HISTORY OF GENERAL ANAESTHESIA AND GENERAL

ANAESTHETIC AGENTS

Dr. Umer Sufyan M

Introduction :

Anaesthesia is a reversible condition of comfort,

quiescence and physiological stability in a patient

before, during and after performance of a

procedure.

General anaesthesia is for surgical procedure to

render the patient unaware / unresponsive to the

painful stimuli.

History of Anaesthesia

Pre-1846 - the foundations of anaesthesia

1846 - 1900 - establishment of anaesthesia

20th Century - consolidation and growth

21st Century - the future

• Strangulation – Assyrians

• Cerebral concussion

• Applying intense cold or compression

SOME STRANGE METHODS OF ANAESTHESIA

Status of surgery Barber shop surgeons

Types of surgery Amputations & dental

extractions No antisepsis Appalling mortality

Indications Unbearable pain Crippling deformity Imminent death

Surgeons used to boast of speed of surgery

Drug methods Alcohol

Opium (poppy)

Hyoscine (Mandrake)

Cannabis (Hemp)

Cocaine (New World)

Non-drug methods Cold

Concussion

Carotid compression

Nerve compression

Hypnosis

Blood letting

Middle Ages the anesthetic effects of cold water and ice were recognized.

In 17th century, Marco Aurelio Severino described the technique of “refrigeration anesthesia” in which snow was placed in parallel lines across the incisional plane such that the surgical site became insensate within minutes. The technique never became widely used, likely because of the challenge of maintaining stores of snow year-round.

manipulation of the psyche to relieve surgical pain was undertaken by French physicians Charles Dupotet and Jules Cloquet in the late 1820s with hypnosis, then called mesmerism.

Greek physician from the first century AD, commented on the analgesia of mandragora, a drug prepared from the bark and leaves of the mandrake plant. He observed that the plant substance could be boiled in wine, strained, and used “in the case of persons … about to be cut or cauterized, when they wish to produce anesthesia.”Mandragora was still being used to benefit patients as late as the 17th century.

Alcohol was another element of the pre-ether armamentarium because it was thought to induce stupor and blunt the impact of pain

Laudanum was an alcohol-based solution of opium first compounded by Paracelsus in the 16th century. It was wildly popular in the Victorian and Romantic periods, and prescribed for a wide variety of ailments from the common cold to tuberculosis. it was frequently misused and abused. Laudanum was given by nursemaids to quiet wailing infants and abused by many upper-class women, poets, and artists who fell victim to its addictive potential.

In 1773 Nitrous oxide was first prepared by Joseph Priestley. In 1799 Davy commented that nitrous oxide transiently

relieved a severe headache, obliterated a minor headache, and briefly quenched an aggravating toothache. quoted ; “As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood takes place.”Davy's lasting nitrous oxide legacy was coining the phrase “laughing gas” to describe its unique property.

1818: Michael Faraday (1791-1867) described “narcotic effects” of ether

1821: Benjamin Brodie (1783-1862) demonstrated to Royal College of Surgeons that ether inhalation could induce insensibility in a guinea pig - “….ether acted like a narcotic poison……”

In 1831 David Waldie suggested

chloroform, which had first been prepared.

Benjamin Brodie

Michael Faraday

In Dec 10 1844 Horace Wells observed a lecture-exhibition on nitrous oxide by an itinerant “scientist,” Gardner Quincy Colton, who encouraged members of the audience to inhale a sample of the gas. Wells observed a young man injure his leg without pain while under the influence of nitrous oxide. Sensing that it might provide pain relief during dental procedures, Wells contacted Colton and boldly proposed

Horace well

Horace Wells, The next day Wells had a tooth extracted while breathing nitrous oxide. An attempt in 1845 by Wells to demonstrate his discovery at the Massachusetts General Hospital in Boston ended in failure when the patient cried out and nitrous oxide fell into disuse.

In january 1842 William E. Clarke, a medical student from Rochester, New York, given the first ether anesthetic.

Clarke entertained his companions with nitrous oxide and ether. By these experiences, he administered ether, from a towel, to a young woman named Hobbie. One of her teeth was then extracted without pain by a dentist named Elijah Pope but it was suggested that the woman's unconsciousness was due to hysteria and Clarke was advised to conduct

no further anesthetic experiments.

March 30, 1842, Crawford Williamson Long administered ether with a towel for surgical anesthesia in Jefferson, Georgia. His patient, James M. Venable, was a young man who was already familiar with ether's exhilarating effects, enable had two small tumors on his neck but refused to have them excised because he feared the pain that accompanied surgery.

Knowing that Venable was familiar with ether's action,

Dr. Long proposed that ether might alleviate pain and gained his patient's consent to proceed. After inhaling ether from the towel and having the procedure successfully completed, Venable reported that he was unaware of the removal of the tumors. In determining the first fee for anesthesia and surgery, Long settled on a charge of $2.00.

In 1846 William T.G. Morton, a Boston dentist and medical student, performed the first public demonstration of general anesthesia using diethyl ether.

William T G Morton

“Inventor and Revealer of Inhalational Anaesthesia: Before Whom, in All Time, Surgery was Agony; By Whom, Pain in Surgery was Averted and Annulled; Since Whom, Science has Control of Pain.”

Oct 16 1846 Gilbert Abbott underwent surgical excision of a neck tumor at the Massachusetts General Hospital in the operating room now known as "the ether dome." The era of modern anesthesia and a revolution in the medical care of the surgical patient had begun.

Nov 4 1847 James young Simpson and his friends inhaled chlorofom after dinner at a party in Simpson's home on the evening and they promptly fell unconscious and, when they awoke, were delighted with their success. Simpson quickly set about encouraging the use of chloroform.

The relief of obstetric pain had significant social ramifications and made anesthesia during childbirth a controversial subject.

Simpson argued against the prevailing view, which held that relieving labor pain opposed God's will. Simpson asserted that labor pain was a result of scientific and anatomic causes, and not the result of religious condemnation.

He did articulate many concepts that his contemporaries were debating at the time.

Chlorofom Popularised by James.Y.Simpson & practiced by John Snow

John Snow used chlorofom to deliver the last two children of Queen Victoria

Snow gave analgesic doses of chloroform on a folded handkerchief. This technique was soon termed “chloroform à la reine”

Victoria abhorred the pain of childbirth and enjoyed the relief that chloroform provided. She wrote in her journal, “Dr. Snow gave that blessed chloroform and the effect was soothing, quieting, and delightful beyond measure.”

John Snow (1813-1858)

In 1934 The anesthetic properties of cyclopropane were discovered accidentally by Ralph Waters chemists analyzing impurities in propylene.

In 1956 came the introduction of halothane by Charles Suckling, a nonflammable volatile halogenated alkane that quickly became the dominant anesthetic.

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DEFINITION: General anaesthetics are the drugs which produce reversible

loss of all sensations and consciousness.

FEATURES OF GENERAL ANAESTHETICS: Loss of all sensations particularly, pain Sleep and amnesia Immobility and muscle relaxation Abolition of reflexes

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GENERAL ANAESTHETICS LOCAL ANAESTHETICS

Act on CNS. Whole body is involved.

Consciousness is lost. Care of vital functions is

essential. Can be given in non-

cooperative pts. Preferred in major

surgeries.

Act on peripheral nerves. Restricted areas of body

involved. Consciousness is

unaltered. Care of vital functions –

not essential. Not possible in non-

cooperative pts. Preferred in minor

surgeries.

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STAGES OF ANAESTHESIA:

By GUEDEL in 1920 referring to the anaesthetic

Ether

Stage I. Stage of analgesia: Starts from beginning of anaesthetic inhalation and lasts

upto the loss of consciousness. No amnesia ,Conciousness and sense of touch present

Stage II. Stage of excitement and delirium: Patient shows violent combative behaviour but definitely

amnesic Irregular rise in BP &RR

Stage III. Surgical Anaesthesia:

Regular respiration and relaxation of skeletal muscle occurs Plane 1 - Roving eyeballs, respiration and skeletal muscle

tone are normal. Plane 2 - Loss of corneal & laryngeal reflexes, respiration is

slow but regular. Plane 3 - Dilatation of pupil , loss of light, corneal and

laryngeal reflexes. Plane 4 - Complete muscle relaxation, pupils dilated,

respiration is abdominal

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Stage IV . Medullary paralysis: Stage appears due to overdosing Severe deppression of respiratory centre as well as

vasomotor center in medulla, this stage is fatal and death ensue .

MECHANISM OF ACTION:Ligand gated ion channels are the major targets GABA A - R gated Cl- channel :– inhalational

anaesthetics, barbiturates, BZD, propofol, potentiate the action of inhibitory transmitter GABA to open Cl- channel.

Glycine: – in the spinal cord & medulla is augmented by barbiturates , propofol & inhalational anaesthetics

Fluorinated anaesthetics & barbiturates: – inhibit neuronal cation channel gated by nicotinic cholinergic receptor

N2O & ketamine inhibit the excitatory NMDA type of glutamate receptor.

GA inhibit release of the presynaptic excitatory neurotransmitters. Also alter the postsynaptic responsiveness to the released neurotransmitter by increasing the activity of the inhibitory ion channels in the post synaptic receptors and enhance inhibitory neurotransmission within the CNS

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Main site of causation of ;

Unconsciousness → Thalamus or RAS

Amnesia → Hippocampus

Immobility on surgical stimulation → Spinal cord.

Important properties which determine the potency of

inhalational anaesthetics :-

MAC value

Blood-gas partition coefficient

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MAC(minimum alveolar conc.): It is the conc. of anaesthetic required to prevent

movement in 50% of patients in response to a standard surgical incision.

Smaller MAC value- more potent is the anaesthetic. Anaesthetic with high lipid solubility has lower MAC

value Methoxyflurane - most potent with least MAC value. Nitrous oxide - least potent with highest MAC value.

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BLOOD-GAS PARTITION COEFFICIENT: Determined by solubility of an agent in the blood. It determines the speed of onset & recovery of an

anaesthetic drug. Greater the blood-gas partition effect, lesser is the speed

of onset & recovery. Desflurane is the fastest acting drug as it has least BGP

coefficient.

Open system

Open is the old fashioned method of dropping ether or chloroform over a gauze or lint. Later modernised by the likes of the Schimmelbusch mask.

Schimmelbusch mask

Breathing Circuits

Semi-open Systems

In the early 1950’s, Prof. WW Mapleson from University of Wales, Cardiff, classified the several breathing systems around depending on what components they contained and what position they took in the system.

It is known today as ‘The Mapleson Alphabet’ Partial rebreathing is allowed through a partially closed

valve.conditions are intermediate with moderate flow rates.

Closed systems use a CO2 absorbent so that the gases are re-circulated, the classification is defined by the amount of fresh gas flow.

Sodalime are used to absorb co2.Preferred in conditions with high production of co2.

Closed system

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CLASSIFICATION:

General anaesthetics

Inhalational Intravenous

Inhalational: Gas: Nitrous Oxide Volatile liquids:

Ether

Halothane

Enflurane

Isoflurane

Desflurane

Sevoflurane

Intravenous: Inducing agents:

Thiopentone, Methohexitone sodium, propofol and etomidate

Benzodiazepines (slower acting):

Diazepam, Lorazepam, Midazolam

Dissociative anaesthesia:

Ketamine

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NITROUS OXIDE:

Colourless ,odourless non irritating and non-inflammable gas.

Good analgesic but weak anaesthetic agent due to high MAC.

Produces analgesia when inhaled in a conc. of 35- 40% with

air. ENTONOX - 50% Nitrous oxide + 50% Oxygen.

If administered along with air, produces a stage of excitement

and delirium and also produces amnesia. hence, it is known as

laughing gas.

Safest anaesthetic agent. Has no serious, deleterious effects on

circulation, respiration, liver and kidneys.

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SECOND GAS EFFECT –Nitrous oxide is insoluble in

blood and thus rapid induction and rapid reuptake of

Nitrous oxide from alveolar gas leads to rapid rise in

concentration of coadministered halogenated anaesthetic

agent and it increases the speed of induction of these

volatile anaesthetic agents

When anaesthetic is discontinued ;the anaesthetic moves

from blood to alveoli.

In case of NO the amount may be about 10% of expired

volume and this may be sufficient to reduce the alveolar

partial pressure of oxygen causing transient mild Hypoxia

known as Second Effect & the hypoxia is called Diffussion

hypoxia.

This hypoxia can be prevented by administration of 100%

oxygen 5-10 min after discontinuing nitrous oxide

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Therapeutic uses:

Tooth extraction.

Obstetric analgesia.

Painful procedures such as change of dress in burns pts,

cleaning and debridement of wounds and cauterisation

Used as a carrier gas for inhalational agents like

Halothane.

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Advantages:

Non inflammable and non – irritant.

Rapid induction and recovery due to low B/G Partition

coefficient.

Analgesic property

Nausea and vomiting are uncommon.

Disadvantages:

Not a potent anaesthetic.

Poor muscle relaxant.

Special apparatus is required.

Carbon dioxide accumulation & hypoxia on prolonged use

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Bone marrow depression and megaloblastic anaemia

seen on prolonged use.

ETHER:

Colourless volatile liquid with a pungent odour..

Ether when exposed to air, moisture or light form ether

peroxides or acetic aldehyde which are irritant.

To avoid this, ether is stored in sealed containers or

amber coloured bottles.

Potent anaesthetic .

Marked muscle relaxant action.

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advantages:

Can be administered without complicated apparatus.

Can be used during an emergency without pre-

anaesthetic medication.

Can be used during delivery.

Good bronchodilator ,safe in asthmatics.

Causes satisfactory muscle relaxation.

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Disadvantages:

Inflammable and explosive.

Induction and recovery are slow.

Irritant and may cause nausea and vomiting.

Increase in salivary and bronchial secretion may

cause cough or laryngeal spasm.

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HALOTHANE:

Volatile liquid structurally similar to chloroform with a

characteristic sweetish & fruity odour.

Produces loss of consciousness in a conc. of 2 - 3% in

oxygen vapour.

P/K

60-80% of halothane is eliminated unchanged through

lungs in first 24 hrs. About 20% is retained in the body

and is metabolized.

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Advantages:

Non-irritant and non inflammable.

Inhibit pharyngeal and laryngeal reflexes, making tracheal

intubation easy.

Potent anesthetic , speedy induction & recovery

Inhalational agent of choice in bronchial asthma.

Disadvantages:

Special apparatus is required.

Causes malignant hyperthermia in susceptible individuals.

Halothane induced hepatitis.

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Causes hypotension by direct depression of

myocardium .

Sensitizes heart to catecholamines causing cardiac

arrhythmias.

Can raise intracranial tension due to cerebral

vasodilatation.

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MALIGNANT HYPERTHERMIA:

Autosomal dominant inheritance.

Features- rapid rise in body temp, muscle rigidity,

tachycardia, hyperkalemia, rhabdomyolysis, acidosis.

Physiology - caused by heat production in skeletal

muscle due to excessive release of calcium from

sarcoplasmic reticulum.

Associated with mutations in the gene encoding for

RYANODINE receptors which controls calcium release

from sarcoplasmic reticulum.

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Triggered by halogenated anaesthetics and neuromuscular

blocking drugs.

The most reliable test to establish genetic susceptibility is

the

caffeine-halothane contracture test using skeletal muscle

biopsy tissue.

Diagnosis - increase co2, rise in creatine kinase levels,

myoglobinuria, muscle biopsy.

Treatment - early detection, hyperventilation, IV

Dantrolene(1mg/kg), ice packs/cooling blankets, lasix/

mannitol / fluids.

ENFLURANE:

Anaesthesia by enflurane resembles to anaesthesia by

halothane

Non irritant and non inflammable .

Like halothane it causes hypotension.

Causes bronchodilatation.

Cause uterine relaxation.

Sensitizes heart to the action of catecholamines

It is contra indicated in epileptic patients.

ISOFLURANE:

Advantage :

Rapid induction and recovery.

Stable and non inflammable.

Bronchodilator.

Good muscle relaxant.

Potent coronary vasodilator.

Does not sensitize myocardium to adrenaline.

Disadvantages:

Respiratory irritant

CORONARY STEAL PHENOMENON

DESFLURANE:

Properties are similar to those of isoflurane but with

faster onset and recovery.

Respiratory irritant, causes cough and laryngospasm.

Useful for daycare surgery.

SEVOFLURANE:

More potent than desflurane and does not cause

respiratory irritation.

Inhalational agent of choice in children

can produce a nephrotoxic metabolite

METHOXYFLURANE:

Most potent inhalational agent due to least MAC.

Slowest induction and recovery.

Nephrotoxic and hepatotoxic due to highest amount of

flouride.

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INTRAVENOUS ANAESTHETICS

THIOPENTONE SODIUM:

Ultra short acting barbiturate which induces anaesthesia

within a minute.

Crosses BBB rapidly following an I.V. bolus inj

Due to its high lipid solubility diffuses rapidly out of brain

and is redistributed to body fats, muscles and other tissues.

Induction dose is 3-5 mg/kg.

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Therapeutic uses;

Induction of general anaesthesia.

As anaesthetic agent for operations of short duration like

fracture reduction, dilatation and curettage, laryngoscopy

and bronchoscopy.

In pts with H/O malignant hyperthermia.

As an anticonvulsant in emergency treatment of intractable

seizures.

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Adverse effects:

Laryngospasm may occur when intubation is attempted

while anaesthesia is light.

No muscle relaxant activity.

No analgesic activity.

Bronchospasm hence contraindicated in asthmatics.

Can ppt fulminant attack in acute intermittent porphyria.

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ETOMIDATE:

Similar to thiopental in all aspects but rapidly metabolised

than thiopental& causes less hangover.

Less cardiovascular & respiratory depression than thiopental.

Causes involuntary movements during induction, post

operative nausea and vomiting & pain at the injection site.

On prolonged use causes adrenocortical suppression. Hence

CI in adrenal insufficiency.

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PROPOFOL

Di isopropyl alcohol

Available as 1% or 2% emulsion in soyabean oil

Induction of anaesthesia with 1.5- 2.5 mg/kg occurs within

30 sec and reversal is also rapid.

No nausea and vomiting.

Therapeutic uses:

Good agent for day care surgery.

Can be given in Porphyrias and also in Neurosurgeries.

Malignant hyperthermia.

Adverse effects:

Pain at the site of injection.

Apnoea.

Cv unstable - ↓BP&HR due to ↓PR.

Depresses respiratory centre.

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KETAMINE:

It is related to phencyclidine.

Acts as an antagonist at NMDA receptors.

Potent bronchodilator.

It induces a state of DISSOCIATIVE ANAESTHESIA

characterised by complete analgesia combined with

amnesia and sedation without actual loss of consciousness.

Patient can open his eyes & can obey instructions.

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Anesthesia can be induced by both IM (5-10 mg/kg) and

IV(1-2 mg/kg) routes.

It increases BP, heart rate and CO by raising blood levels of

Nor adrenaline. Can be used in pts with shock.

It should be avoided in pts with ischaemic heart disease.

Therapeutic uses:

Used as an inducing agent & for maintenance of anesthesia

during diagnostic procedures like cardiac catheterisation and

bronchoscopy.

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Can be used in short procedures like dressing of burns,

forceps delivery, manual removal of placenta and dental

work.

Disadvantages:

May cause nystagmus, involuntary movements &

hypertonus.

Increases intraocular and intracranial pressures.

It is a drug of abuse.

May cause delirium, hallucinations.

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Contraindications:

Pts suffering from HTN, cardiac decompensation or

cerebrovascular accident.

During operations of eye as it ↑ intraocular pressure.

Barbiturates & Diazepam are chemically incompatible with

ketamine.So, they should never be administered from same

syringe.

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METHOHEXITONE: 3 times more potent than thiopentone. Induces seizures, so it is an agent of choice for

electroconvulsive therapy.

MIDAZOLAM: Short acting BZD . Used in premedication as IM or for sedation as IV in

endoscopic procedures. It is water soluble & less irritant to veins than Diazepam.

PREANAESTHETIC MEDICATION:

Drugs used prior to the administration of an anaesthetic

agent to make anaesthesia more safer & more agreeable to

the pt. It is given ;

For sedation to reduce anxiety & apprehension.

To obtain an additive or synergistic effect so that induction

is smooth & rapid.

To counteract some adverse effects of anaesthetic drugs

such as salivation, bradycardia & vomiting.

To relieve pre and post operative pain.

to suppress respiratory secretions and to reduce reflex

excitability.

Usually, a combination of drugs are used. Most commonly used

drugs for preanaesthetic medication are:

OPIOID ANALGESICS - morphine(10-15mg IM), pethidine(50-100

mg IM), buprenorphine(300 mcg IM).These drugs possess very

strong analgesic activity.

- may depress respiration & cause resp.arrest.

- may cause vasomotor depression.

- may induce vomiting & cause antidiuresis.

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SEDATIVES - BZD are preferred because of their safety,

muscle relaxant property and less resp.depression.

ANTIMUSCARINIC DRUGS - Anticholinergic drugs (eg,

atropine and glycopyrrolate) may be used to decrease

oral and airway secretions and to treat bradycardia;

H2 BLOCKER/PROTON PUMP INHIBITOR –

Ranitidine (150mg)/famotidine (20mg)/

omeprazole (20mg ) given night before and in the

morning reduces chance of regurgitation.

ANTIEMETICS – Metoclopramide 10-20mg IM

preoperatively effective in reducing post operative vomiting

Domperidone is nearly as effective and doesn't produce

extrapyramidal side effects

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NEUROLEPT ANALGESIA:

Neuroleptics- drugs which induce state of apathy and

mental detachment- pt is mildly sedated & uncaring about

his surroundings.

Neurolept analgesia – combined use of neuroleptic drug

with an opioid analgesic.

Most commonly used combination is the neuroleptic

Droperidol 2.5 mg and opioid analgesic Fentanyl citrate

50 mcg.

Neurolept analgesia can be converted to Neurolept-anaesthesia by concurrent administration of 65% Nitrous oxide and 35 % Oxygen

DRUG INTERACTIONS :

1. Patients on antihypertensives given general anaesthetics -

BP may fall markedly.

2. Narcoleptics, opioids, clonidine and monoamine oxidase

inhibitors potentiate anaesthetics.

3. Halothane sensitizes heart to Adrenaline.

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4. If a patient on corticosteroids is to be anaesthetized,

100 mg of hydrocortisone is given intraoperatively

because anaesthesia is a stress – can precipitate adrenal

insufficiency and cardiovascular collapse

5. Insulin need of a diabetic is increased during GA :

Switch over to plain insulin even if the patient is on oral

hypoglycaemics.

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References:-

Rang & Dale - Pharmacology – sixthEdition

R.S.Satoskar - Pharmacology & Therapeutics –Twenty second Edition.

Goodman & Gilman's – The Pharmacological Basis Of - Therapeutics - twelth Edition.

H.L Sharma & K.K Sharma – The Principles of Pharmacology –second Edition.

K.D Tripathi - Essentials Of Medical Pharmacology. Seventh Edition

Lippincott’s - Illustrated Reviews Pharmacology - Fourth Edition.

Barash clinical anaesthesia –sixth Edition

Millers anaesthesia –seventh edition

Thank you