General AnestheticsHerni Suprapti dr MKes

Natural medicines

Physical methods

Control surgical pain

Cannabis Henbane Mandrake Opium poppy

Sedative effects

Cold Nerve compression Carotid artery occlusion Cerebral concussion

Physical methods

1842: Ether

1846: New era of anesthesia ◦ no pain during surgical procedures

Five primary effects: Unconsciousness Amnesia Analgesia Inhibition of autonomic reflexes Skletal muscle relaxation

State of General Anesthetics

an ideal anesthetic drug

induce rapid, smooth loss of consciousness, be rapidly reversible upon discontinuation,

and possess a wide margin of safety.

Modern anesthesiology

balanced anesthesia techniques: combinations of◦ intravenous and ◦ inhaled drugs

to take advantage of the favorable properties of each agent while minimizing their adverse effects.

The choice of anesthetic technique is determined by the type of diagnostic, therapeutic, or surgical intervention to be performed.

For minor superficial surgery or for invasive diagnostic procedures, oral or parenteral sedatives can be used in combination with local anesthetics, so- called monitored anesthesia care techniques. These techniques provide profound analgesia, with retention of the patient's ability to maintain a patent airway and to respond to verbal commands.

For more extensive surgical procedures, anesthesia may begin with preoperative benzodiazepines, be induced with an intravenous agent (eg, thiopental or propofol), and be maintained with a combination of inhaled (eg, volatile agents, nitrous oxide) or intravenous (eg, propofol, opioid analgesics) drugs, or both.

For minor superficial surgery or for invasive diagnostic procedures:◦ oral or parenteral sedatives can be used in

combination with ◦ local anesthetics

so- called monitored anesthesia care techniques

These techniques provide profound analgesia, with retention of the patient’s ability to maintain a patent airway and to respond to verbal commands.

For more extensive surgical procedures:◦anesthesia may begin with preoperative

benzodiazepines,◦be induced with an intravenous agent

(eg, thiopental or propofol), ◦and be maintained with a combination inhaled (eg, volatile agents, nitrous

oxide) or intravenous (eg, propofol, opioid

analgesics) drugs, or both.

MECHANISM OF GENERAL ANESTHETIC ACTION General anesthetics have been in clinical

use for more than 160 years but their mechanism of action remains unknown.

Initial research focused on identifying a single biologic site of action for these drugs.

In recent years this “unitary theory” of anesthetic action has been supplanted by a more complex picture of molecular targets located at multiple levels of the central nervous system (CNS).

MECHANISM OF GENERAL ANESTHETIC ACTION Anesthetics affect neurons at various cellular locations,

but the primary focus has been on the synapse. ◦ A presynaptic action may alter the release of neurotransmitters,

whereas ◦ a postsynaptic effect may change the frequency or amplitude of

impulses exiting the synapse. At the organ level, the effect of anesthetics may result

from:◦ strengthening inhibition or from ◦ diminishing excitation within the CNS.

Studies on isolated spinal cord tissue have demonstrated that excitatory transmission is impaired more strongly by anesthetics than inhibitory effects are potentiated.

MECHANISM OF GENERAL ANESTHETIC ACTION

Inhibitory◦ Chloride channels (-aminobutyric acid-A [GABA-

A] and glycine receptors) and ◦ Potassium channels

Excitatory

◦ acetylcholine (nicotinic and muscarinic receptors), ◦ amino acids (AMPA, kainate, and NMDA receptors)◦ serotonin (5-HT2 and 5-HT3 receptors).

◦Inhaled anesthetics

◦Intravenous anesthetics

INHALED ANESTHETICS

Volatile anesthetics ◦ Halothane◦ Enflurane◦ Isoflurane◦ Desflurane◦ Sevoflurane◦

Gaseous anesthetics ◦ Nitrous oxide◦ Xenon

PHARMACOKINETICS Inhaled anesthetics, volatile as well as gaseous, are

taken up through gas exchange in the alveoli. Uptake from the alveoli into the blood and distribution

and partitioning into the effect compartments are important determinants of the kinetics of these agents.

As previously mentioned, an ideal anesthetic should have a rapid onset (induction), and its effect should be rapidly terminated.

To achieve this, the effect site concentration in the CNS (brain and spinal cord) will need to change rapidly.

Several factors determine how quickly the CNS concentration changes.

PHARMACOKINETICSUptake & Distribution A. Inspired Concentration and Ventilation B. Factors Controlling Uptake

◦ 1. Solubility◦ 2. Cardiac output◦ 3. Alveolar-venous partial pressure difference

Elimination A. Ventilation B. Metabolism

PHARMACODYNAMICS

Organ System Effects of Inhaled Anesthetics A. Cerebral Effects B. Cardiovascular Effects C. Respiratory Effects D. Renal Effects E. Hepatic Effects F. Effects on Uterine Smooth Muscle

Cerebral Effects

Anesthetic potency is currently described by the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision

(see Box: What Does Anesthesia Represent & Where Does It Work?).

Cerebral Effects

Traditionally, 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 Stage II—excitement Stage III—surgical anesthesia Stage IV—medullary depression

Cerebral Effects 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. Duration and severity of this light stage of anesthesia is shortened by rapidly increasing the concentration of the agent.

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: This deep stage of anesthesia represents severe depression of the CNS, including the vasomotor center in the medulla and respiratory center in the brainstem. Without circulatory and respiratory support, death would rapidly ensue.

A. Acute Toxicity

B. Chronic Toxicity

Toxicity of Anesthetic Agents

1. Nephrotoxicity

2. Hematotoxicity

3. Malignant hyperthermia

4. Hepatotoxicity (halothane hepatitis)

Acute Toxicity

1. Mutagenicity   2. Carcinogenicity

Chronic Toxicity

INTRAVENOUS ANESTHETICS

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