GENERAL ANESTHETICS

Tutik Juniastuti

GENERAL ANESTHESIA :

- Is a state characterizied by uncons cious- ness, analgesia, amnesia, skeletal muscle relaxation, and loss of reflexes

- Drugs used as general anesthetics are CNS depressants with actions that can be induced and terminated more rapidly than those of conventional sedative-hypnotics

GENERAL ANESTHETICS

Inhaled Intravenous

Gas Volatile liquids Barbiturates Benzodiazepines(Nitrous (Halothane) (Thiopenthal) (Midazolam)Oxide)

Dissociative Opioids(Ketamine) (Fentanyl)

Miscellaneous (Etomidate, Propofol)

General anaesthesia usually involves the administration of different drugs for premedication, induction of anaesthesia and maintenance of anaesthesia

Premedication has two main aims: The prevention of the parasympathomimetic effect

of anaesthesia (bradicardia, brochial secretion) The reduction of anxiety or pain

STAGE OF ANESTHESIA

a. Stage 1. Analgesia

b. Stage 2. Disinhibition

c. Stage 3. Surgical Anesthesia

d. Stage 4. Medullary Depression

Stage 1. Analgesia The patient has decreased awareness of

pain, sometimes with amnesia Consciousness may be impaired but is not

lost

Stage 2. Disinhibition The patient appears to be delirious and

excited Amnesia occurs, reflexes are enhanced,

and respiration is typically irregular; retching and incontinence may occurs

Stage 3. Surgical Anesthesia

The patient is unconscious and has no pain reflexes; respiration is very regular; and blood pressure is maintained

Stage 4. Medullary Depression

The patient develops severe respiratory and cardiovascular depression that requires mechanical and pharmacologic support

Mechanisms of Action Are varied As CNS depressants, these drugs usually

increase the threshold for firing of CNS neurons The potency of inhaled anesthetics is roughly

proportionate to their lipid solubility Mechanisms of action include effects on ion

channels by interactions of anesthetic drugs with membrane lipids or proteins with subsequent effects on cen tral neurotransmitter mechanisms

Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate y‑aminobutyric acid (GABA)‑mediated inhibition at GABAA receptors

These receptors are sensitive to clinically relevant concentrations of the anesthetic agents and exhibit the appropriate stereospecific effects in the case of enantiomeric drugs

Ketamine does not produce its effects via facilitation of GABAA receptor functions, but possibly via its antagonism of the action of the excitatory neurotransmitter glutamic acid on the N‑methyl D‑aspartate (NMDA) receptor

Most inhaled anesthetics also inhibit nicotinic ACh receptor isoforms at moderate to high concentration

The strychnine‑sensitive glycine receptor is another ligand‑gated ion channel that may function as a "target" for certain inhaled anesthetics.

CNS neurons in different regions of the brain have different sensitivities to general anesthetics; inhibition of neurons involved in pain pathways occurs before inhibition of neurons in the midbrain reticular formation.

INHALED ANESTHETICSA. CLASSIFICATION AND PHARMACOKINOICS

Nitrous oxide (a gas) Several easily vaporized liquid halogenated

hydrocarbons Halothane Desflurane Enflurane Isoflurane Sevofurane Methoxyflurane

The speed of induction of anesthetic effects

depends on several factorst

1. Solubility

The more rapidly a drug equilibrates with the blood, the more quiddy the drug passes into the brain to produce anesthetic eflects. Drugs with a low blood:gas partition coefficient (eg, nitrous oxide) equilibrate more rapidly than those with a higher blood solubility (eg, halothane)

2.Inspired gas partial pressure

A high partial pressure of the gas in the lungs results in more rapid achievement of anesthetic levels in the blood. This effect can be taken advantage of by the initial administration of gas concentrations higher than those required for maintenance of anesthesia.

3.Ventilation rate

The greater the ventilation, the, more rapid is the rise in alveolar and blood partial presure of the agent and the onset of anesthesia. This effect is taken advantage of in the induction of the anesthetic state.

4. Pulmonary blood flow

At high pulmonary blood flows, the gas partial pressure rises at a slower rate, thus, the speed of onset of anesthesia is reduced. At low flow rates, onset is faster. In circulatory shock, this effect may accelerate the rate of onset of anesthesia with agents of high blood solubility.

5. Arteriovenous concentration gradient

Uptake of soluble anesthetics into highly perfused tissues may decrease gas tension in mixed venous blood. This can influence the rate of onset of anesthesia because achievement of equilibrium is dependent on the difference in anesthetic tension between arterial and venous blood.

B. ELIMINATION

Anesthesia is terminated by redistribution of the drug from the brain to the blood and elimination of the drug through the lungs.

The rate of recovery from anesthesia using agents with low blood:gas partition coefficients is faster than that of anesthetics with high blood solubility

This important property has led to the introduction of several newer inhaled anesthetics (eg, desflurane, sevoflurane), which, because of their low blood solubility, are characterized by recovery times that are considerably shorter than is the case with older agents.

Halothane and methoxyflurane are metabolized by liver enzymes to a significant extent

Metabolism of halothane and methoxyflurane has only a minor influence on the speed of recovery from their anesthetic effect but does play a role in potential toxicity of these anesthetics.

C. MlNIMUM ALVEOLAR ANESTHETIC CONCENTRATION

The potency of inhaled anesthetics is best measured by the minimum alveolar anesthetic concentration (MAC), defined as the alveolar concentration required to eliminate the response to a standardized painfid stimulus in 50% of patients.

Each anesthetic has a defined MAC but this value may vary among different patients depending on age,.cardiovascular status, and use of adjuvant drugs. Estimations of MAC value suggest a relatively 'steep* dose‑response relationship for inhaled anesthetics. MACs for infants and elderly patients are lower than those for adolescents and young adults. When several anesthetic agents are used simultaneously, their MAC values am additive.

D. EFFECTS OF INHALED ANESTHETIC

1. CNS effects Inhaled anesthetics decrease brain metabolic rate. They reduce vascular resistance and thus increase

cerebral blood flow. This may lead to an increase in intracranial pressure. High concentrations of enflurane may cause

spike‑and‑wave activity and muscle twitching, but this effect is unique to this drug.

Although nitrous oxide has low anesthetic potency (ic, a high MAC), it exerts marked analgesic and arrinestic actions.

2. Cardiovascular effects Most inhaled anesthetics decrease arterial blood

pressure moderately. Enflurane and halothane are myocardial depressants

that decrease cardiac output, whereas isoflurane causes peripheral vasodilation.

Nitrous oxide is less likely to lower blood pressure than are other inhaled anesthetics. Blood flow to the liver and kidney is decreased by most inhaled agents. Halothane may sensitize the myocardium to the arrhythmogenic effects of catecholarnines.

3. Respiratory effectsRate of respiration may be increased by

inhaled anesthetics, but tidal volume and minute ventilation are decreased, leading to in increase in arterial CO2 tension.

Inhaled anesthetics decrease ventilatory response to hypoxia even at subanesthetic concentrations (eg, during recovery).

Nitrous oxide has the smallest effect on respiration.

Most inhaled anesthetics are bronchodilators, but desflurane is a pulmonary irritant and may cause bronchospasm.

The pungency of enflurane causing breath‑holding limits its use in anesthesia induction.

4. ToxicityPostoperative hepatitis has occurred (rarely)

after halothane anesthesia in patients cxperiencing hypovolemic shock or other severe stress.

Fluoride released by metabolism of methoxyflurane (and possibly enflurane) may cause renal insufficiency after prolonged anesthesia.

Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anemia.

Susceptible patients may develop malignant hyperthermia when anesthetics are used together with neuromuscular blockers (especially succinylcholine).

This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor.

The uncontrolled release of calcium by the sarcoplasmic rcticulum of skeletal muscle leads to muscle spasm, hyperthermia, and autonomic lability. Dantrolene is indicated for the treatment of this life‑threatening condition, with sup portive management.

INTRAVENOUS ANESTHETICSA. BARBITURATES Thiopental and methohexital

Have high lipid solubility, which promotes rapid entry into the brain and results in surgical anesthesia in one circulation time (< I min).

These drugs are used for induction of anesthesia and for short surgical procedures.

The anesthetic effects of thiopental are terminated by redistribution from the brain to other highly perfused tissues, but hepatic metabolism is required for elimination from the body.

Barbiturates are respiratory and circulatory depressants; because they depress cerebral blood flow, they can also decrease intracranial pressure.

B. BENZODIAZENNES

Midazolam is widely used adjunctively with inhaled

anesthetics and intravenous opioids. The onset of its CNS effects is slower than

that of thiopental, and it has a longer duration of action.

Cases of severe postoperative respiratory depression have occurred.

The benzodiazepine receptor antagonist, flumazenil, accelerates recovery from midazolam and other benzodiazepines.

C. KETAMINE This drug produces a state of "dissociative

anesthesia” in which the patient remains conscious but has marked catatonia, analgesia, and amnesia.

Ketamine is a chemical congener of the psychotomimetic agent, phencyclidine (PCP).

The drug is a cardiovascular stimulant, this action may lead to an increase in intracranial pressure. Emergence reactions, including disorientation, excitation, and hallucinations, which occur during recovery from ketamine anesthesia, can be reduced by the preoperative use of benzodiazepines.

D. OPIOIDS

Morphine and fentanyl are used with other CNS depressants (nitrous

oxide, benzadiazcpines) in anesthesia regimens and are especially valuable in high‑risk patients who might not survive a full general anesthetic.

Intravenous opioids may cause chest wall rigidity that can impair ventilation.

Respiratory depression with these drugs may be reversed postoperatively with naloxone.

Neuroleptanesthesia is a state of analgesia and amnesia produced when fentanyl is used with droperidol and nitrous oxide.

Newer opioids related to fentanyl have been introduced for intravenous anesthesia.

Alfentanil and remifentanil have been used for induction of anesthesia. Recovery from the actions of remifentanil is faster than recovery from other opioids used in anesthesia because of its rapid metabolism by blood and tissue esterases.

E. PROPOFOLPropofol produces anesthesia as rapidly as

the intravenous barbiturates, and recovery is more rapid.

Propofol has antiemetic actions, and recovery is not delayed after prolonged infusion. The drug is commonly used as a component of balanced anesthesia and as an anesthetic in outpatient surgery.

Propofol may cause marked hypotension during induction of anesthesia, primarily through decreased peripheral resistance.

Total body clearance of propofol is greater than hepatic blood flow, suggesting that its elimination includes other mechanisms in addition to metabolism by liver enzymes.

F. ETOMIDATEThis imidazole derivative affords rapid

induction with minimal change in cardiac function or respiratory rate and has a short duration of action.

The drug is not analgesic, and its primary advantage is in anesthesia for patients with limited cardiac or respiratory reserve.

Etomidate may cause pain and myoclonus on injection and nausea postoperatively.

Prolonged administration may cause adrenal suppression.