Download General Anesthetics

Pharmacology – II [PHL 322]
General Anesthetics
Dr. Mohd Nazam Ansari
What are General Anesthetics?
 A drug that brings about a reversible loss of
consciousness.
 Anesthetics are not to be confused with sleep
medicine.
 These drugs are generally administered by an
anesthesiologist in order to induce or maintain
general anesthesia to facilitate surgery.
Background
 General
anesthesia
was
absent until the mid-1800’s
 William Morton administered
ether to a patient having a neck
tumor
removed
at
the
Massachusetts General Hospital,
Boston, in October 1846.
 The discovery of the diethyl
ether as general anesthesia was
the result of a search for means
of eliminating a patient’s pain
perception and responses to
painful stimuli.
COMPONENTS OF ANAESTHESIA
The famous components of general anaesthesia are
TRIAD
1. UNCOSCOUSNESS.
2. ANALGESIA
3. MUSCLE RELAXATION.
But those triad are under modifications:
Unconsciousness replaced by amnesia or loss of awareness
Analgesia replaced by no stress autonomic response
Muscle relaxation replaced by no movement in response to
surgical stimuli
Anesthetics divide into 2 classes:
 Inhalation Anesthetics
 Gasses or Vapors
 Usually Halogenated
(hydrogen is replaced
with a halogen atom like
Fluorine, Chlorine,
Iodine, Bromide).
 Intravenous Anesthetics
 Injections



Subcutaneous
Intramuscular
intravenous
Inhaled Anesthetics
 Volatile Liquids
 Ether
 Halothane
 Enflurane
 Isoflurane
 Sevoflurane
 Desflurane
 Gases
 Nitrous oxide
 Cyclopropane
 Ethylene
Physical and Chemical Properties of
Inhaled Anesthetics




Although halogenations of hydrocarbons and ethers
increase anesthetic potency, it also increase the potential
for inducing cardiac arrhythmia 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.
The presence of double bonds tends to increase
chemical reactivity and toxicity.
Intravenous Anesthetics
 Used in combination with Inhaled anesthetics to:
 Supplement general anesthesia
 Maintain general anesthesia
 Control blood pressure
 Protect the brain
 Inducing Agent (~11 sec)
 Thiopentone sodium
 Propofol
 Etomidate
 Slower Acting Drugs
 Benzodiazepines


Diazepam (5-10 min)
Lorazepam
 Dissociative anesthesia

Ketamine
 Neurolept analgesia

Fentanyl + Droperidol
Anesthetic
Suppression of
Physiological
Response to
Surgery
Hypotheses of General Anesthesia
1.
Lipid Theory: based on the
fact that anesthetic action is
correlated with the oil/gas
coefficients. (solubility of
anesthetics is in oil)
2. Protein (Receptor) Theory:
based on the fact that
anesthetic potency is
correlated with the ability of
anesthetics to inhibit enzymes
activity of a pure, soluble
protein. Also, attempts to
explain the GABAA receptor is
a potential target of
anesthetics action.
Mechanism of Action
 UNKNOWN!!
 Most Recent Studies:
 General Anesthetics acts on the CNS by modifying the
electrical activity of neurons at a molecular level by
modifying functions of ION CHANNELS.
 This may occur by anesthetic molecules binding directly
to ion channels or by their disrupting the functions of
molecules that maintain ion channels.
Molecular mechanism of the GA :
 GABA –A : Potentiation by Halothane, Propofol, Etomidate
 NMDA receptors : inhibited by Ketamine
Molecular Actions: GABAA Receptor
 Ligand-gated ion channels
 Chloride channels gated by the inhibitory GABAA
receptor
 GABAA receptor mediates the effects of gammaamino butyric acid (GABA), the major inhibitory
neurotransmitter in the brain
 GABAA receptor found throughout the CNS
 Most abundant, fast inhibitory, ligand-gated ion
channel in the mammalian brain
 Located in the post-synaptic membrane
Molecular Action: GABAA Receptor
Molecular Action: GABAA Receptor
 Receptor sits in the membrane of
its neuron at the synapse
 GABA, endogenous compound,
causes GABA to open
 Receptor capable of binding 2
GABA molecules, between an
alpha and beta subunit
 Binding of GABA causes a
conformational change in
receptor
 Opens central pore
 Chloride ions pass down
electrochemical gradient
 Net inhibitory effect, reducing
activity of the neuron
Injectable anesthetics - Mechanisms
Ketamine (Ketalar) – Causes dissociative anesthesia. Patients feel
dissociated from the environment. Similar to neuroleptic anesthesia, but
caused by a single agent. Phencyclidine (PCP) has similar effects.
Ketamine is injectable.
Mechanism – Blocks NMDA glutamate receptors
Etimodate (Amidate) – is a ultrashort acting hypnotic without analgesic
properties. Used only for induction because of the very short, 5 minute,
duration.
Mechanism – GABA receptor. Similar to barbiturates
Propofol (Diprivan) – Another IV anesthetic. Similar to thiopental in
anesthetic effects and application, but has little renal or hepatic
interaction and/or toxicity. Low incidence of side effects, little postoperative confusion.
Mechanism – Probably similar to the volatile anesthetics and
ethanol. GABA, nACh
15
Pathway for General Anesthetics
Induction /Recovery
Induction and Recovery
Induction rate and recovery are important considerations. The more
lipophilic compounds have slower induction and recovery. N2O is not
lipophilic, has low solubility, and therefore has fast induction and
recovery. The low solubility of N2O means that the equilibration with
blood from gas is quite rapid.
Induction of anesthesia involves a series of equilibration events. The
anesthetic first equilibrates with the alveoli and may be slow,
equilibration into the blood is rapid. The blood must become
saturated for transfer to the tissues to occur, this can be slow.
Inhaled and
exhaled gases
Aveoli
Blood
Tissues, including
Brain
Elimination
 Recovery processes are similar (reversed) to those of
induction
 Major route of elimination is via the lungs and the
agents follow a gradient back to the alveoli
 Agents with low blood solubility are eliminated
quickly
 Minimal metabolism, primarily in the liver
MAC (Minimum Alveolar Concentration)
 MAC is the concentration necessary to prevent
responding in 50% of population.
 Values of MAC are additive:
 Avoid cardiovascular depressive concentration of potent
agents.
 Provides a means to compare the potency of the
various inhalational agents
 Serves as a guide to determining dose
General Actions of Inhaled Anesthetics
 Respiration
 Depressed respiration and response to CO2
 Kidney
 Depression of renal blood flow and urine output
 Muscle
 High enough concentrations will relax skeletal muscle
 Cardiovascular System
 General reduction in arterial pressure and peripheral vascular
resistance.
 Central Nervous System
 Increased
metabolism
cerebral
blood
flow
and
decreased
cerebral
Toxicity and Side Effects
 Depression of respiratory drive
 Decreased CO2 drive (medullary chemoreceptors), Takes MORE CO2 to
stimulate respiration
 Depressed cardiovascular drive
 Example: Halothane may depress the myocardium and cause ventricular
arrhythmias
 Fluoride-ion toxicity from methoxyflurane
 Metabolized in liver = release of Fluoride ions
 Decreased renal function allows fluoride to accumulate = nephrotoxicity
 Malignant hyperthermia
 Some anesthetic agents can trigger malignant hyperthermia which is a
hypermetabolic state of skeletal muscles (rare, inherited, and potentially lethal
syndrome).
 Excess calcium ion leads to excessive ATP breakdown/depletion, lactate
production, increased CO2 production. Signs: tachycardia + metabolic acidosis;
also hyperthermia, muscle rigidity, sweating, arrhythmia.
 May be lethal if not treated with Dantrolene: to block release of Calcium from
sarcoplasmic reticulum and increases reuptake of Ca++
STAGES OF ANESTHESIA
 Irregular descending depression of CNS
 STAGE 1 (ANALGESIA/ONSET/INDUCTION):
 Extends from the administration of anesthesia to the




time of 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.
Some minor and major operation can be carried out.
 STAGE 2 (EXCITEMENT/DELIRIUM):
 Extends from the time of loss of consciousness to





beginning of regular respiration
Characterized by struggling, delirium, irregular
respiration, and breatholding are commonly seen.
Muscle tone increases, jaws are tightly closed,
vomiting, involuntary micturation or defecation
may occur.
Heart rate and BP may rise.
Pupils are dilated.
No operation.
 STAGE 3 (Surgical Anesthesia):
 Extends from the regular respiration to the loss of most of
the reflexes.
 Muscle tone decreases, BP falls, HR increases, constricted
pupils, and regular respirations.
 Surgical procedure is started.
 STAGE 4 (Impending Death/ Stage of Danger):
 Cessation of breathing, to failure of circulation and death.
 Pupil is widely dilated.
 It is due to anesthesia overdose.
 Stage of Maintenance
 During the maintenance phase, anesthetic doses are
adjusted based upon signs of the depth of anesthesia
 Stage of Emergence- resumption of normal CNS function
 resumption of normal respiration
Selection of anesthetic technique
 Safest for the patient
 Appropriate duration
 i.v. induction agents for short procedures
 Facilitates surgical procedure
 Most acceptable to the patient
 General vs. regional techniques
 Associated costs
Anesthesiology: Pre-anesthetic medication
It is the use of drugs prior to anesthesia to make it
more safe and pleasant.
 To relieve anxiety – benzodiazepines.
 To prevent allergic reactions – antihistaminics.
 To prevent nausea and vomiting – antiemetics.
 To provide analgesia – opioids.
 To prevent bradycardia and secretion – atropine.
Thank you