Mekelle University, college of health

science ,Department of Anesthesiology

Pharmacology for Anaesthetists

by; Hagos G.(MSc. in anaesthesia)

Stages of anesthesia

• StageI; Disorientation, altered

consciousness, in adequet Analgesia, Vital
signs are normal
• StageII; Excitatory stage, delirium,
uncontrolled movement, irregular
breathing possible nausea and vomiting
can occur
• Goal is to move through this stage as
rapidly as possibly

2
cont…
• Stage III : Surgical anesthesia
Plane 1: “light” anesthesia
Plane 2: Loss of blink reflex, regular respiration .
Surgical procedures can be performed at this
stage.

Plane 3: Deep anesthesia. Shallow breathing,

assisted ventilation needed. Level of anesthesia
for painful surgeries

Plane 4: Diaphragmatic respiration only, assisted

ventilation is required. Cardiovascular impairment.

3
Cont…
• Stage IV : Medullary paralysis –
respiratory and vasomotor control ceases
• Too deep; essentially an overdose and
represents anesthetic crisis. This is the
stage between respiratory arrest and
death due to circulatory collapse.

4
pharmacology
• Pharmacology; is the sciences of drug.
 It deals with history, source, physical
and chemical properties of drugs,
mechanism of action, absorption,
distribution, biotransformation,
excretion, and the use of drugs.
• Drug-it is a single chemical agent used in
the prevention, diagnosis and treatment of
disease.

5
Cont..
• Pharmacy-it is the art and science of
compounding and dispending drugs.
• Clinical pharmacology-it is the scientific
study of drugs in man.
• Chemotherapy-treatment of systemic
infection/any disease with specific drugs
that have selective toxicity for the
infecting/ malignant cell with no or minimal
effect to the host cells.

6
Cont…

• Toxicology-is the science of poisons and

poisoning
• Teratogenicity-administration of certain
drugs in the first trimester of pregnancy i.e
period of organogenesis which result in
fetal deformity

7
Principles of drug action

The basic types of drug action can be

grouped as follows
• Depression: it is a selective depression of
the targeted cells. Example barbiturates
• Stimulation: selective enhancement of
the activity of specialized cells. Example
adrenaline stimulates the heart

8
Cont…
• Irritation: these are non selective, often
noxious effect. Strong irritation often
results in inflammation and tissue narcosis
and morphological damage.
• Replacement: it is replacement of
hormones or their congeners in deficiency
states. Example- insulin for diabetes
mellitus, levodopa for parkinsonism
• Cytotoxic : selective cytotoxic action for
invading parasites or cancer cell to
attenuate them without harming the host
cell
9
Mechanism of drug action

– Physical action-it is simply by

physical interaction of the drug to our
body- by osmotic activity
– Chemical action-the drug reacts extra
cellular according to simple chemical
equation.eg. acid - base neutralization
– Enzymes – can be induction or
inhibition
– Through receptors-important terms in
relation to drug receptor are;
10
Mechanism…
• Affinity – the ability to combine with the
receptor
• Efficacy/ intrinsic activity – the a ability to
produce a response
• Agonist – is an agent that produces both
affinity and efficacy. Eg adrenaline is agonist
of adrenergic receptors
• Anatagonist – an agent that has only affinity
but no have intrinsic activity. Eg. Naloxon is
a pure anatagonist of opoid receptor

11
Drug antagonism…

I. Competitive Antagonism; is the most

frequently encountered type of drug antagonism in
clinical practice
 The antagonist has little or no efficacy
II. Physiological; agonist and antagonist have
different sites of cellular action. example is
acetylcholine and epinephrine.
III. Chemical antagonism; involves a direct
chemical interaction between the agonist and
antagonist in such a way as to render the agonist
pharmacologically inactive.

12
Drug interactions
 Pharmacokinetic interaction;
– Out side the body-precipitation of thiopental
with sux. Mixture
– At the site of absorption; e.g. effect of opioids
and metoclopramide on gastric empting
– use of vasoconstrictors to delay local
anesthetic drug absorption, second gas effect
– Affecting metabolism-enzyme
induction/inhibition e.g.. Cimetidine(inhibition)
or barbiturates(induction)

13
Cont…

 pharmacodynamics;
• summation-net effect equals sum of
individual drug effect
• synergism-net effect exceeds the sum of
individual drug effects
• Potentiation-one drug increases the
effect of another

14
Description of drug action
• Desensitization; decrease in cellular
sensitivity or response due to repeated
exposure to agonists
 Acute desensitization:- usually occurs rapidly
and readily reversible
Chronic desensitization:-usually develops
slowly and less readily reversible
– May occur due to receptor loss in
pathological conditions associated with
autoimmune process(eg myasthenia
gravis)

15
Description of …
• Tolerance :-the requirement of higher
dose to produce similar response
It can be either natural or acquired
1.Natural tolerance; it may exist in
certain species
 E.g. rabbits are resistant to
atropine because of atropinase
 Dark skinned races such as
negroes require large dose of
ephedrine
16
Cont…
2.Acquired tolerance; it is of the
following types
I. Acute (Tachyphylaxis);rapid decrease
in pharmacological response. This is
classically observed after the
administration of indirect acting
sympathomimetic like;
ephedrine,amphatamine

17
Cont…
II. Chronic tolerance;
A. pharmacokinetic tolerance ; drug
induced hepatic microsomal enzymes
responsible for the degradation of other
drugs.e.g barbiturates so pts can tolerate
large dose of drugs like phenitoin and
warfarin.

18
Cont…
B . Pharmacodynamic tolerance; this
occurs at cellular level where adaptive
changes with in the affected system
result in reduced response to a drug on
chronic administration.
C. Cross tolerance; development of
tolerance to pharmacologically related
drugs,e.g alcoholics are capable of
tolerating large dose of barbiturates
and general anesthetics.

19
Basic principles of drug calculation

• Drugs in anaesthesia are commonly

expressed in grams, milligrams or
micrograms which refer to their mass.
• Examples: 500mg thiopentone,
600mcg atropine. The words milli-, micro-
and nano- which appear in front of “gram”
refer to how many multiples of 10 are
present

20
Percent weight in volume
• This is expressed as % w/v which is to
mean the number of gram of a solute
dissolved in 100ml of a solvent
• When using drugs prepared in this way it
is necessary to calculate the number of
mg in ml of solution.
• This is easiest done by multiplying the
percentage of the solution by 10.
• E.g. 2.5% of any drug means there is 25
mg/ml of that specific drug.
21
Cont…

• total miliequivalent /L =
mg%of a sub.x valencyx10
atomic wt or mw
• e.g. The normal calcium level in the blood
is 10%. What is the normal value in
terms of meq/l?
The atomic wt of calcium is 40, and valency
is 2;

22
Basic drug calculation cont….

• Drug mass units

 1 gram=1000mg=100,000microgram
 1L=1000ml
 1ml=15-20 drops in a normal iv infusion

23
Calculation of infusion rates

•The flow rate of intravenous of fluid and/or

drugs may be expressed interms of ml/hr or
drop/min.
• Fluid/drug in ml/hr or drop/min =
total fluid to be run in ml x drop factor
total time in minute
Where drop factor is 15-20
E.g .1000 ml in 4 hrs is 83 drops/min,(drop
factor 20 gtt)

24
Cont….
• To calculate the desired drug concentration
– Use the formula; Dc = Av
Ac Dv
WHERE;
Dv- desired concentration
Dv- desired volume
Ac- available concentration
Av- available volume
• To express a ratio (e.g. 1:200) as a percentage, the
following formula is used (R = ratio):
R x 100 = %,

25
Cont…

E.g.. 1. How many mls of diluents is

required to prepare1:200,000 adrenaline
solutions from 10ml of0.01%
concentrated adrenaline solution
2. What would be the drops/min of
oxytocin (40 IU)in 500ml ,to be run in 4hrs
postoperatively to prevent PPH.(DF 20
gtt)

26
 Pharmacokinetics (assignment )

Achieving the appropriate drug effects

at any time during surgery, at the end
of surgery, and after surgery is an
important objective of anesthesia.
From a pharmacologic perspective,
anesthesia is concerned with
controlling the time course of drug
effect.
Cont…

• What the body does to drug

• Study of how drugs enter the body, reach
their site of action and are eliminated from
the body
• Absorption
• Distribution
• Metabolism
• excretion

28
Absorption

• It is transfer of drugs from site of

administration to blood stream
• Rate and efficiency depends on rout of
administration

29
 Physical factors influencing
absorption
• Blood flow to the absorption site
• Total surface area available for absorption
• Contact time at the absorption surface
 Bioavailability
it is fraction of administered drug that
reaches the systemic circulation

30
Factors that influence bioavailability
• First-pass hepatic metabolism
• Solubility of drug
• Nature of the drug formulation

31
Drug distribution

• Distribution plays a key role in anesthetic

pharmacology because it is a major
determinant of end-organ drug
concentration.
• A drug’s distribution depends primarily on
- Organ perfusion
- Protein binding and
- Lipid solubility

32
Cont…
• After absorption, a drug is distributed by the
bloodstream throughout the body.
• Highly perfused organs(the vessel-rich group)
take up a disproportionately large amount of
drug compared with less perfused organs(the
muscle, fat, and vessel-poor group).
• As long as a drug is bound to a plasma
protein, it is unavailable for uptake by an
organ regardless of the extent of perfusion to
that organ.
33
Cont…
• After, the highly perfused organs are
saturated during initial distribution, the greater
mass of the less perfused organs continue to
take up drug from the bloodstream
• As plasma concentration falls, some drug
leaves the highly perfused organs to maintain
equilibrium.
• This redistribution from the vessel-rich group
is responsible for termination of effect of
many anesthetic drugs

34
Rules of drug administration-

6R’S
• The right drug
• The right dose
• The right patient
• The right route
• The right time
• The right documentation

35
ROUTES OF ADMINISTRATION
• Orally
• Rectally:
• Inhalation: Absorption through mucous
membranes:
• Topical:
• Parenteral:
– Intravenous:
– Intramuscular:
– Subcutaneous
– Intra muscular

36
Routes of Administration cont..

37
Drug Metabolism

• The chemical modification of drugs with

the overall goal of getting rid of the drug
• Enzymes are typically involved in
Metabolism
drug------metabolism-----more polar
drug-----excretion

38
Consequences of Metabolism

• Drug Metabolism = Drug Inactivation

• The metabolite may have:
 Equal activity of the drug
 No or reduced activity of the drug
 Increase activity (Pro drug)
 Toxic properties, not seen with the parent
drug

39
Metabolic reactions
• There are two main patterns of drug
metabolism. These are:
1) phase l
2) phase ll
phase i:it includes;
a. Oxidation
b. Reduction
c. hydrolysis

40
Phase I

Oxidation:
• is the addition of oxygen and/or the
removal of hydrogen. Most oxidation steps
occur in the endoplasmic reticulum. The
most important enzyme: microsomal P-
450

41
Phase l cont…
Reduction:
• Add a hydrogen or remove oxygenazo (-
N=N-) or nitro groups (-NO2) ----->
amines (-NH2)
for example nitrazepam
Hydrolysis
• Addition of water with breakdown of
molecule
In blood plasma (esterases) and liver

42
Phase II
• Also known as conjugation reaction
– it involves the addition of molecules naturally
present in the body to the drug molecule.The
drug
may have undergone a phase I reaction
a.Glucuronidation: main conjugation reaction
in the body. This occurs in the liver.
– Natural substrates are; bilirubin and thyroxin
• b. Acylation. Acylation, especially
acetylation with the acetyl group, e.g.
sulfonamides
43
Phase ll cont…

c. Glycine: Glycine addition

(NH2CH2COOH) for example; nicotinic
acid
d. Sulfate: Sulfate (-SO4) for example
morphine, paracetamol

44
Elimination

• Elimination Half Time

• Time for plasma concentration to decline
by 50%
• Elimination Half Life
• Time for 50% of a drug to be eliminated
from the body

45
Elimination
• Elimination = all the various processes that
terminate the presence of a drug in the body.
• Processes:
- metabolism
- renal excretion
- hepato-biliary excretion
- pulmonary excretion (inhaled
anesthetics mainly)
- other: saliva, sweat, breast milk, tears

46
Renal Excretion
• Both metabolically changed and
unchanged drugs
• LMW substances: filtered from blood
through the Bowman membrane of the
capsule
• Some: actively secreted
• Reabsorption in the tubule: depending
on the lipid solubility, degree of ionization,
molecular shape, carrier mechanism (for
some)
47
Renal Excretion cont…
• Weak acid: best reabsorbed from an
acidic urine.
• Important to know if the drug is
dependent on renal function or excretion.

48
Hepatobiliary Excretion

• Drugs metabolites – excreted in the

intestinal tract with the bile.
• Majority: reabsorbed into the blood and
excreted through urine. (enterohepatic
cycle).

49
Pulmonary Excretion

• Volatile anesthetics and anesthetic gases:

in large part eliminated unchanged
through the lung

50
Intravenous anesthetics
• These are drugs that, when given
intravenously in an appropriate dose, cause a
rapid loss of consciousness.
• These drugs commonly used in anaesthesia
practice :
 To induce Anaesthesia prior to other drugs being
given to maintain Anaesthesia
 As the sole drug for short procedures
 To maintain anaesthesia for longer procedures by
intravenous infusion
 To provide sedation.

51
 Ideal properties of iv anesthetic
agents
• stable in solution
• Long shelf life
• No pain on intravenous injection
• Safe in intra arterial injection
• Non-irritant
• Compatible with other drugs/solutions
• cheap

52
Ideal properties cont…
• Rapid onset (mainly unionized
at physiological pH)
• High lipid solubility
• Rapid clearance
• Organ independent metabolism
• No active/toxic metabolites
• High therapeutic ratio
• Minimal CVS and Resp. effects

53
Ideal properties cont…
• No histamine release/hypersensitivity
• No emetic effects
• No involuntary movements
• No emergence phenomena
• No adrenal suppression
• Analgesic at sub-anesthetic doses

54
Cont…

 no single anesthetic agent meets the

ideal
 so, a combination of drugs is used to;
 take advantage of their best properties
 minimize the undesirable side effects

55
 Classification of IV Anesthetic
drugs
Class examples
•Phencyclidines - ketamine
•Barbiturates - thiopental, methohexital
•Phenols - propofol
•Imidazoles - etomidate
•benzodiazepines - midazolam

56
Barbiturates

Mechanism of action
•depress the reticular activating system—a
complex polysynaptic network of neurons and
regulatory centers—located in the brain stem that
controls several vital functions, including
consciousness.
•They suppress transmission of excitatory
neurotransmitters (e.g., acetylcholine) and
enhance transmission of inhibitory
neurotransmitters (GABA)
57
Cont…

• Barbiturates are barbituric acid derivatives.

• They have hypnotic potency and
anticonvulsant activity.
• Examples of barbiturates
- Thiopental
- Methohexital
- Pentobarbital
- phentobarbital

58
Cont…
•Barbituric acid is formed by the condensation of
urea and malonic acid

59
Cont…

60
• X is oxygen (oxybarbiturates) or sulfur
(thiobarbiturates).
• The thiobarbiturates such as thiopentone are
generally more lipid-soluble and so have a
more rapid onset of action.
• R3 is usually hydrogen, but in the case of
methohexitone a methyl group is substituted
which increases convulsive effect and shortens
elimination half-life.

61
• The R1 and R2 groups can be short alkyl or
aryl chains in the hypnotic barbiturates or
longer (more than 5 carbon) chains in the
anticonvulsants.
• Branched chains give greater hypnotic than
anticonvulsant effect.
• Phenobarbitone has phenol and ethyl groups
at R1 and R2 and is an anticonvulsant

62
Absorption
•In clinical anesthesiology, barbiturates are
administered intravenously for induction of
general anesthesia. Exceptions include rectal
thiopental or methohexital for induction in
children and intramuscular pentobarbital
Distribution
•The duration of action of highly lipid-soluble
barbiturates(e.g. Thiopental) is determined by
redistribution, not metabolism or elimination.

63
Thiopental
(thiopentone)
redistri-
bution in
muscle
and fat

64
Biotransformation
•Biotransformation of barbiturates principally
involves hepatic oxidation to inactive water-
soluble metabolites.
Excretion
•High protein binding decreases barbiturate
glomerular filtration, whereas high lipid
solubility tends to increase renal tubular
reabsorption.

65
Thiopental

• Sodium salt in powder with 6% sodium

carbonate and nitrogen to enable an alkaline
solution.
 Na2CO3 + H2O NaHCO3 + NaOH
• Incompatible with acidic drugs.
• 500mg/vial - 2.5% solution is stable for 48 hrs
and bacteriostatic Solution with pH – 10.5

66
Cont…

• 65-85% protein bound

• pKa 7.6(weak acid)- unionized- 60% at pH
7.4
• Vd 2.5L/kg
• Hepatic oxidation (P450) to mostly inactive
metabolites
• t½=11h.
• Enzyme induction occurs post single dose
• Induction dose 3-5mg/kg IV
67
Pharmacodynamics of thiopental

• CNS; Single dose induces GA in 30 -40 sec,

classical description ‘one arm brain
circulation’ with clear end point
decrease in: CMRO2, CBF, ICP , IOP
• CVS; : decrease in SVR, VR, CO,
Vasodilatation, produce reflex tachycardia.
• More pronounced in hypovolemia, acidosis,
reduced protein binding

68
Cont…
• R/S; decrease in RR/ TV/Apnoea, preserves airway
reflexes, bronchospasm (Histamine release)
Blunt response to hypoxia/hypercarbia
• Renal; decrease in UO (due to increased ADH from
CNS depression and decrease in COP
• Other; Anaphylaxis, Precipitates acute porphyric
crises (absolute contraindication)
• Painful injection,necrosis with extravasation,
• Catastrophic with intra arterial injection

69
•Indications of thiopental
-induction of anesthesia
-maintenance of anesthesia for short procedures
-control of convulsive states
-for supplement of regional anesthesia
•Absolute contraindications
-airway obstruction
-status asthmathicus
-unavailability of equipment for conduction of general
anaesthesia
- severe cardiovascular collapse and shock
-porphyria
-previous hypersensitivity
70
cont…

PRECUATIONS
•CVS disease
•severe hepatic disease
• renal diseases
•Extremes of age

71
Methohexitone

• Reconstituted to form a 1% solution

• Excitatory phase prior to onset of GA, has
precipitated seizures in patients with Hx
epilepsy
• Higher hepatic clearance than
thiopentone(11ml/min/kg Vs 3.4) ~ faster
offset with no hangover.
•70- 80% protein bound and unionized (76%)
Dose is 1-2mg/kg
72
Ketamine

Mechanism of Action
•In contrast to the depression of the reticular
activating system induced by thiopental,
ketamine functionally “dissociates” the
thalamus(which signals sensory impulses from
the reticular activating system to the cerebral
cortex) from the limbic cortex (which is
involved with awareness of sensation).

73
Ketamine

• nonbarbiturate, rapid acting general anesthetic

• dissociated from the environment, immobile,
and unresponsive to pain
• profound analgesic
• selectively blocks the associative pathways
producing sensory blockade

74
Ketamin cont…

• Preserved pharyngeal-laryngeal reflexes

• normal or slightly enhanced skeletal muscle
tone
• cardiovascular and respiratory stimulation

75
Absorption
•Ketamine is administered intravenously or
intramuscularly.
•Peak plasma levels are usually achieved within
10-15min after IM injection.
Distribution
•Ketamine is more lipid soluble and less protein
bound than thiopental.
•Awakening from ketamine anesthesia is due to
redistribution to peripheral compartments.
76
Biotransformation
•Ketamine is biotransformed in the liver to
several metabolites, some of which (e.g.
norketamine) retain anesthetic activity.
•End products of biotransformation are excreted
renally.

77
Indications of Ketamine

• sole agent for procedures that do not require

skeletal muscle relaxation
• induction of anesthesia prior to the
administration of other anesthetic agents
• Post op /chronic pain manegment
• supplementation of low potency agents

78
Caution and contraindications of
ketamine
• lack of knowledge of the drug
• lack of resuscitative equipment
• inability to maintain a patent airways
• allergy to ketamine
• history of psychosis
• cerebro-vascular disease
• Patients for whom hypertension is hazardous
• Raised intracranial pressure
• Open eye procedures
79
Dose and routes Ketamine

• can be injected IM or IV
• Induction of anesthesia: 1-2 mg/kg Slow IV
• Maintenance: 30-90 mcg/kg/min IV drip or
0.2-0.5mg/kg every 10-15 min.
• Intramuscular: 5-10 mg/kg IM
• 10 mg/kg IM will produce approximately 12-
25 min of surgical plane.

80
Effects on Organ Systems

CVS
•In contrast to other anesthetics agents, ketamine
increases arterial BP, HR and COP.
•These indirect CV effects are due to central
stimulation of the sympathetic nervous system
and inhibition of the reuptake of norepinephrine .
•These changes increase myocardial
work ;ketamine souled be used with caution in
patients with CVS disease

81
• Ketamine has direct myocardial depressant
effect during exhaustion of catecholamine
stores(e.g. severe end stage shock).
• On the other hand, ketamine’s indirect
stimulatory effects are often beneficial to
patients with acute hypovolemic shock.

82
 Respiratory
•Ventilatory drive is minimally affected by
induction doses of ketamine.
•However, rapid IV bolus administration or
pretreatment with opioids occasionally produces
apnea.
•Ketamine is a potent bronchodilator, making it
a good induction agent for asthmatic patients.

83
• During ketamine anesthesia, upper AW
reflexes remain largely intact.
• However, patients that are at increased risk for
aspiration should be intubated.
• Ketamine causes increased salivation but, this
can be attenuated by premedication with an
anticholinergic agent(e.g. atropine).

84
 Cerebral
•Ketamine increases
-cerebral O₂ consumption
-cerebral blood flow and
-intracranial pressure
•Thus, ketamine is contraindicated to use in
patients with increased ICP.

85
Propofol
• Propofol is a di isopropylphenol intravenous hypnotic
agent that produces rapid induction of anesthesia with
minimal excitatory activity
Mechanism of action
• Propofol induces a state of general anesthesia by
facilitation of inhibitory neurotransmission mediated
by GABA.
• Propofol preparations can support the growth of
bacteria, so good sterile technique must be performed
including cleaning the rubber stopper with an alcohol
swab prior to opening it.
86
 Absorption
•Propofol is available only for IV administration
for the induction of general anesthesia and for
moderate to deep sedation.
Distribution
•The high lipid solubility of propofol results in
an onset action of that is almost as rapid as that
of thiopental

87
• Awakening from a single bolus dose is also
rapid due to a very short initial distribution
half-life (2-8 min).
• Recovery from propofol is hangover free. This
makes it a good agent for outpatient
anesthesia.

88
Dose and Routes

• Conscious sedation;
25 - 50 mg IV, Titrate slowly to desired effect
(on set of slurred speech)
• Induction;
2.5-3 mg/kg IV, given slowly over 30 seconds in
• Maintenance: 0.1-0.2mg/kg/min IV
• Antiemetic; 10 mg IV

89
Effects on organ systems

CVS
•The major CV effect of propofol is a decrease
in arterial BP due to drop in systemic vascular
resistance (inhibition of sympathetic
vasoconstrictor activity).
•Hypotension is more pronounced with propofol
than with thiopental but is usually reversed by
the stimulation during laryngoscopy and
intubation.

90
 Respiratory
•Like thiopental, Propofol is a profound
respiratory depressant that usually causes apnea
following an induction dose.
•Propofol depresses the upper AW reflexes more
than thiopental does. Hence, propofol is helpful
during LMA placement in the absence of muscle
relaxation (paralysis).
•Although propofol can cause histamine release,
induction with propofol is less accompanied by a
lower incidence of wheezing in asthmatic and non
asthmatic patients compared with thiopental.
91
 Cerebral
•Propofol decreases cerebral blood flow and
intracranial pressure.
•In patients with increased ICP, Propofol can
cause a significant reduction in CPP unless steps
are taken to support mean arterial BP.
•Unique to Propofol are its antipruritic and
antiemetic properties.
•Its antiemetic effects make it a preferred drug
for outpatient anesthesia.
92
• Induction is occasionally accompanied by
spontaneous movement or hiccupping.
• Although these reactions may occasionally
mimic tonic-clonic seizures, propofol appears
to have anticonvulsant properties.
• Propofol has been successfully used to
terminate status epileptic patients.
• Tolerance does not develop after long-term
propofol infusions.
93
 Others
•An infusion of propofol is used commonly to provide
sedation for adult patients undergoing minor procedures
and on the intensive care unit.
•It is also the most commonly used drug to provide total
intravenous anaesthesia, TIVA. Propofol infusion is
contraindicated for sedation in children due to concerns
regarding its safety. A propofol infusion syndrome’ has
been described; effected children developing metabolic
acidosis, lipidaemia, cardiac arrhythmias and an increased
mortality.
•Experience suggests Propofol is safe to use in patients
susceptible to porphyria.
94
Caution and contraindications of
Cautions !!!!
• Reduce doses in elderly, hypovolemic, high
risk surgical patients and with use of narcotics
and sedative hypnotics
• Minimize pain by injecting into a large vein
and/or mixing IV lidocaine (0.1 mg/kg) with
the induction dose of Propofol or prior
administration of 2ml of 1% lidocaine

95
• Lack of resuscitation equipment
• Inability to maintain a patent airway/Airway
obstruction
• Conditions in which reduction in blood
pressure can’t be tolerated. E.g. patients with
fixed cardiac output (severe aortic or mitral
stenosis, pericardial tamponade) and those in
shock status.

96
Etomidate

Mechanism of action
•Etomidate depresses the reticular activating
system and mimics the inhibitory effects of
GABA.
•Etomidate is structurally unrelated to other
anesthetic agents.
•Etomidate has no analgesic property.

97
• Carboxylated imidazole compound.
• Dosage (0.2 -0.4mg/Kg)
• pH -6.9
• Duration of action: 3 to 12 minutes.
• 0.2% preperation with 35% propylene glycol
• Large Vd.(Mod lipid solubility. pKa -4.2 -
76% bound to albumin)
• Rapid onset and offset
• Metabolised in liver and plasma esterases to
inactive water soluble metabolites
98
 Absorption
•Etomidate available only for IV administration
and is used for induction of general anesthesia.
Distribution
•Although it is highly protein bound, etomidate
is characterized by a very rapid onset of action
due to its high lipid solubility and large
nonionized fraction at physiological pH.

99
• Redistribution is responsible for decreasing the
plasma concentration to awakening levels.
Biotransformation
• Hepatic microsomal enzymes and plasma
esterases rapidly hydrolyze etomidate to an
inactive metabolite.
Excretion
• The end product of hydrolysis is primarily
excreted in the urine.
100
Effects On Organ Systems
CVS
•Etomidate has minimal effects on the cardiovascular
system.
• It is considered a cardio stable IV anesthetic drug.
• A mild reduction in peripheral vascular resistance is
responsible for a slight decline in arterial blood
pressure.
•Myocardial contractility and cardiac output are usually
unchanged.
• Etomidate does not release histamine.

101
 Respiratory
•Ventilation is affected less with Etomidate than
with thiopental or benzodiazepines.
• Even induction doses usually do not result in
apnea unless opioids have also been
administered.

102
 Cerebral
•Etomidate decreases the cerebral metabolic rate,
cerebral blood flow, and intracranial pressure to
the same extent as thiopental.
•Because of minimal cardiovascular effects, CPP
is well maintained.
•PONV are more common with etomidate than
following thiopental induction, but can be
minimized by antiemetic medications.
103
 Endocrine
•Induction doses of etomidate transiently inhibit
enzymes involved in cortisol and aldosterone
synthesis.
•Long-term infusions of Etomidate lead to
adrenocortical suppression by inhibition of 11β-
hydroxylase and 17α- hydroxylase, that may be
associated with an increased mortality rate in
critically ill patients.
104
MOC-etomidate

• Methoxycarbonyl-etomidate (MOC
etomidate), a new compound derived from
the anesthetic etomidate, is as fast-acting
and provides the same hemodynamic
stability as its parent drug, but does not
cause dangerousadrenal gland
suppression as etomidate can.

105
Cont…

• MOC-etomidate is an etomidate analogue

that retains etomidate's important
favorable pharmacological properties.
However, it is rapidlymetabolized, ultra-
short acting, and does not produce
prolongedadrenocortical suppression
following bolus administration

106
Side effects of intravenous sedative-
hypnotics when used for induction of
anesthesia
Induction Thiopental Methohexital Propofol Ketamine
side effects
Change in -8 -8 -17 +28
blood
pressure (%)
Change in +14 +15 +7 +33
heart rate (%)
Induction pain 0 30-50 10-30 0
(%)
Induction 6 20 40 Rare
apnea (%)
Recovery 10 5 5 Common
restlessness
(%)
Recovery 7-10 5 0-5 common
vomiting (%) 107
Neuroleptanalgesia

•It is characterized by general quiescence,

psychic indifference and intense analgesia
without total loss of consciousness.
E.g. Combination of Fentanyl and
Droperidol

108
Cont…

• It is associated with decreased motor

functions, suppressed autonomic reflexes,
cardiovascular stability with mild amnesia.
• It causes drowsiness but respond to
commands.
• Used for endoscopies, angiography and
minor operations.

109
Benzodiazepines.

Clinical considerations
•Benzodiazepines exert five principal pharmacologic effects:
– Sedation
– Anxiolysis
– Anticonvulsant actions
– Spinal cord-mediated skeletal muscle relaxation
– amnesia
•Benzodiazepines have replaced barbiturates for preoperative
medication and production of sedation during monitored
anesthesia care

110
•Patients may receive either single oral doses or
intravenous (IV) bolus injections for short-term
sedation during a surgical procedure, or repeated
IV boluses
or
•continuous infusions for postoperative sedation
in the intensive care unit (ICU).

111
 Absorption
•BDZs are commonly administered orally,
intramuscularly, and intravenously to provide
sedation or induction of general anesthesia.
•Intramuscular injection of diazepam is painful
and unreliable. In contrast, midazolam and
lorazepam are well absorbed after intramuscular
injection.

112
 Distribution
•Diazepam is quite lipid soluble and rapidly
penetrates the blood–brain barrier.
•Redistribution is fairly rapid for the
benzodiazepines and, like the barbiturates, is
responsible for awakening.

113
 Biotransformation
•The benzodiazepines rely on the liver for
biotransformation into water-soluble glucuronide
end products.
• The phase I metabolites of diazepam are
pharmacologically active.

114
 Excretion
•The metabolites of benzodiazepine
biotransformation are excreted chiefly in the
urine.
•Renal failure may lead to prolonged sedation in
patients receiving midazolam due to the
accumulation of a conjugated metabolite.

115
Mechanism of Action

• Benzodiazepines act as GABA (γ-

aminobutyric acid) potentiators. They bind to
BZ receptors on the GABA-BZ receptor
complex, which allows them to allosterically
modulate and enhance the activity of GABA.
This results in increased hyperpolarization at
target neurons, making them less responsive to
excitatory stimuli.

116
Effects on organ system

CVS
•The benzodiazepines display minimal
cardiovascular depressant effects even at induction
doses.
•Arterial blood pressure, cardiac output, and
peripheral vascular resistance usually decline
slightly, whereas heart rate sometimes rises.
•Midazolam tends to reduce blood pressure and
peripheral vascular resistance more than
diazepam.
117
 Respiratory
•BDZs depress the ventilatory response to CO2.
•This depression is usually insignificant unless the
drugs are administered intravenously or in association
with other respiratory depressants.
•Although apnea may be less common after
benzodiazepine induction than after barbiturate
induction, even small intravenous doses of diazepam
and midazolam have resulted in respiratory arrest.
•Ventilation must be monitored in all patients receiving
intravenous benzodiazepines, and resuscitation
equipment must be immediately available

118
 Cerebral
•BDZs reduce cerebral oxygen consumption,
cerebral blood flow, and intracranial pressure
•They are very effective in preventing and
controlling grand mal seizures.
•The mild muscle-relaxant property of these
drugs is mediated at the spinal cord level, not at
the neuromuscular junction.
•Benzodiazepines have no analgesic properties.

119
Diazepam

• Benzodiazepine with sedative and amnesic

properties
• Depresses the CNS at the limbic and
subcortical levels of the brain
• Depresses the ventilatory response to PaCO 2

120
Cont…

• Mild muscle relaxation mediated at the spinal

cord level; not at the neuromuscular junction
• Highly alkaline pH
• No analgesic properties

121
Indications Diazepam

• Basal sedation
• Induction agent
• Drug Of Choice for sedation

122
Dose and routes Diazepam
• IV, IM, PO, and rectally
• Pre-op sedation: 5 to 10 mg PO 1h before
surgery
• Induction of anesthesia: 0.1-0.2 mg/kg IV
• Seizures: 5-10 mg IV
• Basal sedation: Increments of 2.5 mg until pt.
falls into light sleep (5-30 mg may be
required)

123
Midazolam
• benzodiazepine that has a rapid onset with
sedative and amnesic properties
• depresses the CNS at the limbic and
subcortical levels of the brain
• depresses the ventilatory response to PaCO 2

124
cont…

• no analgesic properties
• mild muscle relaxation mediated at the spinal
cord; not at the neuromuscular junction
• water soluble--which allows for better
absorption following IM injection

125
Indications of Midazolam

• pre-op sedative
• induction of anesthesia
• Conscious sedation
• commonly used for short diagnostic or
endoscopic procedures

126
Dose and routes Midazolam

• may be given IM, PO, or IV

• Pre-op sedation: 0.07-0.08 mg/kg IM 1 hr
prior Induction of anesthesia: 0.2–0.35 mg
mg/kg IV
• Conscious sedation: 0.035 mg/kg initially,
then titrated slowly to a total dose of 0.1
mg/kg

127
Reversal Agent

Flumazenil;
•selective, competitive antagonist of
benzodiazepines
•relatively short duration of action between one
and two hours
•As a competitive antagonist, flumazenil
prevents or reverses, in a dose-dependent
manner, all the agonist effects of
benzodiazepines.
128
Indications flumazenil
•Reversal of benzodiazepine sedation or
overdose
Dose and routes flumazenil
•The recommended initial dose is 0.2 mg IV (8 to 15
mcg/kg IV), which typically reverses the CNS effects of
benzodiazepine agonists within about 2 minutes. If
required, further doses of 0.1 mg IV (to a total of 1 mg
IV) may be administered at 60-second intervals.

129
• Generally, total doses of 0.3 to 0.6 mg IV have
been adequate to decrease the degree of sedation
to the required extent in patients sedated or
anesthetized with benzodiazepines,
• Whereas total doses of 0.5 to 1.0 mg IV are
usually sufficient to completely abolish the effect
of a therapeutic dose of a benzodiazepine.
• An alternative to repeated doses of flumazenil to
maintain wakefulness is a continuous low-dose
infusion of flumazenil, 0.1 to 0.4 mg/hour

130
Side effects

• CNS excitation including seizures, nausea,

dizziness, and agitation
• May precipitate acute withdrawal

131