Membrane-depressant drugs

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). 

QRS interval prolongation of greater than 0.12 seconds in the limb leads (Figure 1-4) strongly indicates serious poisoning by tricyclic antidepressants (see p 90) or other membrane-depressant drugs (eg, quinidine [p 324], fleoainide [p 78], ohioroquine [p 165], and propranolol [p 131]). 

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. Cardiac disturbances, including hypotension and bradycardia, are the most common manifestations of poisoning. Atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membrane-depressant drugs such as propranolol. The ECG usually shows a normal QRS duration with increased PR intervals QRS widening occurs with massive intoxication. 

Rarely, CBZ can cause depression of atrioventricular conduction and ventricular automaticity. This is secondary to the drugs membrane—depressant effects, similar to those of quinidine and procainamide ( 372). Thus, patients with significant, preexisting atrioventricular conduction disturbances should not receive CBZ ( 77). 

Bicarbonate, sodium Membrane-depressant cardiotoxic drugs (tricyclic antidepressants, quinidine, etc) 1-2 mEq/kg IV bolus usually reverses cardiotoxic effects (wide QRS, hypotension). Give cautiously in heart failure (avoid sodium overload). 

All beta-blockers cause an increase in atrioventricular conduction time this is most pronounced with drugs that have potent membrane-depressant properties and no partial agonist activity. Sotalol differs from other beta-blockers in that it increases the duration of the action potential in the cardiac Purkinje fibers and ventricular muscle at therapeutic doses. This is a class III antidysr-hythmic effect, and because of this, sotalol has been used to treat ventricular (54-56) and supraventricular dysrhythmias (57). The main serious adverse effect of sotalol is that it is prodysrhythmic in certain circumstances, and can cause torsade de pointes (58,59). 

Bicarbonate, sodium Membrane-depressant cardiotoxic drugs, eg, quinidine, tricyclic antidepressants... 

B. CNS toxicity, including convulsions, coma, and respiratory arrest, is commonly seen with propranolol and other membrane-depressant and lipid-soluble drugs. 

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). 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Permeability-pH profiles, log Pe - pH curves in arhficial membrane models (log Pjpp - pH in cehular models), generally have sigmoidal shape, similar to that of log Dod - pH cf. Fig. 3.1). However, one feature is unique to permeabihty profiles the upper horizontal part of the sigmoidal curves may be verhcally depressed, due to the drug transport resistance arising from the aqueous boundary layer (ABL) adjacent to the two sides of the membrane barrier. Hence, the true membrane contribution to transport may be obscured when water is the rate-limiting resistance to transport. This is especially true if sparingly soluble molecules are considered and if the solutions on either or both sides of the membrane barrier are poorly stirred (often a problem with 96-well microhter plate formats). 

As the name implies, these drugs have a high affinity for the serotonin transporter both on neuronal and also platelet membranes. There is abundant evidence that the SSRIs inhibit the reuptake of 3H-5-HT into platelets, brain slices and synaptosomal fractions, as illustrated in Table 7.10, but it is clear that there is no direct relationship between the potency of the drug to inhibit 5-HT reuptake in vitro and the dose necessary to relieve depression in the clinic. In experimental studies, it is clear that the increased release of 5-HT from the frontal cortex only occurs following the chronic (2 weeks or longer) administration of any of the SSRIs. Thus the inhibition of 5-HT reuptake may be a necessary condition for the antidepressant activity, but it is not sufficient in itself. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

---