General Anesthetics

MN Islam PhD
Molecular Pharmacology
What are General Anesthetics?

 A drug that brings about a reversible loss of

consciousness.
 These drugs are generally administered by
an anesthesiologist in order to induce or
maintain general anesthesia to facilitate
surgery.
General Anaesthesia

Physiologic state of GA Ideal Properties of GA

- Analgesia -smooth and rapid onset of action
-allow rapid recovery upon
- Loss of consciousness discontinuation
-WIDE SAFTY MARGIN
- Inhibition of sensory - Low AE

- Inhibition of autonomic reflex

NB: no single anaesthesia meet these
- SKM relaxation properties

Extent of effect depend upon the type of agent, dose and clinical
situation
Anesthetics divide into 2 classes:

 Inhalation Anesthetics  Intravenous Anesthetics

– Gasses or Vapors – Injections
– Usually Halogenated – Anesthetics or induction
agents
 Inhaled Anesthetics

 Nitrous oxide- gas at ambient temperature and pressure important

component of many anesthetic regimens

 Halothane
 Enflurane
Volatile liquid
 Sevoflurane
 Desflurane
Halogenated
 Isoflurane compounds:
 Methoxyflurane Contain
Fluorine
and/or
bromide
Simple, small
molecules
Intravenous anaesthesia
 Several drug use as alone or in combination ( balance
anaesthesia)
 List of drugs
a. Barbiturates ---Thiopental and methohexital
b. Benzodiazepine --- Midazolam and diazepam
c. Opiod analgesic --- Morphine, Fantanyl, sufantenil,
alfentanil, remifantanil
d. Propofol
e. Ketamine
f. Miscellaneous- droperidol, etomide, dexmedetomide
Sign and stage of anaesthesia

 Anaesthetic effect can be divide into four stage

I. Stage of analgesia- patient experience first analgesia without
amnesia. Later at stage I both analgesia and amnesia
produces

II. Stage of excitement- patient often delirious and excited but

completely amnesic. Rp irregular both in volume and rate and
vomiting may occur. Patient may struggle and for this reason
effort have been made to reduce the duration of this stage
and which ends with reestablishment of regular breathing
Sign and stage of anaesthesia
III. Stage of surgical anaesthesia: recurrence of regular
respiration and cessation of spontaneous breathing.
Four planes
Plane1. Revolving eyeballs- this plane ends when
eyeball fixed
Plane 2: Loss of corneal response
Plane 3: Pupils start dilating and light reflex is lost
Plane 4: Intercostal paralysis, shallow abdominal
respiration and dilated pupil.

IV. Modularly Paralysis: complete cessation of breath,

circulation fail and death.
Pathway for General Anesthetics
 Anesthetic
Suppression of
Physiological
Response to
Surgery
Mechanism of Action of General
Anaesthesia
 Earlier evidence- nonspecific
interaction of anaesthetic agent with
lipid matrix of nerve membrane-
interaction that lead to secondary
change in ion flux.
 More recent evidence- modification
of ion channel by more specific
interaction . Inhaled anaesthetics and Intravenous anaesthetic
 Ionic mechanism for different
anaesthetics may vary.
 Primary molecular target of GABAA receptor-
chloride channel, a major mediator of inhibitory
synaptic transmission.
Inhaled anaesthetics, barbiturates,
benzodiazepines, etomidate and propofol
facilitate GABA mediated inhibition at GABA A
receptor sites. These receptors are sensitive
to clinically relevant concentration of
anaesthetic agents.
agents with GA properties directly activate
GABAA receptors, but at low concentration they
also can facilitate the action of GABA to
increase chloride ion influx.
Bnz has no direct effect on ion channel even at
higher dosage rather they facilitate GABA
action.
Mechanism of GA anasthetics
 Reconstitution study with transfected cell
revealed that anaesthetics molecules do
not directly bind to the GABA binding
site but with specific sites in the
transmembrane segment 2 and 3 of the
GABAA receptor α2 subunit, Ser270 and
Ala291, are critical for enhancement of
GABAA receptor function by inhaled
anaesthetics. These binding site may
vary between different anaesthetise.
 Ketamine does not produce it effect via
GABAA receptor function, but it may
function through antagonism of action of
excitatory neurotransmitter Glutamic
acid on the NMDA receptor.
 In addition to GABA chloride channel
action, inhaled anaesthetics have reported
to cause hyperpolarization of the
membrane via activation of their ligand-
gated potassium channel.
 The channel are ubiqetus in central
nervous system and are linked to several
neurotransmitters, including Ach,
Dopamine, nor epinephrine, and serotonin
( decrease the duration of opening of
nicotinic receptor- an action that decrease
the excitatory effect od Ach).
 Strychine-sensitive glycine receptor is
another ligand-gated channel that may
function as target for inhaled anaesthetics
which can elicit channel opening directly
Mechanism of action of General
Anaesthetics
 Neuron of substantia gilatinosa of  A progressive depression of ascending
dorsal horn of spinal cord are very pathways in the reticular activating
sensitive to relatively very low system together with suppression of
spinal reflex result stage III , including
anaesthetic concentration.
muscle relaxation
Interaction with this neurons
interrupt sensory transmission in
 Neuron in respiratory and vasomotor
spinothalamic region including
system of medulla are relatively
transmission of nocieptor stimuli ( insensitive to GA but at high
stage-1, analgesia) concentration their activity is depressed
and result to cardiorespiratory collapse. (
 The disinhibitory effect of GA stage iv)
together with blockade of many
small neuronal action lead to
complete amnesia in stage -ii
 Physical and Chemical Properties of
Inhaled Anesthetics

 Although halogenations of hydrocarbons and ethers increase anesthetic

potency, it also increase the potential for inducing cardiac arrhythmias in the
following order F<Cl<Br.
 Ethers that have an asymmetric halogenated carbon tend to be good
anesthetics (such as Enflurane).
 Halogenated methyl ethyl ethers (Enflurane and Isoflurane) are more stable,
are more potent, and have better clinical profile than halogenated diethyl
ethers.
 fluorination decrease flammibity and increase stability of adjacent
halogenated carbons.
 Complete halogenations of alkane and ethers or full halogenations of end
methyl groups decrease potency and enhances convulsant activity. Flurorthyl
(CF3CH2OCH2CF3) is a potent convulsant, with a median effective dose
(ED50).
 The presence of double bonds tends to increase chemical reactivity and
toxicity.
Inhaled GA

F Br F F F F H F
F C C H H C C O C H F C C O C H
F Cl Cl F F F F F

Enflurane Isoflurane
Halothane

F
F H F F C F H O
F C C O C H H C O C H N N
F Cl F F C F F
Nitrous Oxide
Desflurane F
Sevoflurane

CHCl3 CH3 CH2 O CH2 CH3

Chloroform Diethyl Ether

Pathway for General Anesthetics
and Its pharmacokinetics
 Pharmacokinetics of Inhaled
Anesthetics

1. Solubility

Amount that reaches the brain (solubility)

- Indicated by Blood:air partition ratio (lipid solubility)
- Desflurane and nitrous oxide (<0.5)
- Halothane- greater vaue-2, methoxyflurane is >10 (rarely
use)
- Low soluble molecules-few molecules required to rise its
partial pressure in blood-increase arterial pressure rapidly
(NO2)
- Converse with moderate to high soluble
anesthetics( bottom with Methoxyflurane)
2. Anesthetic Concentration

Anesthetic Concentration in the Inspired Air

Concentration has direct effect alveoli and rate of tension
in arterial blood
Increase conc = increase rate of induction (Fick’s law)
(advantages is taking of this effect in anesthetic practice)
- Moderate solubility blood solubility-enflurane, Isoflurane
and halothane- slow onset
- 3-4% conc of halothane administer initially followed by
1-2% maintenance dose when adequate anesthesia is
induced.
3. Pulmonary ventilation
3. Pulmonary Ventilation
Rate and depth of ventilation influence the gas tension in arterial
blood.
- Magnitude of effect varies with different agents blood:gas
partition coefficients.
- An pulmonary ventilation accompanied by only slight rise in
arterial tension with low solubility and significant with high
blood solubility
- Eg- 4 folds increase in ventilation increase arterial tension 2
fold with halothane but with NO2 it is only 15% raise in
arterial tension.
- - Therefore hyperventilation ……..
4. Pulmonary Blood flow

-Blood flow to and from lung influences gas transfer

-Increase CO= Increase blood flow= decrease of gas tension in

arterial blood (slow raise) with moderate to high soluble agents
bcz blood flow capacity increase exposes large blood thus
tension raise slowly

-Opposite effect with low blood flow

-Thus hypoventilation, circulatory shock, decrease CO accelerate

induction rate
5. Arteriovenous Conc gradient:

- Arteriovenous concentration…anesthetics uptake by tissues

- Depending upon the rate of tissue uptake….venous returning to lung
contain significantly less anesthetics than arterial blood.

- Greater the difference more uptake---- highly perused tissue like

viscera, kidney, liver, adipose tissue and more time taken to
established the equilibrium with brain tissue.

- With the agent of high lipid solubility initially venous concentration is

very low and equilibrium established slowly.

- Since adipose tissue having less blood supply thus it cause less likely
accumulation of agents during the time require for surgery.
Variables that Control Partial Pressure
in Brain

 Direct Physician's Control

– Solubility of agent
– Concentration of agent in inspired by air
– Magnitude of alveolar ventilation

 Indirect Physician’s Control

– Pulmonary blood flow-function of CO
– Arteriovenous concentration gradient
Elimination

 Time to recovery depend upon elimination of

anaesthetic from the brain
 Many of the process of recovery same as induction
 One of the most important factor governing the
rate of recovery is blood:gas partition coefficient
 Other factors Pul bld flow, mangnitude of the
ventilation, solubility of anaesthetics in the tissues
Elimination

 Two feature of recovery is quite different from induction

a. While transfer of anaesthetic from lung to plasma, induction
enhanced by increasing the concentration but reverse process
can not be enhanced
b. Anaesthetics tension in different tissues is variable during
recovery but during induction anaesthetic concentration remain
zero in all tissues
Inhaled anaesthetics that are relatively insoluble in the blood and
brain eliminate faster than more soluble anaesthetics (eg. NO 2,
Desflurane, Sevoflurane- rapid recovery rate compare to
halothane and Isoflurane)
Organ system effects

 CVS
- decrease mean arterial pressure in direct proportion to AV conc (due to
reduction CO)
- halothane and EnF- reduce arterial pressure due to reduction of CO
- IDS- reduce arterial pressure due to reduction VR
- Change heart rate by altering the rate of SA node depolarization
directly
- Or indirectly by shifting the balance of autonomic nervous system
activity.
- Bradycardia- halothane through vegul stimulation (ES have little effect)
- DI- marked increase in heart rate
CVS

 Increase right atrial pressure ,Decrease

myocardial function ( EH greater than I)
 Reduces myocardial oxygen consumption
 NO2 effect is relatively less ( combo)
 Rp system:

- All cause dose dependent decrease in TV and increase Rp rate

(decreased TV is failed to compensate by increase of Rp rate). All the
agents are Rp depressant and extent of depression vary with the agents

- Isoflurane and Enflurane being the most depressant

- Increase level of PaCO2 in arterial bld ( apnoea/hypoxia)

- Over come by assisting ventilation
- Depressed mucucilliary function of Rp tract- long time anaesthesia led
to Atelectasis and post operatory infection
- Air way irritation.......................secration
Effect on Brain (NO2 least effects)

- Metabolic rate
- Increase cerebral blood flow ( undesirable
specially in presence of increased
intracranial pressure)
 Organs system effects:

 Kidney
– Depression of renal blood flow and urine output
– Increase rVR
– Auto regulation renal flow is impaired
 Liver
- Decrease hepatic blood flow ( 15-45%)
- intraoperative change in LFT is seen but permanent change rarely
occure
Organs system effects:

 UT smooth muscles:
- Halothane is potent muscle relaxant
Toxicity

 Hepatotoxicity (halothane)
- bld transfusion, hypovolemic shock, surgical
stressors
- 20000-35,000:1 –severe hepatitis (obese)
Toxicity

 Nephrotoxicity
- Formation of fluoride ions ( ES)
- Enf- metabolized form F- ions
- Sev- degradation by CO2 absorbent-
formation of haloalkene comp-A – proximat
tubule necrosis (in rat).
Toxicity

 Malignant hyperthermia
Autosomal dominant genetic disorder of SM
(sccinylcholine).
- Syndrome: tachycardia, hypotension, muscle
rigidity, rised temp, hyperkelemia, hyper
acidosis ( mortality)
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