General and Local
anaesthetic agents
Mr. Kamwela
OBJECTIVES
On completion of this lesson, students will be able to:
1. Explain information related to local anesthetics
2. Demonstrate understanding of general anesthetics
3. describe the four stages of general anesthesia.
4. Identify drugs that are used in conjunction with
anesthesia
INTRODUCTION
General anaesthesia is the absence of sensation
associated with a reversible loss of consciousness.
General anaesthesia usually involves the
administration of different drugs for:
1. premedication
2. induction of anaesthesia
3. maintenance of anaesthesia
Premedication
1. relief from anxiety; benzodiazepines
2. reduction in secretions and vagal reflexes;
antimuscarinics
3. Postoperative antiemesis; antiemetics
4. pain relief; opioid analgesics, NSAIDs
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.
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.
Stage 2: Disinhibition
In stage 2, the patient appears to be delirious and excited.
Amnesia occurs, reflexes are enhanced, and respiration is
typically irregular; retching and incontinence may occur.
STAGES OF ANESTHESIA
Stage 3: Surgical Anesthesia
In stage 3, the patient is unconscious and has no pain
reflexes; respiration is very regular, and blood pressure is
maintained.
Stage 4: Medullary Depression
In stage 4, the patient develops severe respiratory and
cardiovascular depression that requires mechanical and
pharmacologic support to prevent death.
Inhalation agents
Inhaled anesthetics have varying potency in
proportion to their lipid solubility.
MAC (minimal alveolar anesthetic concentration) is
defined as the alveolar concentration of an inhaled
anesthetic that is required to prevent a response to a
standardized painful stimulus in 50% of patients
MAC is a measure of potency: ED50.
The more lipid soluble the anesthetic, the lower the
MAC and the greater the potency
Inhalation agents
The main factors that determine the speed of
induction and recovery
1. Properties of the anaesthetic:
blood: gas partition coefficient (i.e. solubility in
blood)
oil: gas partition coefficient (i.e. solubility in fat)
2. Physiological factors:
alveolar ventilation rate
cardiac output
Inhalation agents
Halothane
was the first fluorinated volatile anaesthetic.
MOA
Potentiates GABA action on GABAA receptors and opens K+
channels to reduce neuronal activity, especially in cerebral
cortex, thalamus and hippocampus.
Lipid solubility important for action.
Inhalation agents
Abs/Distrib/Elim
Given by inhalation with oxygen.
Rate of equilibration with body and onset of
anaesthesia depends on the ‘blood/gas solubility’.
Halothane has a medium onset of action.
Mostly eliminated unchanged by the lungs.
Inhalation agents
Clinical use
Maintenance, and less frequently induction, of general
anaesthesia.
• It has been largely replaced by less toxic agents e.g
sevoflurane and isoflurane.
Adverse effects
Cardiac and respiratory depression. Cardiac dysrhythmias.
Post-operative nausea and vomiting.
Rarely malignant hyperthermia and liver damage (due to
metabolites).
Inhalation agents
Nitrous oxide
CNS depression, unconsciousness (in combination
with other anaesthetics). Analgesia. Euphoria
Abs/Distrib/Elim
Administered by inhalation.
Low blood/gas partition coefficient results in rapid
onset of action.
Eliminated unchanged via lungs. No metabolism.
Inhalation agents
MOA
Reduces opening of NMDA receptor channels.
Increases opening of potassium channels.
No action on GABAA receptors.
Analgesic action inhibited by opioid antagonists,
suggesting release of endogenous opioids.
Inhalation agents
Clinical use
General anaesthesia.
Because of low potency will not produce full surgical anaesthesia
by itself; must be combined with more potent agents.
In subanaesthetic doses used as analgesic for childbirth and
emergency pain relief.
Adverse effects
Postoperative nausea and vomiting, and prolonged exposure to
nitrous oxide may result in bone marrow depression.
Oxygen may be required during recovery due to possibility of
‘diffusion anoxia’.
Inhalation agents
Isoflurane
is the most widely used volatile anaesthetic.
It is more soluble in blood than sevoflurane or enflurane
(blood/gas ratio = 1.4) and so onset and recovery are slower.
It causes dose related hypotension by decreasing systemic
vascular resistance.
Only 0.2% of the absorbed dose is metabolized and none of
the metabolites has been associated with hepatotoxicity.
Inhalation agents
Sevoflurane
has a low blood gas coefficient (0.6) and emergence and
recovery from anaesthesia are rapid.
This may necessitate early postoperative pain relief.
It is very pleasant to breath and is a good choice if an
inhalation agent is required for induction, for example, in
children.
Intravenous agents
Thiopental
Ultrashort-acting anaesthetics.
Pharmacokinetics
I.v. injection.
Very lipid soluble allowing rapid CNS penetration.
Rapid onset (20s) and short acting (5–10min).
Short duration due to rapid redistribution in body,
particularly to muscle.
Thiopental is slowly metabolised (T0.5 8–10h)
Intravenous agents
MOA
Binds to particular site (different to benzodiazepine binding
site) on GABAA receptor to enhance opening of intrinsic Clchannel by GABA.
Higher concentrations directly activate receptor.
Clinical use
Anaesthesia for short procedures and to induce anaesthesia
for subsequent maintenance with volatile agents.
Intravenous agents
Dose
by slow intravenous injection usually as a 2.5% (25 mg/mL)
solution,
ADULT over 18 years, initially 100–150 mg (reduced in
elderly) over 10–15 seconds (longer in elderly), followed by
further quantity if necessary according to response after 30–
60 seconds; or up to 4 mg/kg (max500 mg);
CHILD 1 month–18 years, initially up to 4 mg/kg, then 1
mg/kg repeated as necessary (max. total dose 7 mg/kg)
Intravenous agents
Adverse effects
Cardiovascular and respiratory depression
Hangover
reconstituted solution is highly alkaline—
extravasation causes tissue necrosis and severe pain
Intravenous agents
KETAMINE
takes effect more slowly (1–2 min) than thiopental
Dissociative anesthetic
NMDA-receptor antagonist
high incidence of dysphoria, hallucinations, etc.
during recovery,
Cardiovascular stimulation, increased intracranial
pressure
Intravenous agents
dose
By intramuscular injection, short procedures, initially 6.5–13
mg/kg, adjusted according to response (10 mg/kg usually
produces 12–25 minutes of surgical anaesthesia)
Diagnostic manoeuvres and procedures not involving
intense pain, initially 4 mg/kg
By intravenous injection over at least 60 seconds, short
procedures, initially 1–4.5 mg/kg, adjusted according to
response (2 mg/kg usually produces 5–10 minutes of surgical
anaesthesia)
Intravenous agents
Propofol
is the most widely used intravenous anaesthetic.
It induces anaesthesia within 30 s.
Recovery from propofol is rapid without nausea or hangover.
Propofol is inactivated by redistribution and glucuronide
conjugation in the liver.
The rapid elimination of propofol prevents significant
cumulation and recovery from continuous infusion is
relatively fast.
Local anaesthetic agents
Local Anaesthetics: What are They?
Produce reversible blockade of nerve impulse
generation and transmission
Leads to loss of sensation in affected organs or
regions of the body without loss of consciousness
Weak bases, 2o or 3o aromatic amines that are poorly
water soluble;
Most exist as amphiphilic cations
Basic Structure
Structures include 3
regions: aromatic ring,
intermediate (-CH-)n chain,
and amine moiety;
The aromatic ring is linked
to the intermediate chain
via an amide or ester link as
shown
Local Anesthetics
Local anesthetics provide regional anesthesia.
Drugs come in 2 types.
1. Esters include procaine, cocaine, benzocaine, which
are metabolized by plasma and tissue esterases.
2. Amides include lidocaine, bupivacaine,
mepivacaine which metabolized by liver amidases.
The Aromatic Ring
Confers hydrophobicity to the molecule
The more hydrophobic it is, the more potent and
longer the duration of action
Lipid solubility increases access to site of action,
decreases metabolic breakdown, and increases
toxicity
Intermediate Chain
Consist of 2 or 3 hydrocarbon chains connected to
the aromatic ring by amide(-N-C-) or ester(-C-O-)
linkages
Ester LA are rapidly hydrolysed by plasma
pseudocholinesterases, while amides are more stable
Most topical LA are esters, while the majority of LA
injectables are amides
Amino Terminal
Ionisable group responsible for the hydrophilicity of
the molecule;
Confers amphilicity to the LA molecule
This ionized group interacts with the receptor ion
channel to inhibit impulse generation or propagation
Mechanisms of LA action
Inhibition of nerve generation and propagation result
from blockade of Na+ flux through ion channels
LA molecules diffuse through the membrane into the
cytoplasm where the hydrophilic amino group
interacts with the ion channel proteins
Amphiphilic nature of the LA molecules enhances
incorporation into membrane interphases
Mechanisms of LA action
Nerve fiber sensitivity
Nerve fibers most sensitive to blockade are of smaller
diameter and have high firing rates
The order of sensitivity is:
type B and C > type Aδ > type Aβ and Aγ > type Aα
Recovery is in reverse order
ROUTES OF ADM
The usual routes of administration include topical
application (eg, nasal mucosa, wound [incision site]
margins), injection in the vicinity of peripheral nerve
endings (perineural infiltration) and major nerve
trunks (blocks), and injection into the epidural or
subarachnoid spaces surrounding the spinal cord
USES OF LOCAL ANAESTHETICS
tooth extraction
Initial assessment of minor surgery
Measurement of IOP using applanation tonometry
Removal of foreign bodies from the eye
Ocular surgery
Correction of strabismus
Topical Local Anaesthetics-Eye
Often prepared as solution of their hydrochloride salts
Efficacy determined by their ability to suppress corneal activity
Efficacy is defined as the maximum effective concentration
(MEC) i.e. the concentration at which maximal suppression is
obtained, beyond which no further increase in suppression is
observed;
In clinical practice, optimum effective concentration is used, i.e.
the dose used to achieve therapeutic objective with minimal side
effects
 0.5% tetracaine is less irritating to the eye than the maximum effective
concentration of 1% and thus is better suited for clinical use.
Tetracaine
An ester of para-aminobenzoic acid (PABA)
Available as 0.5 % and 1 % solutions
Onset of action 10 –20 seconds
Duration of action 10 –20 mins
DO NOT inject, can cause significant systemic toxicity
Used primarily for tonometry and minor superficial
procedures
May be used for cataract surgery and lens implantation
Side Effects include stinging and burning, allergic reactions,
and ultrastructural damage to the corneal membranes
Tetracaine drops are used in ophthalmology to
anaesthetize the cornea, but less toxic drugs such as;
oxybuprocaine and proxymetacaine, which cause
much less initial stinging, are better.
Injectable LAs
Used for more extensive ophthalmic procedures
For infiltration or regional block anaesthesia
1 % solution of lidocaine (preservative-free) injected into the
anterior chamber for cataract surgery
Duration of action varies depending on binding to nerve
protein, dose, clearance form site, blood flow
Lidocaine
is the most widely used agent.
It acts more rapidly and is more stable than most other local
anaesthetics.
When given with epinephrine, its action lasts about 90 min.
Bupivacaine
has a slow onset (up to 30 min) but a very long duration of
action, up to 8 h when used for nerve blocks.
 It is often used in pregnancy to produce continuous
epidural blockade during labour.
It is also the main drug used for spinal anaesthesia
Vasodilation
Some LA’s have intrinsic vasodilatory properties
This reduces potency and duration of action
Lidocaine has vasodilatory action; it duration of
action is shorter than that of mepivacaine
Use of LAs with Vasoconstrictors
Vasoconstrictors such as adrenaline may be added to prolong
duration of action, localise action, delay systemic absorption, and
systemic toxicity
Long acting LAs do not benefit from vasoconstrictors
Undesirable effects of vasoconstrictors include:
 Hypoxia
 Tissue necrosis
 Delayed wound healing
 Intense vasoconstriction
 Anxiety, restlessness, tremor, palpitation, tachycardia, etc
References
Rang HP, Dale M.M. Ritter J.M. Moore P.K. (2015). Pharmacology 8th
Edition. Churchill Livingstone. UK. ISBN 978-0-7020-3471-8.
McKay G.A., Reid J.L., Walters M.R. (2013). Lecture notes: Clinical
Pharmacology & Therapeutics, 9th Edition. Wiley-Blackwell. ISBN
9781118344811.
Katzung B.G. (2011). Basic & Clinical Pharmacology, 12th edition.
McGraw Hill, Medical Publishing Division. New York. ISBN
9780071764018.