GENERAL AND LOCAL ANAESTHETICS

Dr. Jonathan Kiprop

Fac. Dr. Gichuhi
30th June, 2017

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 GENERAL ANAESTHETICS

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 Outline
1. Introduction

2. Overview

3. Pre-anaesthetic medications

4. Inhalation anaesthetics

5. Intravenous anaesthetics

6. Conclusion

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 Introduction
General anaesthesia global reversible depression of CNS
sufficiently to permit performance of surgery.

History

1845 Horace Wells: Nitrous oxide

1846 William Morton Dentist: Ether

1846 Crawford Long (Physician): Ether

1930 IV Barbiturates

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 Conceptual framework
• Pre-anaesthetic evaluation

• Pre-anaesthetic medication

• Induction of anaesthesia

• Maintenance

• Surgery

• Reversal/ emergence

• Post-operative monitoring

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 Pre-anaesthetic Medication

• It is the administration of drugs prior to general anaesthesia

(GA) so as to make anaesthesia safer for the patient.

• Ensures comfort to the patient & to minimize adverse effects of

anaesthesia
 Aims
• Relief of anxiety & apprehension pre-operatively & facilitate
smooth induction

• Amnesia for pre- & post-operative events

• Potentiate action of anaesthetics, so less dose is needed

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 Aims…

• Antiemetic effect extending to post-operative period

• Decrease secretions & vagal stimulation caused by anaesthetics

• Decrease acidity & volume of gastric juice to prevent reflux &

aspiration pneumonia
 Drugs used for pre-anesthetic
medication
• Anxiolytics

- Provide relief from apprehension & anxiety

- Post-operative amnesia

e.g. Diazepam (5-10mg oral), Lorazepam (2mg i.m.) (avoided co-

administration with morphine, pethidine)
 Cont..
• Sedatives-hypnotics-

- e.g. Promethazine (25mg i.m.) has sedative, antiemetic &

anticholinergic action

- Causes negligible respiratory depression & suitable for

children
• Anticholinergics-

- Atropine (0.5mg i.m.) or Hyoscine (0.5mg i.m.) or

Glycopyrrolate (0.1-0.3mg i.m.) one hour before surgery(not used
nowadays)

- Reduces salivary & bronchial secretions, vagal bradycardia,

hypotension

- Glycopyrrolate(selective peripheral action) acts rapidly,

longer acting, potent antisecretory agent, prevents vagal
bradycardia effectively
• Anti-emetics-

- Metoclopramide (10mg i.m.) used as antiemetic & as

prokinetic gastric emptying agent prior to emergency surgery

- Domperidone (10mg oral) more preferred (does not produce

extrapyramidal side effects)

- Ondansetron (4-8mg i.v.), a 5HT3 receptor antagonist, found

effective in preventing post-anaesthetic nausea & vomiting
• Drugs reducing acid secretion -
- Ranitidine (150-300mg oral) or Famotidine (20-40mg oral)
given night before & in morning along with Metoclopramide
reduces risk of gastric regurgitation & aspiration pneumonia

- Proton pump inhibitors like Omeprazole (20mg) with

Domperidone (10mg) is preferred nowadays
 Principles of GA
General anesthesia is a state characterized by reversible loss of
consciousness, analgesia, amnesia, skeletal muscle relaxation,
and loss of reflexes.

Objectives of General Anaesthetics

1. Sustain physiologic homeostasis during surgery

2. Minimize potentially deleterious effects of anaesthetic agents

& techniques

3. Improve post operative outcomes

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 Cont..
• Ideal anaesthetic drug

– Induce rapid and smooth loss of consciousness

– Rapidly reversible upon discontinuation

– Possess wide margin of safety

• None of the agents can achieve all the desired effects when
used alone.

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 Important terms
• Balanced anesthesia: Anesthesia produced by a mixture of
drugs, often including both inhaled and intravenous agents
– Rationale…take advantage of favourable properties of each agent
while minimizing the SE

• Inhalation anesthesia: Anesthesia induced by inhalation of

drug

• Minimum Alveolar Anesthetic Concentration (MAC): The

alveolar concentration of an anesthetic that is required to
prevent a response to a standardized painful stimulus in 50%
of patients.
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 Important terms
• Analgesia: A state of decreased awareness of pain,
sometimes with

• Amnesia: partial or total loss of memory

• Induction: administration of a drug or combination of drugs

at the beginning of an anaesthetic that results in a state of
general anaesthesia…upto surgical anaesthesia plane 2

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 Classification of GA

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 Stages of Anesthesia
• Modern anesthetics act very rapidly and achieve deep
anesthesia quickly.

• With older and more slowly acting anesthetics, the

progressively greater depth of central depression associated
with increasing dose or time of exposure is traditionally
described as stages of anesthesia.

• Stage 1: Analgesia
– In stage 1, the patient has decreased awareness of pain, sometimes
with amnesia. Consciousness may be impaired but is not lost. Normal
reflexes but eyelash reflex may be abolishded
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 Stages of Anaesthesia
• Stage 2: Disinhibition/excitement
– the patient appears to be delirious and excited. Amnesia occurs,
reflexes are enhanced, and respiration is typically irregular; retching
and incontinence may occur. Laryngospasm, regurgitation, coughing

• Stage 3: Surgical Anesthesia

– the patient is unconscious and has no pain reflexes; respiration is very
regular, and blood pressure is maintained.

• Stage 4: Medullary Depression

– patient develops severe respiratory and cardiovascular depression that
requires mechanical and pharmacologic support.
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 Mechanism of Action
• Exact mechanism unknown

• Affects neurons at various cellular location- synapse

– Presynaptic effect - alters the release of neurotransmitters

– Post synaptic effect- may change the frequency or amplitude of

impulses exiting the synapse.

• Organ level: strengthen inhibition or diminishes excitation

within the CNS

a)Inhibitory ion channels: Cl-and K channels, GABA & glycine.

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Anaesthetic drugs may ↑ inhibitory
Synaptic activity or diminish the
Excitatory activity.

Barbiturates,
benzodiazepines
propofol potentiate
movement of Cl⁻ through the
GABAA receptor gated Cl⁻ channels

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 Cont…
 Gycline: Barbiturates, propofol & benzodiazepines

b) Excitatory ion channels: activated by ACH (nicotinic &

muscarinic receptors), excitatory amino acids ( N-methyl-D-
Aspartate (NMDA), or serotonin (5-HT₂ or 5-HT₃).

 NMDA receptors blocked by : N₂O & ketamine

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B.) Intravenous Anaesthetics

a. Fast inducers –

i.) Thiopental, Methohexital

ii.) Propofol, Etomidate

b. Slow inducers –

i.) Benzodiazepines – Diazepam, Lorazepam & Midazolam

c. Dissociative anaesthesia – Ketamine

d. Opioid analgesia – Fentanyl

• Opioid analgesics-

- Morphine (8-12mg i.m.) or Pethidine (50-100mg i.m.) used

one hour before surgery

- Provide sedation, pre-& post-operative analgesia, reduction

in anaesthetic dose

- Fentanyl (50-100μg i.m. or i.v.) preferred nowadays (just

before induction of anaesthesia)
 Intravenous Anaesthetics

1. Barbiturates

2. Propofol

3. Etomidate

4. Ketamine

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 Barbiturates
1. Sodium thiopental

2. Thiamylal

3. Methohexital

 Formulated as sodium salts & reconstituted in water or

isotonic saline to produce alkaline solution, pH10-11

 Mixing with more acidic drugs used in induction can result in

precipitation of barbiturates

 Thus delay administration of other drugs until barbiturates

have cleared from IV tubing

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 Barbiturates
 Induction anaesthesia: 3-5mg/kg within a minute

 duration of anaesthesia 5—8minutes

 Neonates & infants requires high induction dose (5—8mg/kg)

 Pregnant women & elderly patients require less dose (1—

3mg/kg).

 Thiopental & Thiamylal produce little or no pain on injection

site

 Methohexital elicits mild pain

 Veno-irritation can be reduced by injection into a large vein or

give lidocaine prior to injection.
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 Barbiturates cont…
 Intra-arterial injection of thiobarbiturates can induce severe
inflammatory & potentially necrotic reaction thus should be
avoided.

 Thiopental evokes garlic taste prior to inducing anaesthesia

 Methohexital & lesser extent other barbiturates can induce

excitement phenomena→ muscle tremors, hypertonus &
hiccups

Pharmacokinetics

 Duration of action depends on redistribution

 Lipid solubility makes thiopental rapidly acting.

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 Barbiturates cont…
 Half life 12hours

 Highly bound to plasma proteins – 85%

 Metabolised in the liver

 Renal excretion of inactive metabolites

 Small fraction of thiopental undergoes desulfuration to longer

acting hypnotic pentobarbital.

 Prolonged usage of thiopental & thiamylal can cause coma

due to slow elimination & large volume distribution
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 Barbiturates cont…
Systemic Effects

CNS: ↓ cerebral oxygen consumption in a dose dependant manner

↓ cerebral blood flow & ICP

 Thiopental has protective effects against cerebral ischemia &

intra-ocular pressure

 Effective as anticonvulsants-Rx of status epilepticus

CVS: dose-dependant ↓ in BP due to vasodilation, venodilation &

lesser in cardiac contractility

↑HR as compensatory response to lower BP

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 Barbiturates cont…
Respiratory System:

 Respiratory depressant

 Induction dose ↓ minute ventilation & tidal volume with

smaller & inconsistent ↓ in RR

 ↓ reflex responses to hypercarbia & hypoxia

 Higher doses or presence of other respiratory depressants

such as opioids, can result in apnoea

 Safe in asthmatics as it has little effect on bronchomotor tone

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 Barbiturates cont…
Other effects

 Analgesic effect

 Short term administration has no clinically significant effect on

hepatic, renal or endocrine system.

 Single induction dose does not alter tone of gravid uterus

 But may produce transient depression of newborn activity

 Drug induced histamine release

C/I in pts with acute or variegate porphyria- may produce fatal

attacks
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 Propofol
 Most commonly used IV anaesthetic for induction anaesthesia

 Propofol (2,6-diisopropylphenol) alkyl phenol, with hypnotic

properties

 Poor solubility in H₂O, formulated as an emulsion containing

10% soy-bean oil, 2.25% glycerol & 1.2% lecithin, egg yolk
phosphatide fraction

 Solution appears milky white & slightly viscous, pH approx 7.

MOA: potentiation of chloride current mediated thru’ GABAA

receptor

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 Propofol cont..
Clinical Uses..

1. Induction anaesthesia: bolus injection of 1-2mg/kg IV

2. Maintenance anaesthesia: allows for continuous infusion

3. Sedation in monitored anaesthetic care sedation in ICU,

conscious sedation & short duration GA outside operating
room eg interventional radiology suites, emergency room

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 Propofol cont..
Pharmacokinetics

 Rapidly metabolized in liver – resulting in water soluble inactive

metabolites.

 High plasma clearance &exceeds hepatic blood flow →

extrahepatic metabolism mainly in the lungs. Accounts for up to
30% of bolus.

 Excreted in urine

 Plasma half life 2-4min, duration of action 3-8 minutes

 Highly bound to plasma proteins (97%)

 Recovery more complete , no ‘hangover’. Reversal in 8-10min

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 Propofol cont..
System Effects

CNS: hypnotic, no analgesic effects

 General suppression of CNS activity , occasional excitatory

effects such as twitching or spontaneous movement
observed.

 Peripheral vasodilation can ↓ cerebral perfusion pressure →

 ↓cerebral blood flow, cerebral metabolic rate for O₂, ICP &
intra-ocular pressure.

 Safe in patients with seizure disorders

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 Propofol cont..
CVS: most pronounced ↓ in systemic BP due to Vasodilation in
both arterial & venous circulation → ↓ in preload & afterload

 Effect more pronounced in elderly, pts with ↓ intravascular

fluid volume & rapid injection

Respiratory effects

 Respiratory depressant generally produces apnoea after

induction dose

 Maintenance infusion reduces minute ventilation thru’

reduction in tidal volume
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 Propofol cont..
 Reduction in ventilatory response to hypoxia & hypercapnia

 Can cause greater reduction in upper airway reflexes thus

suitable for instrumentation of airway.

NB!! Pts should be monitored to ensure adequate oxygenation &

ventilation

Others

 Significant anti-emetic action

 Good for sedation or anaesthesia for pts at high risk for

Nausea & vomiting
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 Ketamine
 “Dissociative anaesthetic” patient feels detached from
environment & self whilst patient’s eyes remain open with a
slow nystagmic gaze
 profound analgesia, unresponsive to commands & amnesia.
 partially water-soluble & highly lipid soluble phencyclidine
derivative
 Onset of action 60-90sec IV; 1-2min IM
 Duration of induction 10-15min
MOA is complex, but the major effect is probably produced
through inhibition of the NMDA receptor complex.
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 Ketamine cont..
 not commonly used for maintenance anaesthesia, its short
context-sensitive half-time

 Small bolus doses 0.2–0.8 mg/kg IV may be useful during

regional anaesthesia.

 provides effective analgesia with

 It’s usage limited by unpleasant psychotomimetic side effects

 potent analgesia with minimal respiratory depression.

 adjunct administered at sub-analgesic doses to limit or

reverse opioid tolerance

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 Ketamine cont..
Pharmacokinetics
 Multiple administration routes –IV, IM, oral, rectal, epidural
 Metabolism occurs primarily in the liver and involves N -
demethylation by the CYP450 system.
 Norketamine, the primary active metabolite, is less potent
(one third to one fifth the potency of ketamine) subsequently
hydroxylated & conjugated into water-soluble inactive
metabolites.
 inactive metabolite excreted in urine.
 Low protein binding (12%)

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 Ketamine cont..
Systemic Effects

 amnesia is not as complete as with the benzodiazepines.

 Reflexes are often preserved

 The eyes remain open and the pupils are moderately dilated
with a nystagmic gaze.

 Frequently, ↑ lacrimation and salivation

 Premedication with an anticholinergic drug

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 Ketamine cont..
CNS: cerebral vasodilator that ↑cerebral blood flow & cerebral
metabolism rate of O₂.

 Not recommended for use in patients with intracranial

pathology, especially ↑ ICP
 potential to produce myoclonic activity but is considered an
anticonvulsant & may be recommended for treatment of
status epilepticus when more conventional drugs are
ineffective.
 Limited usage due unpleasant emergence reactions-vivid
colourful dreams, hallucinations, out-of-body experiences,
and increased and distorted visual, tactile, and auditory
sensitivity. Fear & confusion
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 Ketamine cont..
 euphoric state may also be induced thus the potential for
abuse.

 Children usually have a lower incidence of & less severe

emergence reactions.

 Combination with benzodiazepine may limit the unpleasant

emergence reactions & also ↑ amnesia.

CVS: produce transient but significant ↑in systemic BP, HR

and cardiac output, by centrally mediated sympathetic

stimulation
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 Ketamine cont..
 ↑ cardiac workload and myocardial oxygen consumption, are
not always desirable & can be blunted by co-administration of
benzodiazepines, opioids, or inhaled anaesthetics.

Respiratory Effects: not thought to produce significant

respiratory depression.

 When singly used, the respiratory response to hypercapnia is

preserved and blood gases remain stable.

 Transient hypoventilation & rarely, a short period of apnoea

can follow rapid administration of a large intravenous dose for
induction anaesthesia.
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 Ketamine cont..
 Relaxes bronchial smooth muscles and may be helpful in pts
with reactive airways & in the management of pts
experiencing bronchoconstriction

 Can be used in asthmatics

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 Ketamine cont..
Clinical Uses

 Unique characteristics: profound analgesia, stimulation of the

sympathetic nervous system, bronchodilation, and minimal
respiratory depression.

 Rapidly produces hypnotic state

 useful option for premedication in mentally challenged and

uncooperative paediatric patients.

 Used in burn pts, debridement, & skin grafting procedures

 Induction anaesthesia achieved with, 1–2 mg/kg IV or 4–6

mg/kg IM
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 Etomidate
 Carboxylated imidazole derivative

 Poorly soluble in water thus supplied as 2mg/ml solution on

35% propylene glycol, pH 6.9

 MOA: Potentiation of GABAA-mediated chloride currents

 IV anaesthetic with hypnotic but no analgesic effects.

 Minimal haemodynamic effects

 Endocrine side effects limits it’s use for continuous infusions

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 Etomidate cont..
Clinical Uses
Alternative to propofol and barbiturates for the rapid IV
induction of anaesthesia, especially in pts with compromised
myocardial contractility.

Pharmacokinetics
 Induction dose produces rapid onset anaesthesia & recovery
depends on redistribution to inactive tissue sites

 Highly plasma protein bound (77%)

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 Etomidate cont..
 Metabolism primarily by ester hydrolysis to inactive
metabolite
 Excreted in urine (78%) & bile (22%)
 ˂3% excreted as unchanged drug
 Short elimination half life
 Larger doses, repeated boluses or continuous infusion can
safely be administered

Systemic Effects
CNS: potent vasoconstrictor as reflected by ↓ in cerebral
blood flow & ICP
Effects similar to those of thiopental
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 Etomidate cont..
CVS: cardiovascular stability after bolus injection
 ↓ in systemic BP is modest or absent & reflects ↓in systemic
vascular resistance
 Systemic BP-lowering effects of etomidate exaggerated in
presence of hypovolaemia
 Optimization of hypovolemic pts required before induction
anaesthesia
 Minimal changes in HR & cardiac output
 Minimal depressant effects on myocardial contractility

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 Etomidate cont..
Respiratory System: less pronounced depressant effects on
ventilation

Apnoea may follow rapid IV injection

Depression of ventilation may be exaggerated when combined

with inhaled anaesthetic or opioids.

Endocrine: adrenocortical suppression by producing dose-

dependant inhibition of 11β-hydroxylase, enzyme for conversion
of cholesterol to cortisol

Suppression last for 4-8hours.

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 Etomidate cont..
Side effects
 Pain on injection site followed by venous irritation
 Involuntary myoclonic movements common but may be
masked by neuromuscular blocking drugs.
 Awakening after a single intravenous dose of etomidate is
rapid, with little evidence of any residual depressant effects.
 postoperative nausea and vomiting may be more common
than in thiopental or propofol.

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 Dexmedetomidine
• Recent IV anaesthetic

• Highly selective alpha 2 adrenergic agonist at locus caeruleus

• Produce sedation, hypnosis, and analgesia

• Approved for brief post op sedation upto 24hrs

• Minimal effect on resp.

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 Conclusion

Induction agents Maintenance reversal

Opioids: fentanyl Fentanyl, morphine Turn off agents
IV: Propofol, Thiopental, propofol
etomidate, midazolam
Muscle relaxants: short
acting: suxamethonium
Long acting: tracuronuim,
vecuronuim, rocuronuim

Inhalation N₂O, Sevo, Deso, Iso

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 Inhalation anaesthetics
1. Gas: nitrous oxide (N₂O)

– Has high vapour pressure but low boiling point. Gas at

room temp.

2. Volatile liquids:

– Ether

– Halothane

– Isoflurane

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 Pharmacokinetics

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 Pharmacokinetics
 Distributes between tissue or between blood and gas, and
equilibrium achieved when the partial pressure of the two tissues
is equal.

 Partial pressure of the anesthetic in tissue is equal to the inspired

gas after sufficient inhalation

 Thus partition co-efficient is the ratio of anesthetic concentration

in two tissues when partial pressures in the two tissues are equal

 Blood:Gas, Blood:Brain, Blood:Fat partition coefficient.

 This shows that inhalational anesthetics are more soluble in some

tissues than in others

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 Pharmacokinetics
 Equilibrium is clinically achieved when partial pressure (PP)

in inspired air is equal to the PP in end-tidal (alveolar) gas

 Equilibrium is achieved quickly for agents that are not

soluble in blood or tissue

 Anesthetic induction requires that brain PP be equal to

mean alveolar concentration (MAC)

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 Pharmacokinetics
 Due to good brain perfusion, anesthetic PP in brain becomes

equal to PP in alveolar gas & in blood within few minutes

 Rate of rise of PP is slower for anesthetics that are soluble in

blood and other tissue

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 Pharmacokinetics
Anaesthetic Blood: Gas Blood: Brain MAC Comment
partition partition
coefficient coefficient

Nitrous oxide 0.47 1.1 ˃100 Low solubility

Rapid onset & recovery

Desflurane 0.42 1.3 6-7 Poor induction agent, rapid

recovery

Sevoflurane 0.69 1.7 2.0 Rapid onset & recovery

Isoflurane 1.40 2.6 1.40 Medium onset & recovery

Enflurane 1.80 1.4 1.7 Medium onset & recovery

Halothane 2.30 2.9 0.75 High solubility

Medium onset & recovery

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 1. Nitrous Oxide (N₂O)
“Laughing gas”

Colourless, odourless gas @ room temp

Non-flammable nor explosive but supports combustion

Weak anaesthetic agent

Pharmacokinetics :

Insoluble in blood & other tissues

Rapidly reaches equilibrium btn gas delivery & alveolar

anaesthetic conc → rapid induction

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 N₂O cont..
Can be combined with halogenated IV anaesthetics to
speed induction anaesthesia

Rapid emergence following discontinuation

Discontinuation may lead to diffusional anoxia/hypoxia ..by

affecting oxygenation by directly displacing oxygen,or by
diluting alveolar carbondioxide thus may decrease
respiratory drive and ventilation. Critical in the first 5-10
minutes . Term coined Fink.

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 N2O
To avoid hypoxia, 100% O₂.

99% eliminated unchanged via lungs

Interact with Vit B₁₂ → megaloblastic anaemia & peripheral

neuropathy

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 N₂O: Clinical Uses
1. Weak anaesthetic agent

2. Analgesia @ low conc.

3. Sedation at 50% conc. → dental procedures

4. Used as adjunct to other anaesthetics

Systemic Effects:
CVS: depressant effects on cardiac function generally are not
observed in pts b/coz of the stimulatory effects of N₂O on the
sympathetic nervous system
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 N₂O cont…
When co-administered with halogenated inhalational
anaesthetics, it generally produces an ↑ in HR, arterial BP, and
cardiac output.

Co-administration with an opioid will generally ↓ arterial BP

& cardiac output.

 increases venous tone in both the peripheral and pulmonary

vasculature.

Should not be used in patients pre-existing pulmonary

hypertension.

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 Respiratory System:

 ↑respiratory rate, ↓ in tidal volume in spontaneously breathing

patients.

 Even modest conc. of N₂O markedly depress the ventilatory

response to hypoxia.

CNS: Administered alone, it can significantly ↑ cerebral blood flow

and ICP.

 Co-administered with IV anaesthetic agents, increases in

cerebral blood flow are attenuated or abolished.

 When added to a halogenated inhalational anaesthetic, its

vasodilatory effect on the cerebral vasculature is slightly reduced
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 N₂O cont..
Muscle: does not relax skeletal muscle or enhance the effects of
neuromuscular blocking drugs.

 N₂O does NOT trigger malignant hyperthermia.

Kidney, Liver, and Gastrointestinal Tract

 Nitrous oxide is neither nephrotoxic nor hepatotoxic

 Note Nitrous oxide is relatively contraindicated in cases of

intestinal obstruction or pneumothorax.

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 2. Halothane
 Halogenated Volatile liquid , light sensitive

 Inflammable nor explosive when mixed with O₂ or air

Pharmacokinetics

 High fat soluble, high blood :gas coefficient (2.3)

 Slow induction & recovery

 Eliminated unchanged via lungs

 Metabolized in liver by CYP450 into trifluoroacetylchloride

metabolite
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 Halothane cont..
Clinical Uses

 Potent, non-pungent anaesthetic & well tolerated for

maintenance anaesthesia

 Used for induction especially in children

Systemic Effects
CVS: Dose dependant ↓ in arterial blood pressure

directly depressed myocardial contractility

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 Halothane cont..
 ↓ mean arterial pressure about 20—25% at MAC.

 Induce reduction on BP & HR → disappear several hours

after administration b/coz of progressive sympathetic
stimulation.

 Sinus bradycardia & atrioventricular rhythms due to direct

depressive effects on SAN

Respiratory System: spontaneous respiration rapid & shallow

↓ alveolar ventilation → ↑ arterial CO₂ tension from

40mmHg ˃ 50mmHg at 1MAC.
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 Halothane cont..
 Inhibits peripheral chemoreceptor responses to arterial
hypoxemia→ no tachycardia &hypertension.

CNS: dilates cerebral vasculature, ↑ cerebral blood flow → ↑ICP

especially in pts with space occupying lesions, oedema, ↑ICP

Attenuates auto-regulation of cerebral flow

Muscle: muscle relaxation via central depressant effects

 potentiates actions of non-depolarized muscle relaxants by ↑

duration of action & magnitude of effects

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 Halothane cont..
 Trigger malignant hyperthermia: heritable genetic disorder of
muscle characterized by muscle rigidity, hyperthermia, rapid
onset of tachycardia & hypercapnia

 Rx: dantrolene; immediate discontinue procedure

 Relaxes uterine smooth muscles- help to manipulation of

foetus in prenatal period or removal of retained placenta

Kidney, liver & GIT:

 Reduced concentrated urine due to halothane-induced

reduction of renal blood flow & GFR
1/6/2019 Dr.Kiprop J. 77
 Halothane cont..
 Not associated with nephrotoxicity

 ↓ splanchnic & hepatic blood flow

 Fulminant hepatic necrosis→ fever, anorexia, nausea &

vomiting, rash & peripheral eosinophilia; develops several
days after anaesthesia

 Halothane hepatitis → immune response to hepatic proteins

that become trifluoroacetylated as a result of halothane
metabolism

1/6/2019 Dr.Kiprop J. 78
 3. Isoflurane
 Volatile liquid

 Neither flammable nor explosive

 Pungent odour

Pharmacokinetics

 Low blood: gas partition coefficient, lower than that of

halothane (1.4)

 Induction & recovery are relatively rapid

 ˃99% excreted unchanged in lungs

 Does not appear to be mutagenic, teratogenic or carcinogenic

1/6/2019 Dr.Kiprop J. 79
 Isoflurane cont..

Clinical Uses
 Maintenance GA

 Induction can be achieved in ˂10min with inhaled conc. of 3%

isoflurane in O₂

 Drugs such as opioids, N₂O decreases conc. required for GA.

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 Isoflurane cont..
Systemic Effects
CVS: Conc - dependant ↓ in arterial BP, cardiac output
maintained & hypotension result in ↓ systemic vascular
resistance.

 Vasodilation in most vascular beds eg skin & muscle

 Coronary vasodilator →↑coronary blood flow &↓ myocardial

O₂ consumption

 Mildly elevated HR as compensatory response to ↓blood

pressure
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 Isoflurane cont..
Rapid changes in isoflurane conc. can produce transient tachycardia
& hypertension due to isoflurane- induced sympathetic stimulation.

Respiratory System: Pts spontaneously breathing isoflurane have a

normal RR but a reduced tidal volume, resulting in a marked
reduction in alveolar ventilation and an ↑ in arterial CO₂ tension

 Depresses the ventilatory response to hypercapnia & hypoxia

 Effective bronchodilator

 Airway irritant & can stimulate airway reflexes such as coughing

& laryngospasm during induction
1/6/2019 Dr.Kiprop J. 82
CNS: ↓ cerebral metabolic O₂ consumption

 Causes less cerebral vasodilation

 Preferred for neurological procedures

 Effects on cerebral blood flow can be reversed with

hyperventilation.

Muscles: skeletal muscle relaxation via central effects

 Enhances effects of depolarizing & non depolarizing muscle

relaxants

 Relaxes uterine smooth muscles

Kidney, Liver & GIT:

↓ splanchnic hepatic & renal blood flow & GFR

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 4.Sevoflurane
 Clear, colourless volatile liquid

 Non-flammable and non-explosive in mixtures of air or

oxygen.

 It can undergo an exothermic reaction with desiccated CO₂

absorbent to produce airway burns or spontaneous
ignition, explosion, and fire.

 Sevoflurane reaction with desiccated CO₂ absorbent also

can produce CO → serious patient injury

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 Sevoflurane cont..
Pharmacokinetics
 Low solubility in blood & other tissues thus rapid induction
anaesthesia, & rapid emergence following discontinuation

 3% of absorbed sevoflurane is biotransformed by CYP2E1 to

lexafluoroisopropanol & organic fluoride

 Interaction with soda lime (CO₂) absorbent produces

pentafluoroisopropenyl fluoromethyl ether

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 Sevoflurane cont..
Clinical Uses
 Inhalation induction anaesthesia especially in children
because it is not irritating to the airway
 Used in outpatient anaesthesia due to its rapid recovery
profile
Systemic Effects
CVS:
 Hypotensive effect due to systemic vasodilation
 Produces a conc-dependent ↓ in cardiac output.
 Unlike isoflurane or desflurane, it does not produce
tachycardia and thus may be a preferable agent in patients
prone to MI.

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 Sevoflurane cont..
Respiratory system: conc- dependant ↓ in tidal volume & ↑ RR
in spontaneously breathing patients.

 Not irritating to airway

 Potent bronchodilator

CNS: effects similar to isoflurane & desflurane.

 ↑ ICP in pts with poor intracranial compliance response to

hypocapnia is preserved during sevoflurane anaesthesia,

 increases in ICP can be prevented by hyperventilation.

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 Sevoflurane cont..
Muscle:
 Produces skeletal muscle relaxation
 Enhances the effects of non-depolarizing & depolarizing
neuromuscular blocking agents.

Kidney, Liver & GIT

 potential nephrotoxicity of compound A
(pentafluoroisopropenyl fluoromethyl ether).
 FDA recommends that sevoflurane be administered with fresh
gas flows of at least 2 L/min to minimize accumulation of
compound A.
 no evidence of renal impairment or hepatic toxicity

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 5. Enflurane
 Clear, colorless, non-flammable & non-explosive liquid

 Mild sweet odor, volatile

 Halogenated ether & structural isomer of isoflurane

Pharmacokinetics

 Administered by vaporizing

 Blood: gas partition coefficient (1:8), relatively slow induction

& recovery.

 2-8% of absorbed enflurane metabolized by hepatic CYP2E1

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 Enflurane cont..
 Metabolite by-product as fluoride but low & non-toxic.

 Isoniazid enhances metabolism of enflurane which ↑ serum

fluoride.

Clinical Use

 Mainly in maintenance of GA

 Can induce GA in ˂10 minutes

 Conc. required to produce anaesthesia ↓ when co-

administered with N₂O or opioids
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 Enflurane cont..
Systemic Effects
CVS: conc- dependant ↓ in arterial BP due to depression of
myocardial contractility & peripheral resistance

 Minimal effects on HR

Respiratory System: similar to those of halothane

 Greater depression of ventilatory response to hypoxia &

hypercarbia

 Effective bronchodilator
1/6/2019 Dr.Kiprop J. 91
 Enflurane cont..
CNS: cerebral vasodilator, ↑ICP in some patients

 ↓cerebral metabolic O₂ consumption may produce electrical

seizure activity. Seizures are self-limiting

C/I: pts with seizure disorders

Muscle: significant skeletal muscle relaxation

 Enhances effects of non-depolarizing muscle relaxants

 Malignant hyperthermia can occur

 Relaxes uterine smooth muscles & may ↑ uterine bleeding.

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 Enflurane cont..
Kidney, Liver & GIT

 Reduce renal blood flow, GFR and urine volume

 Effects reversed with discontinuation

 ↓ splanchnic & hepatic blood flow in proportion to reduced

arterial blood but does not appear to alter liver function or be
hepatotoxic

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 6.Desflurane
 Highly volatile liquid at room temp.

 Delivery of precise conc. requires use of special heated

vaporizer that delivers pure vapour then diluted appropriately
with other gases (O₂, air or N₂O)

 Non-flammable & non-explosive in mixtures of air or O₂

Pharmacokinetics
 Partitions poorly into blood, fat, and other peripheral tissues.

 Alveolar & blood conc. rapidly rise to level of inspired conc

thus
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 Desflurane cont..
 Provide very rapid induction, and rapid emergence from
anaesthesia.

 Minimally metabolized

 ˃ 99% of absorbed desflurane is eliminated unchanged via the

lungs.

Clinical Uses
 Maintenance anaesthesia in adults & children

 Used for outpatient surgical procedures b/coz of fast

induction & recovery
1/6/2019 Dr.Kiprop J. 95
 Desflurane cont..
 Irritates the airway in awake pts provoking coughing,
salivation & bronchospasm.

Systemic Effects

CVS: ↓ arterial BP progressively with depth of anesthesia by

decreasing systemic vascular resistance

 Cardiac output preserved & perfusion in major organ beds

eg splanchnic, renal, cerebral & coronary.

 Marked ↑HR occurs during induction & with abrupt ↑ in

delivery conc. which results from desflurane –induced
stimulation of sympathetic Nervous system
1/6/2019 Dr.Kiprop J. 96
 Desflurane cont..
Respiratory System: ↑ respiratory depression as conc. increases
& ↓ in tidal volume

 Tachypnoea less common in comparison to halothane

Bronchodilation

CNS:

 Frank seizures

 Does not aggravate seizures in epileptic patients

 Reduces cerebral oxygen consumption

 Vasodilation ↑ cerebral blood flow & ↑ ICP

1/6/2019 Dr.Kiprop J. 97
 Desflurane cont..
Muscle:

• Direct skeletal muscle relaxation ↑ with depth of anesthesia

• Enhances effects of depolarizing & non-depolarizing

neuromuscular blocking agents

• Uterine muscle relaxation

Kidney:

• Reduce renal blood flow, GFR and urine volume

• Nephrotoxicity

Liver: no hepatotoxicity
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 Local Anesthetics

1/6/2019 Dr.Kiprop J. 99
 Introduction
• Local anaesthetic agents reversibly block impulse conduction
along nerve axons and other excitable membranes.

• Local anesthesia is the condition that results when sensory

transmission from a local area of the body to the CNS is
blocked.

• Methods of administration:
– Nerve Block

– Infiltration

– Topical

1/6/2019 Dr.Kiprop J. 100

1/6/2019 Dr.Kiprop J. 101
 Classification
AMIDES ESTERS

• Lidocaine Cocaine

• Bupivacaine Procaine

• Ropivacaine Tetracaine

• Dibucaine Benzocaine

• Prilocaine Amethocaine

• Etidocaine

• Mepivacaine

1/6/2019 Dr.Kiprop J. 102

 Amides Vs Esters

1/6/2019 Dr.Kiprop J. 103

 Local Anaesthetics
Esters Amides
• Unstable in solution • Slow-onset

• Fast-onset • Long-acting

• Short acting

• Allergic-reactions common

1/6/2019 Dr.Kiprop J. 104

 Classification— Duration of Action
• procaine
short • chloroprocaine

• Lidocaine, mepivacaine, articaine(fast-onset)

medium • Prilocaine

• Tetracaine, etidocaine
long • Bupivacaine, ropivacaine, levobupivacaine

1/6/2019 Dr.Kiprop J. 105

 Introduction: Chemistry
• Each local anaesthetic agent consists of lipophilic group
connected via ester/amide to an ionized group.

• Esters are prone to hydrolysis therefore shorter duration of

action

• LAs are weak bases

• They exist as either uncharged base/ cation

• Cation is more active at receptor site since it cannot readily

escape from closed channels

• Uncharged form penetrates membranes faster

1/6/2019 Dr.Kiprop J. 106
 Mechanism of Action
• Local anaesthetics act mainly by inhibiting Na+ influx in
neuronal cell membrane. They block voltage-gated Na+
channels.

• Influx of Na+ is interrupted thus no action potential.

• Hence no impulse from 1st order neuron

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 Voltage-Gated Sodium Channels

1/6/2019 Dr.Kiprop J. 108

 Local Anaesthetics
• LA gain access to their receptors from cytoplasm or plasma
membrane

• Non-ionized form reaches effective intracellular levels

• Ionized form more effective

1/6/2019 Dr.Kiprop J. 109

1/6/2019 Dr.Kiprop J. 110
 Cont..
• Affinity for receptors depends on state of channel itself.

• High concentrations of K+ enhance LA activity

• High conc. of Ca2+ antagonize LA

• Inflammation reduces effects of LA because a smaller % LA is

non-ionized & available across membrane

• This is perhaps due to peroxynitrite

1/6/2019 Dr.Kiprop J. 111

 Pharmacokinetics
• Local anesthetics are usually administered by injection into
dermis and soft tissues located in the area of nerves.

• Absorption and distribution are not as important in

controlling the onset of effect as in determining the rate of
offset of local analgesia, and the likelihood of CNS and cardiac
toxicity.

• Topical application of local anesthetics (eg, transmucosal or

transdermal) requires drug diffusion for both onset and offset
of anesthetic effect.
1/6/2019 Dr.Kiprop J. 112
 Cont..

• Onset of action may be accelerated by the addition of sodium

bicarbonate, which enhances intracellular access of these
weakly basic compounds.

• Articaine has the fastest onset of action.

1/6/2019 Dr.Kiprop J. 113

 Absorption
• Systemic absorption of injected local anesthetic from the site
of administration is determined by several factors, including
dosage, site of injection, drug-tissue binding, local blood flow,
use of vasoconstrictors and the physicochemical properties of
the drug itself.

• Highly vascularity results in more rapid absorption and thus

higher blood levels.

• Poorly perfused tissue such as tendon, dermis, or

subcutaneous fat results in prolonged local effect.

1/6/2019 Dr.Kiprop J. 114

 Vasoconstictors
• For regional anesthesia involving block of large nerves,
maximum blood levels of local anesthetic decrease according
to the site of administration in the following order: intercostal
(highest) > caudal > epidural > brachial plexus > sciatic nerve
(lowest).

• Vasoconstrictor reduce systemic absorption of local

anesthetics from the injection site by decreasing blood flow in
these areas. It enhances and prolongs the DOA of the drug.

1/6/2019 Dr.Kiprop J. 115

 Vasoconstictors
• Vasoconstrictors are less effective in prolonging anesthetic
action of the more lipid-soluble, long-acting drugs (eg,
bupivacaine and ropivacaine), possibly because these
molecules are highly tissue-bound.

• Cocaine is unique owing to its intrinsic sympathomimetic

properties.

1/6/2019 Dr.Kiprop J. 116

 Distribution
• The amide local anesthetics are widely distributed after
intravenous bolus administration.

• There is also evidence that sequestration can occur in

lipophilic storage sites (eg, fat).

• It has an initial rapid distribution phase, which consists of

uptake into highly perfused organs such as the brain, liver,
kidney, and heart, followed by

• A slower distribution phase occurs with uptake into

moderately well-perfused tissues, such as muscle and GIT
1/6/2019 Dr.Kiprop J. 117
 Metabolism and Excretion
• Converted into water soluble metabolites and excreted in
urine.

• Amides in the liver and esters in plasma

• Since local anesthetics in the uncharged form diffuse readily

through lipid membranes, little or no urinary excretion of the
neutral form occurs.

• Acidification of urine promotes ionization of the tertiary

amine base to the more water-soluble charged form, which is
more readily excreted.
1/6/2019 Dr.Kiprop J. 118
 Metabolism and Excretion
• Ester-type local anesthetics are hydrolyzed very rapidly in the
blood by circulating butyrylcholinesterase
(pseudocholinesterase) to inactive metabolites.

• Therefore, procaine and chloroprocaine have very short

plasma half-lives (< 1 minute).

• The amide linkage of amide local anesthetics is hydrolyzed by

liver microsomal cytochrome P450 isozymes.

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 Metabolism and Excretion
• variable rate of liver metabolism of individual amide
compounds, the approximate order being prilocaine (fastest)
> lidocaine > mepivacaine > ropivacaine > bupivacaine and
levobupivacaine (slowest).

• Toxicity from amide-type local anesthetics is more likely to

occur in patients with hepatic disease.

• Decreased hepatic elimination of local anesthetics with

reduced hepatic blood flow.

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 Pharmacodynamics
• The blockade of sodium channels by most local anesthetics is
both voltage- and time-dependent:

• Channels in the rested state, which predominate at more

negative membrane potentials, have a much lower affinity for
local anesthetics than activated (open state) and inactivated
channels, which predominate at more positive membrane
potentials

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 B. Structure-Activity Characteristics Of
Local Anesthetics
• The smaller and more lipophilic the local anesthetic, the faster
the rate of interaction with the sodium channel receptor.

• Potency is also positively correlated with lipid solubility

• Lidocaine, procaine, and mepivacaine are more water-soluble

than tetracaine, bupivacaine, and ropivacaine.

• The latter agents are more potent and have longer durations
of local anesthetic action.

1/6/2019 Dr.Kiprop J. 122

 Cont..
• These long-acting local anesthetics also bind more extensively
to proteins and can be displaced from these binding sites by
other protein-bound drugs.

• In the case of optically active agents (eg, bupivacaine), the

S(+)isomer can usually be shown to be moderately more
potent than the R(-) isomer.

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 C. Other Actions On Nerves
• Local anesthetics are capable of blocking all nerves, their
actions are not limited to the desired loss of sensation.

• Motor paralysis may limit the ability of the patient to

cooperate during obstetric delivery or ambulate after
outpatient surgery.

• During spinal anesthesia, motor paralysis may impair

respiratory activity.

• Residual autonomic blockade interferes with bladder

function resulting in urinary retention and may cause
hypotension
1/6/2019 Dr.Kiprop J. 124
 Cont..
• Differential sensitivity of various types of nerve fibers to local
anesthetics depends on fiber diameter, myelination,
physiologic firing rate, and anatomic location.

• In general, smaller fibers are blocked more easily than larger

fibers, and myelinated fibers are blocked more easily than
unmyelinated fibers.

• Fibres at the periphery are blocked first due to early exposure

to higher conc. of LA
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1/6/2019 Dr.Kiprop J. 126
 Other Tissues
• Weak blocking effects on skeletal muscle neuromuscular
transmission, but these actions have no clinical application.

• The mood elevation induced by cocaine reflects actions on

dopamine or other amine-mediated synaptic transmission in
the CNS rather than a local anesthetic action on membranes.

1/6/2019 Dr.Kiprop J. 127

 Clinical Uses
• Minor surgical procedures.

• Local anesthetics are also used in spinal anesthesia and to

produce autonomic blockade in ischemic conditions

• Slow epidural infusion at low concentrations has been used

successfully for postoperative analgesia….tachyphylaxis

• Intravenous local anesthetics may be used for the

perioperative period analgesia.

• Parenteral forms of local anesthetics are sometimes used

adjunctively in neuropathic pain states.

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 Toxicity
CNS Effects

• The important toxic effects of most local anesthetics are in the

CNS.

• All local anesthetics are capable of producing a spectrum of

central effects, including light-headedness or sedation,
restlessness, nystagmus, and tonic-clonic convulsions.

• Severe convulsions may be followed by coma with respiratory

and cardiovascular depression.

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 Toxicity
Cardiovascular Effects

• With the exception of cocaine, all local anesthetics are

vasodilators.

• Patients with pre-existing cardiovascular disease may develop

heart block and other disturbances of cardiac electrical
function at high plasma levels of local anesthetics.

• Bupivacaine, a racemic mixture of two isomers may produce

severe cardiovascular toxicity, including arrhythmias and
hypotension. The (S)isomer, levobupivicaine, is less
cardiotoxic.
1/6/2019 Dr.Kiprop J. 130
 Cont…
• Cardiotoxicity has also been reported for ropivicaine.

• The ability of cocaine to block norepinephrine reuptake at

sympathetic neuroeffector junctions and the drug's
vasoconstricting actions contribute to cardiovascular toxicity.

• When cocaine is used as a drug of abuse, its cardiovascular

toxicity includes severe hypertension with cerebral
hemorrhage, cardiac arrhythmias, and myocardial infarction.

1/6/2019 Dr.Kiprop J. 131

 Cont..
• Prilocaine is metabolized to products that include o-toluidine,
an agent capable of converting hemoglobin to
methemoglobin. Though tolerated in healthy persons, even
moderate methemoglobinemia can cause decompensation in
patients with cardiac or pulmonary disease.

• The ester-type local anesthetics are metabolized to products

that can cause antibody formation in some patients.

1/6/2019 Dr.Kiprop J. 132

 Cont..
• Allergic responses to local anesthetics are rare and can
usually be prevented by using an agent from the amide
subclass.

• Local neurotoxic action in high conc. that includes histologic

damage and permanent impairment of function.

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 Toxicity
• With the exception of cocaine, all local anesthetics are
vasodilators.

• Cocaine leads to vasoconstrition & hypertension. Hence

ulceration.

• Resuscitation from bupivacaine toxicity is by propofol

• Pregnancy increases susceptibility to LA toxicity

1/6/2019 Dr.Kiprop J. 134

 Treatment of Toxicity
• Severe toxicity is treated symptomatically; there are no
antidotes.

• Convulsions are usually managed with intravenous diazepam

or a short-acting barbiturate such as thiopental.

• Occasionally, a neuromuscular blocking drug may be used to

control violent convulsive activity.

• Hyperventilation with oxygen is helpful.

• The cardiovascular toxicity of bupivacaine overdose is difficult

to treat and has caused fatalities in healthy young adults.
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 Management of toxicity

1/6/2019 Dr.Kiprop J. 136

 References
1. Trevor AJ, Katzung, BG & Maters SB (2007). Katzung & Trevor’s
Basic & Clinical Pharmacology, 11th Edition. Chapter 25, 429-
448. USA. McGraw-Hill.

2. Brunton LL, Chabner BA & Knollmann BC (2011) Goodman &

Gilman's The Pharmacological Basis of Therapeutics, 12th
edition. Chapter 13, 221-240.

3. www.emedicine.Medscape.com/article/0verview.

4. www.drugs.com/...html
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 Thank You.

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