Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

LOCAL ANESTHETICS

RNH2 + H+ RN+H3 (Active form)

Figure IV-6-2. Mode of Action of Local Anesthetics

λLocal anesthetics provide regional anesthesia.

λDrugs:

−Esters: procaine, cocaine, benzocaine are metabolized by plasma and tissue esterases

−Amides: lidocaine, bupivacaine, mepivacaine are metabolized by liver amidases

λMechanisms:

−Nonionized form crosses axonal membrane

−From within, ionized form blocks the inactivated Na+ channel

−Slows recovery and prevents propagation of action potentials

λNerve fiber sensitivity:

−Nerve fibers most sensitive to blockade are of smaller diameter and have high firing rates

−The order of sensitivity is:

type B and C > type Aδ > type Aβ and Aγ > type Aα

−Recovery is in reverse order

λAbsorption:

−Coadministration of α1 agonists:

º↓ local anesthetic absorption into the systemic circulation

ºProlong effects and ↓ toxicity

λSide effects:

−Neurotoxicity

−Cardiovascular toxicity

−Allergies (esters via PABA formation)

Note

Na+ Channel Toxins

λTetrodotoxin (from puffer fish) and saxitoxin (algae toxin, “red tide”)

−Block activated Na+ channels

−↓ Na+ influx

λCiguatoxin (exotic fish) and batrachotoxin (frogs)

−Bind to activated Na+ channels

−Cause inactivation

−Prolong Na+ influx

Note

Esters and Amides

Local anesthetics that are esters have just one “i” in their names (e.g., procaine, cocaine); amide local anesthetics have more than one “i” (e.g., lidocaine, bupivacaine).

Note

Cocaine intrinsically causes vasoconstriction by blocking norepinephrine uptake.

º Cautions:

Atypical pseudocholinesterase Hyperkalemia

Malignant hyperthermia

Centrally Acting Skeletal Muscle Relaxants

λBenzodiazepines through GABAA receptors

λBaclofen through GABAB receptors

λUse: spasticity

Chapter Summary

Drugs Used in Anesthesia

λThe more lipid soluble the inhalation anesthetic, the greater its potency (lower MAC value). The more soluble an inhalation anesthetic in the blood (higher blood:gas ratio), the slower will be the onset to anesthesia and the slower will be the recovery.

λThiopental, midazolam, propofol, fentanyl, and ketamine are intravenous anesthetics that are discussed.

λLocal anesthetics (weak bases) infiltrate and anesthetize nerve bundles near sites of injection by binding to inactive Na+ channels in their ionized forms. However, to get to the channel they must diffuse through the lipid bilayer in an unionized form. Thus, their effects are influenced by pH.

λThe smaller and most rapidly firing nerve fibers are the most sensitive to blockade.

λThe coadministration of alpha adrenoceptor agonists decreases local anesthetic absorption into the systemic circulation, prolonging their effects and potentially decreasing their toxicity.

λThe adverse effects of local anesthetics are given.

Sodium Channel Toxins

λTetrodotoxin, saxitoxin, ciguatoxin, and batrachotoxin are sodium-channel toxins found in various fish, frogs, or dinoflagellates.

Skeletal Muscle Relaxants

λThe skeletal muscle relaxants provide muscle relaxation and/or immobility via N-receptor interactions. Most, includingd-tubocurarine, atracurium, and mivacurium, are competitive and nondepolarizing and can be reversed by AChE inhibitors. Succinylcholine is a depolarizing, noncompetitive agonist.

λSpasmolytics reduce excess muscle tone or spasm in injury or CNS dysfunction. They may act in the CNS, the spinal cord, or directly on the muscle.

Benzodiazepines and baclofen reduce the tonic output of spinal motor neurons. Dantrolene blocks Ca2+ release from the muscle sarcoplasm reticulum.

Chapter 6 λ Drugs Used in Anesthesia

Bridge to Pathology/Genetics

Malignant Hyperthermia

A life-threatening syndrome characterized by muscle rigidity, hyperthermia, hypertension, acidosis, and hyperkalemia. Associated with the use of skeletal muscle relaxants, especially succinylcholine, used in anesthesia regimens. Genotypic susceptibility may be related to mutations in the genes encoding ryanodine receptors and/or a protein component of the L-type calcium channel in skeletal muscle.

Treatment

Dantrolene acts directly on skeletal muscle to decrease contractility by blocking Ca2+ release from the sarcoplasmic reticulum. It is used in states that include extreme muscle rigidity, such as malignant hyperthermia associated with inhaled anesthetics and skeletal muscle relaxants or neuroleptic

malignant syndrome associated with antipsychotics.