General Anaesthetics

For Post-Graduates

QUESTION

• INHALATIONAL ANAESTHETICS (20MARKS)

• They are of mainly 2 types

Volatile anesthetics (diethyl ether, halothane, enflurane, isoflurane, desflurane, sevoflurane)

• They have low vapor pressures and high boiling points .

• liquids at room temperature (20 deg C)

Gaseous anesthetics (nitrous oxide, xenon) • They Have high vapor pressures and low boiling

points

History• The use of nitrous oxide to relieve the pain of

surgery was suggested by Humphrey Davy in 1800.

• Crawford Long, a physician in rural Georgia, first used ether anesthesia in 1842.

• In 1846 James Simpson, used chloroform to relieve the pain of childbirth.

Mechanism of action • Not properly understood.• Primary focus (of research) has been on the

synapse. GABAA receptors• Almost all anaesthetics (with the exceptions of

cyclopropane, ketamine and xenon) potentiate the action of GABA at the GABAA receptor.

(GABAA receptors are ligand-gated Cl- channels

made up of five subunits (generally comprising two α, two β and one γ or δ subunit).

• volatile anaesthetics (may) bind at the interface between α and β subunits.

Two-pore domain K+ channels (These belong to a family of 'background' K+

channels that modulate neuronal excitability.) Channels made up of TREK1, TREK2, TASK1,

TASK3 or TRESK subunits (can be) directly activated by low concentrations of volatile and gaseous anaesthetics.

• Thus reducing membrane excitability.

NMDA receptors • (Glutamate the major excitatory neurotransmitter

in the CNS, activates three main classes of ionotropic receptor-AMPA, kainate and NMDA receptors.)

• Nitrous oxide, xenon apppear to reduce NMDA receptor-mediated responses.

• Xenon appears to inhibit NMDA receptors by competing with glycine.

• Other inhalation anaesthetics may also exert effects on the NMDA receptor in addition to their effects on other proteins such as the GABAA receptor

PHARMACOKINETICS• Inhaled anesthetics are taken up through gas

exchange in the alveoli.Uptake & DistributionA. Inspired Concentration and Ventilation• The driving force for uptake is the alveolar

concentration. • Two determinants :

(controlled by the anesthesiologist)(1) inspired concentration or partial pressure(2) alveolar ventilation .

• Increases in the inspired partial pressure increase the rate of rise in the alveoli and thus accelerate induction.

• The increase of partial pressure in the alveoli is expressed as

a ratio of alveolar concentration (F A ) over inspired concentration (F 1 );

• The faster F A /F 1 approaches 1 (1 representing the equilibrium), the faster is the induction.

• The other parameter by which FA/F1 approaches to 1 is alveolar ventilation.

• However The magnitude of the effect varies according to the blood:gas partition coefficient.

Factors Controlling Uptake1. Solubility2. Cardiac output3. Alveolar-venous partial pressure difference

Solubility : • The blood:gas partition coefficient is a useful

index of solubility.

• Defines the relative affinity of an anesthetic for the blood compared with that of inspired gas.

• The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood, are extremely low.

• When an anesthetic with low blood solubility diffuses from the lung into the arterial blood, relatively few molecules are required to raise its partial pressure

• Therefore, the arterial tension of gas rises rapidly.

• Conversely, for anesthetics with moderate to high solubility ( halothane, isoflurane), more molecules dissolve before partial pressure changes significantly, and arterial tension of the gas increases less rapidly.

• A blood: gas partition coefficient of 0.47 for nitrous oxide means that - At equilibrium, the concentration in blood is 0.47 times the concentration in the alveolar space (gas).

Cardiac output—• An increase in pulmonary blood flow (ie,

increased cardiac output) will increase the uptake of anesthetic.

• But anesthetic taken up will be distributed in all tissues, not just the CNS.

• Cerebral blood flow is well regulated and the increased cardiac output will therefore increase delivery of anesthetic to other tissues and not the brain.

Alveolar-venous partial pressure difference—• The anesthetic partial pressure difference

between alveolar and mixed venous blood is dependent mainly on uptake of the anesthetic by the tissues, including non-neural tissues.

• The greater this difference in anesthetic gas tensions, the more time it will take to achieve equilibrium with brain tissue.

Elimination• Recovery from inhalation anesthesia follows

some of the same principles in reverse that are important during induction.

• One of the most important factors governing rate of recovery is the

• Blood : gas partition coefficient of the anesthetic agent. Lesser the value faster is the recovery.

• nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate.

• Recovery also depends on1. Alveolar Ventilation (controlled by

Anaesthesiologist)2. Metabolism of anaesthetic.• Modern inhaled anesthetics are eliminated

mainly by ventilation and are only metabolized to a very small extent.

• However , metabolism have important implications for their toxicity.

• In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is

• halothane > enflurane > sevoflurane >isoflurane > desflurane > nitrous oxide

PHARMACODYNAMICSA. Cerebral Effects• Anesthetic potency is currently described by

the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision.

• Inhaled anesthetics decreases the metabolic activity of the brain.

• Decreased cerebral metabolic rate (CMR) generally reduces blood flow within the brain.

• However, volatile anesthetics also cause cerebral vasodilation, which can increase cerebral blood flow.

• The net effect on cerebral blood flow (increase, decrease, or no change) depends on the concentration of anesthetic delivered.

• Clinical importance : An increase in cerebral blood flow is undesirable in patients who have increased intracranial pressure because of brain tumor, intracranial hemorrhage, or head injury.

• Anesthetic effects on the brain produce four stages or levels of increasing depth of CNS depression

(Guedel’s signs, derived from observations of the effects of inhaled diethyl ether):

• Stage I—analgesia: The patient initially experiences analgesia without amnesia. Later in stage I, both analgesia and amnesia are produced.

• Stage II—excitement: During this stage, the patient appears delirious, may vocalize but is completely amnesic.

Respiration is rapid, and heart rate and blood pressure increase.

Stage III—surgical anesthesia: • This stage begins with slowing of respiration

and heart rate and extends to complete cessation of spontaneous respiration (apnea).

• Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anesthesia.

Stage IV—medullary depression:• Severe depression of the CNS, including the

vasomotor center and respiratory center in the brainstem.

• Without circulatory and respiratory support, death would rapidly ensue.

B. Cardiovascular Effects• All depress normal cardiac contractility

(halothane and enflurane more so than isoflurane, desflurane, and sevoflurane).

• So they tend to decrease mean arterial pressure in direct proportion to their alveolar concentration.

• In halothane and enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance.

• In contrast, isoflurane, desflurane, and sevoflurane produce greater vasodilation with minimal effect on cardiac output.

• Clinical importance : These differences may have important implications for patients with heart failure.

C. Respiratory Effects• All volatile anesthetics possess varying

degrees of bronchodilating properties.• The control of breathing is significantly

affected by inhaled anesthetics. • With the exception of nitrous oxide, all

inhaled anesthetics cause a dose-dependent

decrease in tidal volumeincrease in respiratory rate (rapid shallow

breathing pattern).

• All volatile anesthetics are respiratory depressants (reduced ventilatory response to increased levels of carbon dioxide in the blood)

D. Renal Effects• Inhaled anesthetics tend to decrease

glomerular filtration rate (GFR) and urine flow.

Effects on Uterine Smooth Muscle• Nitrous oxide appears to have little effect on

uterine musculature.

• However, the halogenated anesthetics are potent uterine muscle relaxants (concentration-dependent)

• Toxicity of inhaled AnestheticsA. Acute Toxicity1. Nephrotoxicity— • Metabolism of enflurane and sevoflurane may

generate compounds that are potentially nephrotoxic. (liberate fluoride ions)

2. Hematotoxicity— • Prolonged exposure to nitrous oxide

decreases methionine synthase activity, which could cause megaloblastic anemia

• All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon dioxide absorbers. (desflurane)

3. Malignant hyperthermia— is a heritable genetic disorder of skeletal

muscle that occurs in susceptible individuals exposed to volatile anesthetics while undergoing general anesthesia. ( Halothane)

4. Hepatotoxicity (halothane hepatitis)— Hepatic dysfunction

• a small subset of individuals previously exposed to halothane has developed fulminant hepatic failure.

• Cases of hepatitis of others have rarely been reported.

B. Chronic ToxicityMutagenicity, teratogenicity.• Under normal conditions, inhaled anesthetics

including nitrous oxide are neither mutagens nor carcinogens in patients.

• Nitrous oxide can be directly teratogenic in animals under conditions of extremely high exposure.

• Halogenated agents may be teratogenic in rodents.

Nitrous oxide

Important features.

• Nitrous oxide is completely eliminated by the lungs.

• Non toxic to liver , kidney and brain. No much adverse effects on CVS , RS.

• Probably the safest with 30% oxygen

• N2O is a weak, low potency anesthetic agent.• Action is quick and smooth .• Recovery is rapid. Rarely exceeds 4 min.• It is a poor muscle Relaxant.• It has significant analgesic effects.

• Nitrous oxide is used primarily as an adjunct to other inhalational or intravenous anesthetics mainly during maitenance phase.

• 70% N2O +25-30% oxy + 0.2-2% potent anaesthetic

Adverse effects

Pneumothorax.Megaloblastic anemia peripheral neuropathy (because of methionine

synthetase inactivation

Halothane• Induction is relatively slow.• Halothane is soluble in fat and other body tissues,

it will accumulate during prolonged administration.

• Halothane can sensitize the myocardium to the arrhythmogenic effects of Adrenaline.

Uses : Induction and maintenance anaesthesia in pediatric age group.

Maintenance anaesthesia in adults

• Adverse Effects :Shivering during recoveryMalignant hyperthermiaFulminant hepatic necrosis

Enflurane • Induction of anesthesia and recovery from

enflurane are relatively slow.

• It is primarily utilized for maintenance rather than induction of anesthesia.

• Enflurane provokes seizure attacks in susceptible patients.

• Enflurane produces significant skeletal muscle relaxation

Isoflurane • Induction with isoflurane and recovery from

isoflurane are faster than with halothane.

• It is typically used for maintenance of anesthesia after induction with other agents because of its pungent odor. Another e.g, Desflurane.

Sevoflurane• Eventhough non-explosive in mixtures of air or

oxygen. sevoflurane can undergo an exothermic

reaction with desiccated CO2 to produce airway burns. So it should be used in open system airway ventilation.

• Effects on CVS and RS is modest.

• It is well-suited for inhalation induction of anesthesia (particularly in children)