GENERAL ANAESTHESIA

Father of Modern Anaesthesia, W.T.G Morton using ether

ASSOCIATE PROFESSOR DR ROHI GHAZALI

OUTLINE
Anaesthesia ["without "sensation]

General Anaesthetics: puts person to sleep

Background & Concept Inhaled, I.V. & Balanced

Local Anaesthetics: causes loss of feeling in a part of body without affecting consciousness
Background & Concept

GA Indications & Side effects

Amide & Ester-Linked LA Indications & Side effects

GENERAL ANAESTHETICS

reversible loss of conciousness

Stages of Anaesthesia: Arthur Guedel (1883-1956)

Diethyl Ether ( solubility in blood, slow onset of central action)

I.
II.

Stage of Analgesia: analgesia without amnesia.

Stage of Excitement: delirium, excited, irregular respiration+amnesic.

III. Stage of Surgical Anaesthesia: recurrence of regular respiration + apnea. ocular signs ( anaesthesia). IV. Stage of Medullary Depression: stoppage of respiration till DEATH.

Types of General Anaesthesia

A. Inhaled Agents volatile liquids or gases. Intravenous Agents drugs administered intravenously either alone or in combination. Balanced Agents combination of IV and inhaled drugs including muscle relaxants, LAs, opioid analgesics, CVS drugs.

B.

C.

Mechanism of Action
UNKNOWN!! acts on CNS by modifying electrical activity of neurons at a molecular level by modifying functions of ION CHANNELS.

Anaesthetic Suppression of Physiological Response to Surgery

Inhalational Agents
1. Halogenated HydroCarbon (HHC) - Halothane - Enflurane - Isoflurane - Methoxyflurane - Desflurane - Sevoflurane 2. Nitrous oxide 3. Older agents - Diethyl ether - Chloroform - Cyclopropane
(obsolete: slow onset + recovery + highly explosive)
Ether Nitrous oxide

Pharmacokinetics of Inhaled Anaesthetics

1.

Amount that reaches brain Indicated by oil:gas ratio (lipid solubility). Partial Pressure of anaesthetics 5% anaesthetics = 38 mmHg. Solubility of gas into blood blood:gas ratio, anaesthetics will arrive at brain. Cardiac Output CO= greater induction time

2.

3.

4.

Pathway for General Anaesthetics

DEPTH of anaesthesia induced by an inhaled anesthetic depends primarily on the PARTIAL PRESSURE

Increase in Anaesthetic Partial Pressure in Blood is Related to its Solubility

Agents of low solubility in blood (nitrous oxide), the partial pressure in blood rises quickly.

Rate of Entry into the Brain: Influence of Blood and Lipid Solubility

LOW solubility in blood= fast induction and recovery HIGH solubility in blood= slower induction and recovery.

MAC
Minimum Alveolar Concentration (%) : A measure of potency. 1MAC is the concentration necessary to prevent responding in 50% of population. Values of MAC are additive: AVOID cardiovascular depressive concentration of potent agents.

Anaesthetic

Blood: Gas partition coeff

Minimum Alveolar Concentration (MAC) %

Nitrous oxide
Desflurane

0.47
0.42

> 100
6-7

Sevoflurane
Isoflurane Enflurane Halothane Methoxyflurane

0.69
1.40 1.80 2.30 12.00

2.0
1.4 1.7 0.75 0.16

MAC = a measure of potency A close correlation with lipid solubility ie. Overton-Meyer correlation.

Correlation of anaesthetic potency with lipid:gas partition coefficient. Anaesthetic potency in humans is expressed as minimum alveolar partial pressure (MAC) required to produce surgical anaesthesia. There is a close correlation with lipid solubility, expressed as the oil:gas partition coefficient.

ELIMINATION
Mainly via lungs Low blood solubility Low brain solubility Faster elimination Liver metabolism: Methoxyflurane > Halothane > Isoflurane > Nitrous oxide TOXICITY PARTLY RELATED TO METABOLISM: Halothane Trifluoroacetic acid + Br - + Cl (normal pathway)

Halothane Chlorotrifluoroethyl free radical (low O2 tension) (HEPATOTOXIC)

Methoxyflurane Fl ions (NEPHROTOXIC)

NITROUS OXIDE
used in surgery and dentistry for its anaesthetic + analgesic effects.

Anaesthesia: together with other inhalational or i.v. agents. concentration: 50-70% in oxygen
Note: NOT suitable as sole anaesthetic
sweet smelling + taste + irritant.

Analgesia concentration 50% in oxygen (ENTONOX ) analgesia without loss of consciousness

NITROUS OXIDE
Onset of action: rapid, beginning within 15 - 30 s.

Duration of action: last around 1 - 3 m. unless more of the gas is administered, it will be out of the system within 5 - 10 m.
Side effects: risk of bone marrow depression (accumulates in gaseous cavities). megaloblastic anaemia. Contraindication: pregnancy (teratogenic + foetotoxic).

OTHER INHALATIONAL AGENTS

Ether: analgesic + muscle relaxant properties. obsolete except where modern facilities are not available.
slow onset + recovery, with postoperative nausea + vomiting. highly explosive. irritant to respiratory tract.

Enflurane: faster induction + recovery than halothane (less accumulation in fat) less metabolism than halothane, less risk of toxicity. some risk of epilepsy-like seizures. Desflurane: similar to isoflurane but with faster onset and recovery. respiratory irritant, so liable to cause coughing and laryngospasm useful for day case surgery.

Isoflurane:
similar to enflurane but lacks epileptogenicity. may precipitate myocardial ischaemia in patients with coronary disease. irritant to respiratory tract.
Sevoflurane: similar to desflurane, with lack of respiratory irritation.

TOXICITY OF HHC ANAESTHESIA

Hepatotoxicity (esp. halothane- hepatitis)

Nephrotoxicity (esp. methoxyflurane)

Malignant hyperthermia: all HHC anaesthetics - potentially lethal. genetic disorder of skeletal muscle in susceptible individuals under HHC. symptoms include: tachycardia, hypertension, muscle rigidity, hypoterthermia due to excessive release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle.

Intravenous Agents
Intravenous anaesthetics act much more rapidly, producing unconsciousness in about 20 seconds as soon as the drug reaches the brain from its site of injection. Example: thiopentone etomidate propofol are normally used for induction of anaesthesia.

Intravenous Agents
1. Barbiturates thiopentone methohexital secobarbital 2. Propofol

3. Ketamine
4. Benzodiazepines midazolam diazepam

5. Opioid analgesics fentanyl sufentanil remifentanil

6. Misc. sedative-hypnotics etomidate dexmedetomidine

KETAMINE
Ketamine is used for veterinary medicine. slow onset BUT rapid-acting GA & causes profound analgesia + has a wide margin of safety. MOA: on multiple receptors (the nightmare of the pharmacologist).

a dissociative anaesthetic (1963) to replace phencyclidine (PCP) ie. psychomimetic.

misused & abused drug ie. Super K" or "K. pleasant feeling of being floating + dreamy states + hallucinations + amnesia, BP + respiratory depression. bladder dysfunction.

PROPOFOL
milk of amnesia ~ barbiturates (i.v.) fast onset, very fast recovery with NO hangover. very rapidly liver metabolism + excreted in urine.

patients feel better, in immediate post-op period because nausea + vomiting. causes PAIN at injection site (with pain killers eg. opioid)

PROPOFOL
MOA: GABAA receptor as a potential target of anesthetics acton. Uses: induction and maintenance of anaesthesia as part of total i.v. or balanced anaesthesia. prolonged sedation in ICU patients (continuous infusion). Adverse effects: BP. cardiovascular & respiratory depression,

CONCLUDING REMARKS: Ideal Properties of Anaesthetic Drugs

1. 2.

Smooth + rapid induction of anaesthesia Rapid recovery after cessation Minimum adverse effects Wide margin of safety Adequate skeletal muscle relaxation

3. 4.
5.

Combination of drugs

anaesthetic protocols

SUMMARY

Drug type and name

Mechanism of action

Inhalational Halothane Enflurane Isoflurane Methoxyflurane Desflurane Sevoflurane Nitrous oxide

Intravenous Barbiturates BDZ Opioids Propofol Ketamine Facilitate inhibitory action of GABA at the GABAA receptor by altering Cl- channel opening Agonists at opioid receptors Unclear Antagonist at the NMDA subtype of the excitatory glutamic acid receptor

Non-specific interactions of these agents with the lipid matrix of the nerve membrane which leads to secondary changes in ion flux? Directly act at the GABAA receptor-chloride channel?

Drug

Speed of induction and recovery

Main unwanted effect(s)

Notes

Thiopental Fast (cumulation occurs, giving slow recovery) 'Hangover' Etomidate Fast onset, fairly fast recovery Propofol Fast onset, very fast recovery Slow onset, after-effects common during recovery

Cardiovascular and respiratory depression

Widely used as induction agent for routine purposes

Excitatory effects during Less cardiovascular and respiratory induction and recovery depression than with thiopental Adrenocortical suppression Causes pain at injection site Cardiovascular and respiratory depression Psychotomimetic effects following recovery Postoperative nausea, vomiting and salivation Raised intracranial pressure Rapidly metabolised Possible to use as continuous infusion Causes pain at injection site Produces good analgesia and amnesia

Ketamine

Midazolam Slower than other agents

Little respiratory or cardiovascular depression

LOCAL ANAESTHETICS

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LOCAL ANAESTHETICS
a transient loss of sensation in a defined region

without producing a loss of consciousness. reversibly depress excitation of nerve endings; blockade of impulse conduction along nerve axons from site of pain stimulus to CNS.
Channel Closes

Transmembrane potential (mV)

50
ation

Repolarizati

0
Channel Opens

Depolariz

Action Potential
Cocaine blocks
Resting

on

-50

Resting

-100 0

Undershoot

5 Milliseconds

10

15

History
Cocaine is found in the leaves of Erythroxylon coca, a South American shrub (high altitude in the Andes). Cocaine was introduced into clinical use by chemist Albert Niemann as a local anaesthetic in Germany in 1884. Physician Sigmund Freud used the stimulant effect of cocaine to treat morphine addiction in patients. In 1884, an ophthalmologist Carl Koller used it as the first local anaesthetic on a patient with glaucoma. 1886: John S. Pemberton invented Coca Cola, combining cocaine with Cola nitida extract (kola nut).

Mechanism of Action: Sodium Channels

A small machine with: Ion selector (very specific for Na+) Voltage sensor Gate connected to voltage sensor opens when voltage rises, Na+ enters cell. Inactivation gate closes when voltage gets to +30 mV, ending Na+ flux.
Outside
+++++ Selectivity 70-90 Filter Voltage sensor

mV at rest
----Gate Local Anaesthetic Inactivation gate

Inside

Mechanism of Action:
Local anesthetics blocks Na+ channel from intracellular side: must enter neuron to work lipophilicity, potency [unionized], potency adding bicarbonate, unionized fraction Tetrodotoxin (TTX) binds Na+ channel from outside.

Zombie powder

Factors Affecting Reaction of Local Anaesthetics

Lipid solubility lipid solubility nerve penetration, block sodium channels + faster onset of action. more tightly local anaesthetics bind to protein, duration of onset action. All local anesthetics are weak bases. So, [unionized], faster onset action. pH influence usually at range 7.6 8.9. adding bicarbonate, rate of onset. in pH shifts equilibrium towards [ionized] form, delaying onset action.

Potency, pKa, Lipophilicity

Drug
Low Potency Procaine Intermediate potency Mepivacaine Prilocaine Chloroprocaine Lidocaine High potency Tetracaine Bupivacaine Etidocaine Ropivacaine Levobupivacaine

pKa
8.9 7.7 8.0 9.1 7.8 8.4 8.1 7.9 8.1 8.1

Octanol/H2O
100 130 129 810 366 5822 3420 7320 3420

Factors Affecting Reaction of Local Anaesthetics

Vasodilation Vasoconstrictor keeps anaesthetic at a longer period + prolongs action. delays absorption into bloodstream rate at which drug washes away eg. adrenaline (epinephrine) decreases vasodilator. Side effects of adrenaline adrenaline heart beat stronger & faster + makes people feel nervous.

Nerves Action:
Small diameter nerves are more easily blocked than large diameter nerves Myelinated nerves will be blocked before unmyelinated nerves. Nerves that fire frequently are preferentially blocked over nerves that fire infrequently.

LOCAL ANAESTHETICS
Administration: injection or topical ESTER GROUP Procaine (prototype) Tetracaine Benzocaine Cocaine AMIDE GROUP Lidocaine (prototype) Mepivacaine Bupivacaine Prilocaine Ropivacaine 1. Short-acting : Procaine 2. Intermediate-acting: Lidocaine Mepivacaine Cocaine Prilocaine 3. Long-acting: Tetracaine Bupivacaine Ropivacaine

LAs are weak bases (lipid soluble) + 3 amines.

Pharmacokinetics
Systemic absorption is determined by: dose & physicochemical properties of drug use of vasoconstrictor agent tissue perfusion, site of injection +drug-tissue binding Metabolism: - ester-linked LA (e.g. procaine) rapidly hydrolyzed by plasma cholinesterase to produce p-aminobenzoic acid derivatives short t1/2

- amide-linked LA (e.g. lignocaine, prilocaine) metabolised mainly by N-dealkylation in liver (metabolites often active) longer activity

METHODS OF ADMINISTRATION
1. Surface anaesthesia topical application to external or mucous surface. LA must penetrate tissues. 2. Infiltration anaesthesia Injected directly into tissues to act on local nerve endings, usually with a vasoconstrictor (adrenaline). Effects of vasoconstrictors: in effect of LA and duration of effect of LA in toxicity of LA

METHODS OF ADMINISTRATION
3. Nerve block i. In spinal anaesthesia - intrathecal block. ii. In epidural anaesthesia - injected outside dura. iii. infiltration of anaesthetic - around a single nerve or nerve trunks. 4. IV regional anaesthesia i.v. into an exsanguinated limb (Biers block). A tourniquet prevents agent reaching systemic circulation.

Toxicity
LAs depress other excitable tissues: BRAIN (CNS) HEART smooth muscle neuromuscular junction TWO major forms of LA toxicity: Systemic toxicity ??????? Direct neurotoxicity from local effects of drugs when administered close to spinal cord and other major nerve trunks >> lidocaine transient neuropathic symptoms
e.g for spinal anaesthesia

ESTER-LINKED LA
PROCAINE: Novocaine Indications: infiltration and nerve block local anaesthesia (NOT effective for surface anaesthesia). rapidly metabolized by esterase enzymes and used in patients with liver dysfunction. is not sufficiently effective without a vasoconstrictor. one of the least toxic of currently available local anaesthetics. incidence of allergy is greater than amide-type agents. should not be used in patients taking sulfonamide. Adverse effects: acute toxicity allergy vasodilation

AMIDE-LINKED LA
LIDOCAINE (lignocaine) : prototype local anaesthetic. Indications: all types of LA ( infiltration, nerve block, topically) also as antiarrhythmic agent anaesthesia of only short duration when used without a vasoconstrictor. Pharmacokinetic: quickly absorbed + dealkylated in liver. Toxicity: -ventricular fibrilation or cardiac arrest (massive OD). -CNS effects. -Intermediate in toxicity: twice as toxic as procaine but < toxic than more potent agents, e.g., tetracaine.

SUMMARY
Anesthetic pKa Onset Duration (with adrenaline) in minutes 45 - 90 120 - 240 Max Dose (with adrenaline) 8mg/kg 10mg/kg 4.5mg/kg 7mg/kg 2.5mg/kg 3mg/kg 5mg/kg 7.5mg/kg 4.0mg/kg 7mg/kg

Procaine Lidocaine

9.1 7.9

Slow Rapid

Bupivacaine Prilocaine Articaine

8.1 7.9 7.8

Slow Medium Rapid

4 hours 8 hours 90 - 360 140 - 270

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