General Anesthesia

By:Asst. Prof. Yogendra Mavai

M.Pharm (Pharmacology)

ShriRam College of PharmacyBanmore

1-Introduction and History of General anesthesia

2- Properties of ideal General anesthetic

3- Classification of General anesthetic agents

4- Mechanism of Anesthesia

5- Stages of Anesthesia

6- Inhalation anesthetic agents

7- Intravenous anesthetic agent

8- Complications of General anesthesia

9- Preanesthetic medication

Contents

General anaesthetics (GAs) are drugs which produce reversible loss of all senations and consciousness.

Or, General anaesthetics (GAs) are a class of drugs used to depress the CNS to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures.

General Anesthetics

History of Anesthesia

Ether synthesized in 1540 by Cordus Ether used as anesthetic in 1842 by

Dr. Crawford W. Long Ether publicized as anesthetic in

1846 by Dr. William Morton Chloroform used as anesthetic in

1853 by Dr. John Snow

History of Anesthesia

History of Anesthesia

Endotracheal tube discovered in 1878

Local anesthesia with cocaine in 1885

Thiopental first used in 1934 Curare first used in 1942 - opened

the “Age of Anesthesia”

Basic Principles of Anesthesia

Anesthesia defined as the abolition of sensation

Analgesia defined as the abolition of pain “Triad of General Anesthesia”

need for unconsciousnessneed for analgesianeed for muscle relaxation

General anaesthesia has many purposes including:Analgesia — loss of response to pain,Amnesia — loss of memory,Immobility — loss of motor reflexes,Hypnosis — loss of consciousness,Skeletal muscle relaxation.

Purpose

For the patient- It should be pleasant, nonirritating, should not cause nausea or vomiting. Induction and recovery should be fast with no after

effects. B. For the surgeon – It should provide adequate analgesia, immobility and

muscle relaxation. It should be noninflammable and non explosive so that cautery may be used.

Properties of an ideal anaesthetic

C. For the anesthetist- Its administration should be easy, controllable and versatile.

Margin of safety should be wide - no fall in BP. Heart, liver

and other organs should not be affected.

It should be potent so that low concentrations are needed and

oxygenation of the patient does not suffer.

It should be cheap, stable and easily stored.

It should not react with rubber tubing or soda lime

CLASSIFICATION

Mechanism action of anaesthetiaThe mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs.

Minimal alveolar concentration (MAC) is the lowest concentration of the anaesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision). MAC reflects capacity of the anaesthetic to enter into CNS and attain sufficient concentration in neuronal membrane.

Mayer and Overton (1901) proposed that the

anaesthetic by dissolving in the membrane lipids

increases the degree of disorder in their structure

favouring a gel-liquid transition (fluidization)

which secondarily affects the state of membrane

bound functional proteins, or expands the

membrane disproportionately (about 10 times their

molecular volume) closing the ion channels.

The biochemical mechanism of action of general anaesthetics is not yet well understood. To induce unconsciousness, anaesthetics affect the GABA and NMDA systems. For example, halothane is a GABA agonist and ketamine is an NMDA receptor antagonist

Certain fluorinated anaesthetics and barbiturates in addition inhibit the neuronal cation channel gated by nicotinic cholinergic receptor. As such, the receptor operated ion channels appear to be a major site of GA action. Unlike local anaesthetics which act primarily by blocking axonal conduction, the GAs appear to act by depressing synaptic transmission

Mode of administrationDrugs given to induce or maintain general anaesthesia are either given as:Gases or vapours (inhalational anaesthetics), Injections (intravenous anaesthetics)

InhalationInhalational anaesthetic substances are either volatile liquids or gases, and are usually delivered using an anaesthesia machine. Desflurane, isoflurane and sevoflurane are the most widely used volatile anaesthetics today. They are often combined with nitrous oxide. Older, less popular, volatile anaesthetic, include halothane, enflurane, and methoxyflurane. Researchers are also actively exploring the use of xenon as an anaesthetic.

InjectionInjection anaesthetic are used for induction and maintenance of a state of unconsciousness. Anaesthetist prefer to use intravenous injections, as they are faster, generally less painful and more reliable than intramuscular or subcutaneous injections. Among the most widely used drugs are: Propofol, Etomidate, Barbiturates such as methohexital and thiopentone/thiopental, Benzodiazepine such as midazolamKetamine is used in the UK as "field anaesthesia", for instance at a road traffic incident, and is more frequently used in the operative setting in the US.

Stages of anaesthesia

The four stages of anaesthesia were described in 1937 GAs cause an irregularly descending depression of CNS, i.e. the higher functions are lost first and progressively lower areas of the brain are involved, but in the spinal cord lower segments are affected somewhat earlier than the higher segments. The vital centres located in the medulla are paralysed the last as the depth of anaesthesia increases. Guedel (1920) described four stages withether anaesthesia, dividing the III stage into 4 planes.

Analgesia Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness. Pain is progressively abolished during this stage. Patient remains conscious, can hear and see, and feels a dream like state. Reflexes and respiration remain normal.

Though some minor and even major operations can be carried out during this stage, it is rather difficult to maintain - use is limited to short procedures.

I. Stage-

From loss of consciousness to beginning of regular respiration. Apparent excitement is seen - patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, defecation may occur. Heart rate and BP may rise and pupils dilate due to sympathetic stimulation.

No stimulus should be applied or operative procedure carried out during this stage. This stage can be cut short by rapid induction, premedication etc. and is inconspicuous in modern anaesthesia.

II. Stage- Delirium

Surgical anaesthesia Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes which may be distinguished as: •Plane 1 Roving eye balls. This plane ends when eyes become fixed. •Plane 2 Loss of corneal and laryngeal reflexes.•Plane 3 Pupil starts dilating and light reflex is lost.•Plane 4 Intercostal paralysis, shallow abdominalrespiration, dilated pupil.

III. Stage-

Medullary paralysis Cessation of breathing to

failure of circulation and death. Pupil is widely

dilated muscles are totally flabby, pulse is thready

or imperceptible and BP is very low.

IV. Stage-

Inhalational Anesthetic Agents

Inhalational anesthesia refers to the delivery of gases or vapors from the respiratory system to produce anesthesia

Pharmacokinetics--uptake, distribution, and elimination from the body

Pharmacodyamics-- MAC value

Nitrous Oxide

Prepared by Priestly in 1776 Anesthetic properties described by

Davy in 1799 Characterized by inert nature with

minimal metabolism Colorless, odorless, tasteless, and

does not burn

Nitrous Oxide

Simple linear compound

Not metabolizedOnly anesthetic

agent that is inorganic

Nitrous Oxide

Major difference is low potencyMAC value is 105%Weak anesthetic, powerful analgesicNeeds other agents for surgical

anesthesiaLow blood solubility (quick recovery)

Nitrous Oxide Systemic Effects

Minimal effects on heart rate and blood pressure

May cause myocardial depression in sick patients

Little effect on respirationSafe, efficacious agent

Nitrous Oxide Side Effects

Manufacturing impurities toxicHypoxic mixtures can be usedLarge volumes of gases can be usedBeginning of case: second gas effectEnd of case: diffusion hypoxia

Nitrous Oxide Side Effects

Inhibits methionine synthetase (precursor to DNA synthesis)

Inhibits vitamin B-12 metabolismDentists, OR personnel, abusers at risk

Halothane

Synthesized in 1956 by Suckling

Halogen substituted ethane

Volatile liquid easily vaporized, stable, and nonflammable

Halothane

Most potent inhalational anestheticMAC of 0.75%Efficacious in depressing

consciousnessVery soluble in blood and adipose

Halothane Systemic Effects

Inhibits sympathetic response to painful stimuliInhibits sympathetic driven baroreflex

response (hypovolemia)Sensitizes myocardium to effects of exogenous

catecholamines-- ventricular arrhythmias Johnson found median effective dose 2.1 ug/kg Limit of 100 ug or 10 mL over 10 minutes Limit dose to 300 ug over one hour Other medications

Halothane Systemic Effects

Decreases respiratory drive-- central response to CO2 and peripheral to O2

Respirations shallow-- atelectasis Depresses protective airway reflexes

Depresses myocardium-- lowers BP and slows conduction

Mild peripheral vasodilation

Halothane Side Effects

“Halothane Hepatitis” -- 1/10,000 cases fever, jaundice, hepatic necrosis, death metabolic breakdown products are

hapten-protein conjugates immunologically mediated assault exposure dependent

Halothane Side Effects

Malignant Hyperthermia-- 1/60,000 with succinylcholine to 1/260,000 without halothane in 60%, succinylcholine in 77%

Classic-- rapid rise in body temperature, muscle rigidity, tachycardia, acidosis, hyperkalemia family history

Halothane Side Effects

Malignant Hyperthermia (continued) high association with muscle disorders autosomal dominant inheritance diagnosis--previous symptoms, increase

CO2, rise in CPK levels, myoglobinuria, muscle biopsy

physiology--hypermetabolic state by inhibition of calcium reuptake in sarcoplasmic reticulum

Halothane Side Effects

Malignant Hyperthermia (continued) treatment--early detection, d/c agents,

hyperventilate, bicarb, IV dantrolene (2.5 mg/kg), ice packs/cooling blankets, lasix/mannitol/fluids. ICU monitoring

Susceptible patients-- preop with IV dantrolene, keep away inhalational agents and succinylcholine

Enflurane

Developed in 1963 by Terrell, released for use in 1972

Stable, nonflammable liquid

Pungent odorMAC 1.68%

Enflurane Systemic Effects

Potent inotropic and chronotropic depressant and decreases systemic vascular resistance-- lowers blood pressure and conduction dramatically

Inhibits sympathetic baroreflex responseSensitizes myocardium to effects of

exogenous catecholamines-- arrhythmias

Enflurane Systemic Effects

Respiratory drive is greatly depressed-- central and peripheral responses increases dead space widens A-a gradient produces hypercarbia in spontaneously

breathing patient

Enflurane Side Effects

Metabolism one-tenth that of halothane-- does not release quantity of hepatotoxic metabolites

Metabolism releases fluoride ion-- renal toxicity

Epileptiform EEG patterns

Isoflurane

Synthesized in 1965 by Terrell, introduced into practice in 1984

Not carcinogenic Nonflammable,punge

nt Less soluble than

halothane or enflurane

MAC of 1.30 %

Isoflurane Systemic Effects

Depresses respiratory drive and ventilatory responses-- less than enflurane

Myocardial depressant-- less than enflurane

Inhibits sympathetic baroreflex response-- less than enflurane

Sensitizes myocardium to catecholamines -- less than halothane or enflurane

Isoflurane Systemic Effects

Produces most significant reduction in systemic vascular resistance-- coronary steal syndrome, increased ICP

Excellent muscle relaxant-- potentiates effects of neuromuscular blockers

Isoflurane Side Effects

Little metabolism (0.2%) -- low potential of organotoxic metabolites

No EEG activity like enfluraneBronchoirritating, laryngospasm

Sevoflurane and Desflurane

Low solubility in blood-- produces rapid induction and emergence

Minimal systemic effects-- mild respiratory and cardiac suppression

Few side effectsExpensiveDifferences

Intravenous Anesthetic Agents

First attempt at intravenous anesthesia by Wren in 1656-- opium into his dog

Use in anesthesia in 1934 with thiopental

Many ways to meet requirements-- muscle relaxants, opoids, nonopoids

Appealing, pleasant experience

Thiopental

BarbiturateWater solubleAlkalineDose-dependent

suppression of CNS activity--decreased cerebral metabolic rate (EEG flat)

Thiopental

Redistribution

Thiopental Systemic Effects

Varied effects on cardiovascular system in people-- mild direct cardiac depression-- lowers blood pressure-- compensatory tachycardia (baroreflex)

Dose-dependent depression of respiration through medullary and pontine respiratory centers

Thiopental Side Effects

NoncompatibilityTissue necrosis--gangreneTissue storesPost-anesthetic course

Etomidate

Structure similar to ketoconozole

Direct CNS depressant (thiopental) and GABA agonist

Redistribution

Etomidate Systemic Effects

Little change in cardiac function in healthy and cardiac patients

Mild dose-related respiratory depression

Decreased cerebral metabolism

Etomidate Side Effects

Pain on injection (propylene glycol)Myoclonic activityNausea and vomiting (50%)Cortisol suppression

Ketamine

Structurally similar to PCP

Interrupts cerebral association pathways -- “dissociative anesthesia”

Stimulates central sympathetic pathways

Ketamine Systemic and Side Effects

Characteristic of sympathetic nervous system stimulation-- increase HR, BP, CO

Maintains laryngeal reflexes and skeletal muscle tone

Emergence can produce hallucinations and unpleasant dreams (15%)

Propofol

Rapid onset and short duration of action

Myocardial depression and peripheral vasodilation may occur--

Not water soluble-- painful (50%)Minimal nausea and vomiting

Benzodiazepines

Produce sedation and amnesia

Potentiate GABA receptors

Diazepam

Often used as premedication or seizure activity, rarely for induction

Minimal systemic effects-- respirations decreased with narcotic usage

Not water soluble-- venous irritationMetabolized by liver-- not

redistributed

Lorazepam

Slower onset of action (10-20 minutes)-- not used for induction

Used as adjunct for anxiolytic and sedative properties

Not water soluble-- venous irritation

Midazolam

More potent than diazepam or lorazepam

Induction slow, recovery prolongedMay depress respirations when used

with narcoticsMinimal cardiac effectsWater soluble

A. During anaesthesia 1. Respiratory depression.2. Salivation, respiratory secretions -less now as non-irritant anaesthetics are mostly used.3. Cardiac arrhythmias.4. Fall in BP5. Aspiration of gastric contents: acid pneumonitis.6. Fire and explosion - rare now due to use of non-inflammable agents.

COMPLICATIONS OF GENERAL ANAESTHESIA

B. After anaesthesia 1. Nausea and vomiting.2. Persisting sedation: impaired psychomotor function.3. Penumonia.4. Organ toxicities: liver, kidney damage.5. Nerve palsies - due to faulty positioning.6. Emergence delirium.

PREANAESTHETIC MEDICATION

Preanaesthetic medication refers to the use of drugs before anaesthesia to make it more pleasant and safe.

1.Opioids Morphine (10 mg) or pethidine (50-100 mg).

2. Antianxiety drugs Benzodiazepines like diazepam (5-10mg oral) or lorazepam (2 mg i.m.) have become populardrugs for preanaesthetic medication

3.Sedative-hypnotics Barbiturates like pentobarbitone,secobarbitone or butabarbitone (100 mg oral) have been used night before (to ensure sleep) and in the morning to calm the patient.

4.Anticholinergics Atropine or hyoscine (0.6 mg i.mJi.v.) have been used, primarily to reduce salivary, bronchial secretions and to prevent vagal bradycardia and hypotension.

5.Antiemetics Metoclopramide 10-20 mg i.m.

6. Ondansetron (4-8 mg i.v.) and Granisetron (0.1 mg) has been found to be highly effective in reducing the incidence of post anaesthetic nausea and vomiting.

Thanks for

patient listening