Transcript General Anesthetics

General Anesthesia
By:
Asst. Prof. Yogendra Mavai
M.Pharm (Pharmacology)
ShriRam College of Pharmacy
Banmore
Contents
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
General Anesthetics
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.
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
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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 unconsciousness
need for analgesia
need for muscle relaxation
Purpose
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.
Properties of an ideal anaesthetic
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.
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 anaesthetia
The 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 administration
Drugs given to induce or maintain general anaesthesia are either
given as:Gases or vapours (inhalational anaesthetics), Injections
(intravenous anaesthetics)
Inhalation
Inhalational 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.
Injection
Injection 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 midazolam
Ketamine 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.
I. StageAnalgesia 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.
II. Stage- Delirium
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.
III. StageSurgical 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 abdominal
respiration, dilated pupil.
IV. StageMedullary 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.
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 metabolized
Only anesthetic agent
that is inorganic
Nitrous Oxide
Major difference is low potency
MAC value is 105%
Weak anesthetic, powerful analgesic
Needs other agents for surgical
anesthesia
Low 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 respiration
Safe, efficacious agent
Nitrous Oxide Side Effects
Manufacturing impurities toxic
Hypoxic mixtures can be used
Large volumes of gases can be used
Beginning of case: second gas effect
End of case: diffusion hypoxia
Nitrous Oxide Side Effects
Inhibits methionine synthetase (precursor
to DNA synthesis)
Inhibits vitamin B-12 metabolism
Dentists, 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 anesthetic
MAC of 0.75%
Efficacious in depressing consciousness
Very soluble in blood and adipose
Halothane Systemic Effects
Inhibits sympathetic response to painful stimuli
Inhibits 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 haptenprotein 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 odor
MAC 1.68%
Enflurane Systemic Effects
Potent inotropic and chronotropic
depressant and decreases systemic
vascular resistance-- lowers blood
pressure and conduction dramatically
Inhibits sympathetic baroreflex response
Sensitizes 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,pungent
 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 enflurane
Bronchoirritating, laryngospasm
Sevoflurane and Desflurane
Low solubility in blood-- produces rapid
induction and emergence
Minimal systemic effects-- mild respiratory
and cardiac suppression
Few side effects
Expensive
Differences
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
Barbiturate
Water soluble
Alkaline
Dose-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
Noncompatibility
Tissue necrosis--gangrene
Tissue stores
Post-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 activity
Nausea 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 irritation
Metabolized 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 prolonged
May depress respirations when used with
narcotics
Minimal cardiac effects
Water soluble
COMPLICATIONS OF GENERAL
ANAESTHESIA
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 BP
5. Aspiration of gastric contents: acid pneumonitis.
6. Fire and explosion - rare now due to use of noninflammable agents.
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 (5-10
mg oral) or lorazepam (2 mg i.m.) have become popular
drugs
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.
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for
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