Membrane-depressant agents

Class I Local anesthetics or membrane-stabilizing agents that depress phase 0. 

Mechanism of Action An antianginal and antihypertensive agent that inhibits calcium ion movement across cell membranes, depressing contraction of cardiac and vascular smooth muscle. Therapeutic Effect Increases heart rate and cardiac output. Decreases systemic vascular resistance and BP. 

Bradycardia and AV block are common features of intoxication with calcium antagonists (see p 144) and drugs that depress sympathetic tone or increase parasympathetic tone. These conditions may also result from severe intoxication with membrane-depressant drugs (eg, tricyclic antidepressants, quinidine, or other type la and Ic antiarrhythmic agents). 

Volume loss, venodilation, and arteriolar dilation are likely to result in hypotension with reflex tachycardia. In contrast, hypotension accompanied by bradycardia should suggest intoxication by sympatholytic agents, membrane-depressant drugs, calcium channel blockers, or cardiac glycosides or the presence of hypothermia. 

A. blocker antihistamines are structurally related to histamine and antagonize the effects of histamine on H., receptor sites. They possess anticholinergic effects (except the nonsedating agents astemizole, azelastine, cetirizine, desloratadine, fexofenadine, loratadine, and terfenadine). They may also stimulate or depress the CNS, and some agents (eg, diphenhydramine) have local anesthetic and membrane-depressant effects in large doses. 

A. Cardiovascular. Anticholinergic effects may produce tachycardia. Alpha-adrenergic blockade may cause orthostatic hypotension. With very large overdoses of some agents, quinidine-llke membrane-depressant effects on the heart may occur. Many agents can cause QT prolongation and torsade de pointes (see p 14). 

A. Propranolol and other agents with membrane-depressant (quinidine-like) effects further depress myocardial contractility and conduction. Propranolol is also lipid soluble, which enhances brain penetration and can cause seizures and coma. 

Love JN, Elshami J Cardiovascular depression resulting Irom atenolol intoxication. EurJ Emerg Med 2002 9(2) 111-114. [PMID 12131631] (A patient with massive atenolol ingestion developed hypotension in association with QRS prolongation the authors point out that although rare, even hydrophilic agents can produce membrane-depressant etiects that are more commonly seen with lipophilic drugs like propranolol.)... 

B. The sodium ion ioad and aikaiemia produced by hypertonic sodium bicarbonate reverse the sodium channel-dependent membrane-depressant ( quini-dine-like ) effects of several drugs (eg, tricyclic antidepressants, type la and type Ic antiarrhythmic agents, propranolol, propoxyphene, cocaine, and diphenhydramine). 

The mechanisms of action of the effects of alcohol on the nervous system remain unclear. For some time, researchers thought that the depressant effects of alcohol, like other anesthetic agents, were caused by dissolving into the cell lipid membranes and disrupting the function of various proteins. More recently, researchers have focused on specific receptors such as glutamate (excitatory) and GABA (inhibitory). Despite intensive research, the mechanism of effect of alcohol on the fetus is unknown. 

As with all members of its class, propafenone has its major effect on the fast inward sodium current. The IC agents depress over a wide range of heart rates and shift the resting membrane potential in the direction of hyperpolarization. The 1C agents bind slowly to the sodium channel and dissociate slowly. Therefore, they exhibit rate-dependent block. Inhibition of the sodium channel throughout the cardiac cycle will result in a decrease in the rate of ectopy and trigger ventricular tachycardia. 

MecfMnism of Action An antihypertensive and antianginal agent that inhibits calcium movement across cardiacandvascular smooth-musclecell membranes. Potent peripheral vasodilator (does not depress SA or AV nodes). Therapeutic Effect Increases myocardial contractility, heart rate, and cardiac output decreases peripheral vascular resistance and BP. 

Mectianism of Action An antidepressant, anxiolytic, and antiobsessional agent that selectively blocks uptake of the neurotransmitter serotonin at neuronal presynaptic membranes, thereby increasing its availability at postsynaptic receptor sites. Therapeutic Effect Relieves depression, reduces obsessive-compulsive behavior, decreases anxiety. 

Both the inhaled and the intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain. Older concepts of the mechanism of anesthesia evoked nonspecific interactions of these agents with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux. More recently, evidence has accumulated suggesting that the modification of ion currents by anesthetics results from more direct interactions with specific nerve membrane components. The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they appear to involve interactions with members of the ligand-gated ion channel family. 

The cardiovascular effects of local anesthetics result partly from direct effects upon the cardiac and smooth muscle membranes and partly from indirect effects upon the autonomic nerves. As described in Chapter 14 Agents Used in Cardiac Arrhythmias, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At very high concentrations, they may also block calcium channels. With the notable exception of cocaine, local anesthetics also depress the strength of cardiac contraction and cause arteriolar dilation, both effects leading to severe hypotension. Cardiovascular collapse and death are rare and usually occur only after large doses of 0.75% bupivacaine. 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

Ethanol is a central nervous system (CNS) depressant that initially and selectively depresses some of the most active portions of the brain (reticular activity system and cortex). The mechanism of action most likely involves interference with ion transport at the axonal cell membrane rather than at the synapse, similar to the action of other anesthetic agents. Ethanol can bind directly to the gamma-aminobutyric acid (GABA) receptor in the CNS and cause... 

---