vasoactives as
required. Small boluses doses of adrenaline are preferred. Vasopressin is not recommended. Amiodarone is the drug of choice for ventricular arrhythmias due to local
anesthetic toxicity.



Classification of local anaesthetic (amide / ester)



Relative potency (lipid solubility)

8 times more potent

Toxic dose
Toxic dose with adrenaline



Toxic plasma concentration

>1.5 mcg/kg

>5 mcg/kg

Protien binding (duration of action)



Elimination half time

160 minutes

100 minutes

pKa (onset of action)

% un-ionised at physiological pH 7.4



Christopher Andersen 2012


The ideal intravenous anaesthetic agent. May be described in terms of the pharmaceutical aspects, the pharmacokinetic and pharmacodynamic perspective.
From a pharmaceutical perspective it should be soluble in water, stable in solution, not require reconstitution, stable in the presence of air, light and temperature, not
support bacterial growth, be compatible with outer drugs and fluids, have no additives and be inexpensive. From a pharmacokinetic perspective it should have a rapid
onset of action, high lipid solubility (needs to cross BBB), be non cumulative during infusion, have a rapid and predictable recovery, be completely metabolised to
inactive metabolites, and be safe in renal or hepatic impairment without adjustment. From a pharmocodynamic perspective it shoul not cause pain on injection, and
be safe if it extravasates, have no adverse drug reactions, have a smooth induction, demonstrate analgesic, antiemetic, antiepileptic properties, and muscle relaxation.
It should not cause emergence phenomena, not modify cerebral blood flow, ICP or intra-occular pressure and decrease brain O2 requirements. It should have minimal
cardiovascular or respiratory depression or stimulation. Be safe in paediatric, pregnant and elderly populations.
Factors which affect recovery from IV anaesthesia

Context sensitive half-time (mins)

may be subdivided into surgery factors, patient factors and anaesthetic factors. The surgery factors relate
to the type of procedure, , its duration, and the intraopertaive complications. whether it is planned or emergent. The patient factors relate both to pre-existing disease,
body habitus, sex, age and current disease state which may complicate the common sequelae of GA recovery. Physiological changes accompanying emergence from
general anesthesia can be profound. It is easiest to think of this in terms of systems. Cardiovascular issues are driven by the sympathetic nervous system regaining tone.
Hypertension and tachycardia are common, which is enhanced by pain. Myocardial ischemia can appear or markedly worsen during emergence in patients with
coronary artery disease. Neurologically, emergence excitement occurs in 530% of patients and is characterized by tachycardia, restlessness, crying, moaning and
thrashing, and various neurological signs. This may be exacerbated in people with pre-exisiting behavioural disturbances and psychiatric conditions. Postanesthesia
shivering occurs frequently because of core hypothermia or a delay in the return of central nervous system function compared to peripheral nervous system. Respiratory
issues are significant and exacerbated significantly by prexisting disease such as COPD, restrictive lung disease or sleep apnoea. Airway obstruction may occur during
the postoperative period because residual anaesthetic effects continue to partially obtund consciousness and reflexes. Strong inspiratory efforts against a closed glottis
can lead to negative pressure pulmonary edema. Pulmonary function is reduced postoperatively following all types of anesthesia and surgery, and hypoxemia may
occur. Respiratory suppression associated with opioids can be problematic among postoperative patients with a substantial residual anesthetic effect. Intevention
factors relate both to the procedure performed and the agents employed to maintain the general anaesthesia.
Anaesthetic factors relate to the anaesthesia strategy employed, in particular the type of anaesthesia employed (volatile,
mixed or TIVA). The focus here is on the IV agents. Most of the IV GA agents are characterised by rapid emergence from
GA when given as a bolus, this is due to generally to their redistribution (they are lipophilic to ensure good penetrate to
the CNS) and metabolism. When given as an infusion however context sensitive half times become more important and
this varies considerably between agents. After prolonged infusions, drug half-lives and durations of action are dependMidazolam
ent on a complex interaction between the rate of redistribution of the drug, the amount of drug accumulated in fat, and
the drugs metabolic rate. This phenomenon has been termed the context-sensitive half-time; that is, the half-time of a
drug can be estimated only if one knows the contextthe total dose and over what time period it has been given.
Propofol is rapidly metabolised and has a clearance which exceeds hepatic blood flow suggesting extrahepatic
metabolism. Although clearing the central compartment rapidly, it has a prolonged terminal half life, probably due to
slow release from fat. In prolonged infusions the terminal half life may stretch out to 60 hours but the context sensitive
Infusion duration (hours)
half time does not increase significantly and therefore waking may remain relatively rapid. Thiopentone is also rapidly
distributed to other tissues and this explains the rapid recovery from a single dose (rather than metabolism). When given as an infusion however compartments are
rapidly saturated and the duration of action becomes dependent on the terminal half life and the clearance of the liver which is slow for thio (and may become
saturated - therefore zero order) leading to an increased context sensitive half time. Midazolam is metabolised to metabolites which are cleared quickly in contrast to
diazepam and this accounts for the marked difference in their context sensitive half times (following bolus the recovery profile is similar). Ketamine, like the other drugs
discussed here is rapidly distributed to tissues. It is metabolised hepatically to an active metabolite but it does not have a significantly increased context sensitive half
time. Indeed it may induced hepatic enzymes which leads to tolerance with repeated dosing. Of note in terms of recovery is the marked neurological emergence issues
associated with ketamine.




















Midazolam is presented as a clear

solution at a pH of 3.5. At this pH is almost completely
ionised and therefore water soluble. Since its pKa is 6.5
it is 89% un-ionised at physiological pH and can
therefore cross lipid membranes.

The sodium salt is a pale yellowish-white powder with

a bitter taste and an garlic-like odour. It readily
dissolves in deionized water producing an alkaline
solution due to its ionized sulphur atom (S), which
has strongly basic properties and attracts H+. Once
reconstituted it is stable for ~ one week.

Propofol is a achrial. lipophilic, sterically hindered

alkylated phenol. It is presented as a 1% preparation
and appears a a white opaque liquid-water emulsion
containing soya bean oil or purified egg phosphatide.
It is a weak organic acid with a pKa of 11 and is
therefore almost entirely un-ionised at pH 7.4.

Ketamine is presented as a racemic mixture or as the

single S (+) enantiomer which is 2-3 times as potent,
more quickly metabolised and has less severe
side-effects than as the R (-) enantiomer. It is soluble in
water forming an acidic solution pH 3.5-5.5. It comes in
liquid solution, 100mg/mL in 2mL vials.



Appears to exert its main action by
facilitating GABAA mediated Cl
influx. May also block Na+, NMDA
and Ca2+ channels. It is more
promiscious in affecting multiple
sites compared to Propofol.


Potentiates and directly gates
GABAA facilitating its action. May
have some Na+ and Ca2+ channels
blocking action. 5HT has been
implicated as the reason it has
antiemetic properties.


Distinct from the other IVGAs in
that its primary action is NMDA non
competitive antagonism. Has some
opiod, nicotinic, monoamine
oxidase, Na+, and Ca2 actions as well.


Binds to the gamma subunit of the
GABAA receptor, increasing the
affinity of the receptor to GABA.


Reduced neuronal activity is reflected in a

dose-dependent depression of the EEG, progressing
from an awake pattern to high amplitude / low freq
and activity to burst suppression and
subsequently electrical silence. There is a
corresponding decrease in cerebral blood flow and
Thio may reduce ICP refractory to mannitol and
hyperventilation. At maximal effect it may reduce
cerebral metabolism by as much as 55%.

The nervous system effects of propofol are similar to

those of thiopentone. It has several unique
charateristics including antiemetic and antipruritic
properties which may result from neuro actions at a
subcortical level. Subhypnotic doses may provide
some analgesia in contrast to thio which may be
antalgesic. It has anticonvulsant properties. It exhibits
pharmacological synergism with benzodiazepienes
and opiods allowing reduction in doses.

In keeping with its distinct mechanism of action, the

clinical effects are also distinct. The CNS effects are
characterised by a dissociation between the
thalamocortical and limbic systems, and the clinical
result is intense analgesia, amnesia and a cataleptic
like state of non responsiveness. Psychedelic effects
and emergence reactions are a major issue. It is a
potent cerebrovasodilator, increasing CBF, ICP and
CMRO2 and is relatively contraindicated in neuro sx.


Thio delivered by bolus causes a transient decrease in

aterial pressure and CO, and increase in heart rate and
no change in or a small increase in TPR. The decrease
in BP is caused by venodilation and reduced preload.
Higher doses reduce myocardial contractility but
lower doses have little effect. The increase in HR is
barorecepetor mediated. These effects are dangerous
in pts with IHD, CCF, tamponade and valve disease.

Propofol decreases BP by 15-40%, reductions are

generally greater than with similar doses of thio.
There are significant reductions in TPR and preload
with little effect on contractility. Propofol resets
baroreceptor control of HR leading to unchanged HR
despite a BP drop. It is not arrythmogenic nor does it
sensitise to catecholamins. Haemodynamic effects are
worse in elderly, hypovolaemic and LV dysfunction.

The cardiovascular effects of ketamine result primarily

from inhibition of catecholamine reuptake and
potentiation norad release from sympathetic ganglia.
The direct action of ketamine is actually negatively
iontropic and vasodilatory but indirect effects of
catecholamines usually predominates. In patients
with depleted catecholamine stores ketamine may
result in profound hypotension.


Anaesthetic barbiturates are potent central respiratory

depressants. They produce dose-dependent decreases
in both minute volume and tidal volume. Medullary
responses to hypercapnia and hypoxia are depressed.
Induction doses do not inhibit airway reflexes,
therefore laryngospasm and bronchospasm can occur.

Propofol is a potent respiratory depressant and may

cause a 30-60 second period of apnoea at induction.
There is greater depression of laryngeal reflexes when
compared with thio, therefore reducing risk of
laryngospasm. In contrast to thio it causes some

Ketamine doesnt depress CO2 responsiveness. RR may

decrease during induction and rarely there is apnoea.
Upper airway reflexes and muscle tone are maintained,
the FRC is usually unchanged which differs from the
other IVGAs. There is an bronchial secretions (risk of
cough/laryngospasm) but also bronchodilation.

PHARMACOKINETICS (also see drug cards)

Midazolam is metabolised hepatically into an active
metabolite but cleared quickly and has a short context
sensitive half time.

Following infusion develops zero order kinetics and

subsequently slow context sensitive half time (doses
should be calculated according to Vd steady state).

Unlike thio it has a much more rapid clearance in the

central compartment, therefore despite a Vdss which is
greater than thio it has a much more rapid recovery.
Does adjustment is not required in renal or hepatic

Like all the IVGAs it demonstrates rapid distribution

due to the lipophilicity. Ketamine has high hepatic
clearance which approximates hepatic blood flow.
There is an active metabolite norketamine. May
demonstrate tolerance.

Midazolam, like all of the benzodiazepienes is a

hypnotic, anxiolytic, anticonvulsant and amnesic
agent. Benzodiazepienes reduce the cerebral
metabolic rate of O2 -CMRO2, cerebral blood flow and
suppress rapid eye movement - REM sleep.

Midazolam has minimal cardiovascular effects.

Induction doses may cause modest haemodynamic
effects, mostly attributable to a decrease of TPR.

Benzodiazepienes alone cause minimal respiratory

depression but they have marked synergistic
interactions with other respiratory depressants, such
as volatile anaesthetics and opoids.

Christopher Andersen 2012