L12 Anesthetics (General and local)

General anesthetics

Analgesia 镇痛
Amnesia 失忆，健忘
Loss of consciousness
Inhibition of sensory and autonomic reflexes
Skeletal muscle relaxation

An ideal anesthetic

A smooth and rapid loss of consciousness
A prompt recovery after its administration is discontinued
A wide margin of safety and be devoid of adverse effects

Stages of Anesthesia

From observations of the effects of inhaled diethyl ether, anesthetic effects on the brain can be divided into four stages:

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

II. Stage of excitement: The patient often appears to be delirious (精神错乱) and may vocalize but is definitely amnesic. Respiration is irregular both in volume and rate, and retching and vomiting may occur.

III. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III have been described in terms of changes in ocular movements, eye reflexes, and pupil size, which may represent signs of increasing depth of anesthesia.

IV. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the CNS, including the vasomotor center in the medulla, as well as the respiratory center in the brain stem. Without circulatory and respiratory support, death rapidly happens.

Introduction of General Anesthetics

Putative targets of anesthetic action

1. Enhance inhibitory synaptic activity

Enhance GABA/Glycine receptor

2. Decrease excitatory synaptic activity

Inhibit glutamate receptors, nACh receptors

Type of General Anesthesia (route of administration)

1. Intravenous Anesthetics 静脉麻醉

Some drugs:

barbiturates (eg, thiopental, methohexital)
benzodiazepines (eg, midazolam, diazepam)
Propofol (GABA receptor agonist/potentiator)
Ketamine (NMDA receptor repression)
opioid analgesics (morphine, fentanyl)
miscellaneous sedative-hypnotics (eg, etomidate)

Redistribution of thiopental after an intravenous bolus administration

Propofol (Diprivan): Potentiate GABA and inhibit Sodium channel

Mechanism similar to ethanol
Rapid onset and recovery
Antiemetic activity (止吐活性)

Short-acting barbiturates

Thiopental (Pentothal)

Benzodiazepines

Midazolam

Ketamine (a CNS suppressant that can be abused)

Block glutamate receptors
Dissociative anesthesia:
- Catatonia, analgesia, and amnesia without loss of consciousness
Cardiac stimulant

Etomidate: a GABA receptor modulator

Non-barbiturate
Rapid onset
Minimal cardiovascular and respiratory toxicities
High incidence of nausea and vomiting

2. The Inhaled Anesthetics 吸入麻醉

The most commonly used inhaled anesthetics are isoflurane, desflurane, and sevoflurane, as well as nitrous oxide.

These compounds are volatile liquids that are aerosolized in specialized vaporizer delivery systems.

Gaseous or Volatile
brain uptake
tissue distribution

Mechanism still unknown, But physical interaction such as swelling of nerve cell membranes from gas solution in the lipid bilayer may be operative

Mechanism of Action? (Possible action mechanisms)

To activate GABAA receptor-chloride channel
To activate glycine receptor
To inhibit NMDA channel receptor
To inhibit nicotinic acetylcholine receptor isoforms

Solubility

The inhaled anesthesia need to be soluable in blood

Solubility

One of the most important factors influencing the transfer of an anesthetic from the lungs to the arterial blood is its solubility.
The blood:gas partition coefficient is a useful index of solubility and 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.

Why induction of anesthesia is slower with more soluble anesthetic gases.

Solubility in blood is represented by the relative size of the blood compartment (the more soluble, the larger the compartment).
Relative partial pressures of the agents in the compartments are indicated by the degree of filling of each compartment.
For a given concentration or partial pressure of the two anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be slower with halothane than with nitrous oxide.

3. Balanced Anesthesia 复合麻醉

Although general anesthesia can be produced using only intravenous or only inhaled anesthetic drugs, modern anesthesia typically involves a combination of intravenous (eg, for induction of anesthesia) and inhaled (eg, for maintenance of anesthesia) drugs.

However, volatile anesthetics (eg, sevoflurane) can also be used for induction of anesthesia, and intravenous anesthetics (eg, propofol) can be infused for maintenance of anesthesia

Local Anesthetics 局部麻醉

Overview

Local anesthetics produce a transient and reversible loss of sensation (analgesia) in a circumscribed region of the body without loss of consciousness.
Normally, the process is completely reversible.

Local anesthetics esters or amides

a lipophilic aromatic group
to a hydrophilic, ionizable amine
Most are weak bases

Classification of LA

Esters

Benzocaine
Procaine
Proparacaine

Amide

Bupivacaine
Levobupivacaine
Lidocaine/Lignocaine

Mechanism of LAs

Block inititation and propagation of action potential

Paths of LA to target site

Local anesthetics gain access to the inner axonal membrane by

traversing sodium channels while they are more often in an open configuration
passage directly through the plasma membrane

Sequence of clinical anesthesia

Sympathetic block (vasodilatation) 交感神经阻滞
Loss of pain and temperature sensation 疼痛和体温感觉丧失
Loss of proprioception 肌肉运动知觉的丧失
- Proprioception: the reception of stimuli produced within the organism
Loss of touch and pressure sensation 失去触觉和压力感
Loss of motor function (Somatic) 运动功能的损失(躯体)