Mechanisms

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Drug interactions can generally be classified as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions result from processes that lead to a change in the disposition of one or more drugs and result in a change in clinical response. The most common form of a pharmacokinetic interaction occurs when one drug induces or inhibits the metabolism and/or elimination of another, and the steady-state concentration of a drug is lowered or raised. Alcohol can affect many medications through competition for the same microsomal oxidase system, involved in the metabolism of various drugs [22], Pharmacodynamic interactions result when drugs have separate actions that are either augmented or antagonized when the drugs are used together. Alcohol appears to enhance aspirin-induced gastric mucosal damage and aspirin-induced prolongation of the bleeding time. Alcohol-drug interaction varies greatly in the range between social drinkers and heavy chronic drinkers. This phenomenon is also affected by the time elapsed between the alcohol ingestion and drug administration [23],

Ethanol is rapidly absorbed from the gastrointestinal tract, the main absorption occurring in the small intestine. Some absorption of ethanol, as well as 20% of its first-pass metabolism, takes place in the gastric mucosa where drug-ethanol interactions may occur [24], Pyloric spasm caused by irritating concentrations of ethanol can slow the absorption of drugs and ethanol. During absorption, ethanol can improve the bioavailability of certain drugs which otherwise are poorly soluble or rapidly metabolized during their first pass. These interactions depend greatly on the drug concerned, but part of the inhibition of drug metabolism by ethanol results from the direct depression of the metabolic activity of hepatocytes [22],

The following discussion includes the major cardiovascular medications that can interact with ethanol.

Nitroglycerin

Nitrates induce relaxation of vascular smooth cells in both arteries and veins. At low concentration venodilation predominates, but at higher concentrations arterial vasodilation is also produced. Hypotensive reaction may result from the combination of alcohol and nitroglycerin [25], Unless the clinician is aware of this interaction, the hypotensive episode may be attributed to coronary insufficieny or occlusion [26], Arterial pressure and ventricular wall stress tend to be lower in subjects taking both nitroglycerin and ethanol compared to either drug alone [27],

Sympathetic antagonists (alpha-receptor blockers)

Alpha-adrenergic receptors mediate many of the important actions of endogenous catecholamines. Responses of particular relevance include alpha-1 receptor-mediated contraction of arterial and venous smooth muscle. Alpha-1 receptor antagonists effectively block the vasoconstricting effect of catecholamines and vasodilation may occur in both arteriolar resistance vessels and veins, potentially inducing postural hypotension and reflex tachycardia. They have not been as popular as many other classes of drug in treatment of essential hypertension. Recently, however interest in these antagonists has surged due to their efficacy in treating symptoms of prostatic hyperplasia has become more evident.

Alpha-2 receptors suppress central sympathetic output, increase central vagal tone, facilitate platelet aggregation, and inhibit the release of norepinephrine and acetylcholine from nerve endings. These receptors also regulate metabolic effects through suppression of insulin secretion and inhibition of lipolysis in adipose cells.

Clonidine, a centrally acting antihypertensive agent, acts primarily within the rostral ventrolateral medulla to reduce sympathetic outflow through stimulation of alpha 2 receptors thus increasing the negative feedback on norepinephrine synthesis and release [28], On the other hand, alcohol enhances sympathetic activity [19], In hypertensive rats, a dose of clonidine followed by intravenous alcohol in amounts similar to moderate drinking reversed the clonidine induced hypotensive effect [29], In another animal model with moderately high ethanol blood levels, clonidine was administered intravenously. Both blood pressure and heart rate declined, indicating a dominant effect of the alpha 2 agonist [30],

Alpha-2 receptor antagonists can increase sympathetic outflow and potentiate the release of norepinephrine from the nerve endings, leading to activation of alpha 1 and beta 1 receptors in the heart and peripheral vasculature with a consequent rise in blood pressure [28],

When alcohol is fed to experimental animals, a transient alpha receptor blocking activity has been observed. A single dose of alcohol or chronic use decreased the sensitivity of adrenergic receptors [31 ]. In chronic alcoholism however, elevated norepinephrine levels and impaired arterial baroreceptors activity have been suggested as an underlying mechanism of ethanol-induced hypertension [32],

Guanethidine inhibits the peripheral sympathetic nervous system activity by inhibiting the release of norepinephrine vesicles from the nerve endings. Intravenous administration of acetaldehyde, a major ethanol metabolite that enhances sympathetic activity, elicits a substantial increase of blood pressure following a single dose of guanethidine. However, in animals receiving guanethidine long term, a low dose of acetaldehyde raised arterial pressure whereas a high dose of acetaldehyde diminished the blood pressure [33], Reserpine depletes the postganglionic adrenergic neurons of norepinephrine by inhibiting its uptake into storage vesicles. Such an effect is intensified by alcohol use [34], enhancing the negative inotropic action on the heart.

Sympathetic antagonists (beta-receptors blockers)

Beta-receptor antagonist drugs have been found to be useful in a wide variety of clinical conditions and are firmly established in the treatment ofhypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders. Short-term studies in normal subjects indicate that ethanol increases both the elimination rate and bioavailability of propranolol [35], The plasma clearance rate of propranolol, which is metabolized by the liver, is increased and the blood pressure-reducing effect of the drug is diminished. Ethanol and beta blockade individually affect heart rate and arterial pressure in the opposite direction. The combination of ethanol and propranolol will produce effects that are dose dependent, but both produce negative inotropic effects. Patients receiving propranolol should be dissuaded from adding more than one drink a day to their regimen [36,37], However, subjects in alcohol withdrawal can be therapeutically affected by beta-adrenergic blockade.

Renin-angiotensin system

Angiotensin II has been shown to inhibit voluntary consumption of alcohol, an effect which is negated by ACE-inhibitor [38], Hypothetically, angiotensin converting enzyme inhibitors (ACE-I) should exert an opposite response to the alcohol-angiotensin II effect. However, several investigators have reported that ACE-I also reduced voluntary alcohol intake [39,40], The receptor blocker losartan administered with ethanol also blocks the intoxicating effect of ethanol in a dose dependent manner [41,42],

The renin-angiotensin system is considered to have a significant role in the development ofheart failure and hypertension. The individual abusing alcohol with subclinical cardiac dysfunction responds to angiotensin with a greater rise in the left ventricular end-diastolic pressure, without a significant change of the stroke volume compared to the nonalcoholic subject [43],

Calcium channel antagonists

Phenylalkylamine (verapamil), benzothiazepine (diltiazem), diarylaminopropylamines (bepridil), the first generation dihydropyridine (nifedipine, nimodipine, nitrendipine, isradipine), and second generation dihydropyridine (amlodipine, felodipine) have different negative inotropic, vasodilatory, and A-V node conduction effects on the cardiovascular system.

Acute verapamil therapy has been found to potentiate negative inotropic and chronotropic effects of alcohol in animal models [44,45], Consumption of ethanol following the chronic administration of verapamil results in an increased ethanol concentration in blood with the potential for an increased level of intoxication [46], Higher blood levels are thought to be related to reduced first pass ethanol elimination in the presence of verapamil [47], Perhaps as a consequence, rats treated with large doses of ethanol combined with verapamil have shown to have ultrastructural cardiomyocyte damage [48], Chronic verapamil therapy diminished the negative inotropic effect of ethanol on diabetic myocardium [49], In addition, restoration of intracellular calcium homeostasis has been reported to reverse structural, biochemical, and mechanical dysfunction in diabetic myocardium [50,51],

Chronic alcohol consumption up-regulates dihydropyridine-sensitive neuronal calcium channel binding sites. Several dihydropyridine agents are reported to have protective effects against the ethanol withdrawal syndrome. They promote the development of tolerance to alcohol and perhaps promote consumption [52,53], Ethanol administration in healthy human volunteers resulted in a53% increase in the nifedipine concentration-time curve but the hypotensive effect of nifedipine was not affected by ethanol [54], Engel et al. reported that nifedipine antagonized the stimulant effects of ethanol on locomotion and Tuna and Eroglu found that nifedipine reversed the inhibitory effects of ethanol on locomotor activity [55,56], In rats treated with ethanol, nifedipine did not produce cardiomyocyte damage [57],

The general anesthetic actions of ethanol have been markedly enhanced by nitrendipine while nimodipine potentiated the ataxic and hypothermic action of ethanol [58], By contrast, pretreatment with isradipine did not significantly alter the subject-rated or performance-impairing effects of ethanol [59],

Inotropic agents

Digitalis glycosides are the most commonly used inotropic agents in patients with congestive heart failure and are also employed in patients with arrhythmias. Significant acute interaction between ethanol and this agent has not been reported. One study found that the digitalis failed to improve cardiac function in alcoholic liver disease patients [60], which may be due to the state of the cardiac tissue rather than a drug interaction.

Antiarrhythmic agents

Heavy ethanol consumption is a common cause of atrial fibrillation [61]. In general, most antiarrhythmic agents in therapeutic doses depress the automatic firing rate of spontaneously discharging ectopic sites while minimally affecting the discharge rate of the normal sinus node. Mechanisms by which different drugs suppress normal or abnormal automaticity may not be the same.

  • i) Amiodarone as a potassium channel blocker has both alpha- and beta-adrenergic blocking properties. Filipek et al. reported that a low dose of ethanol did not affect the antiarrhythmic effect of amiodarone in adrenaline-induced arrhythmias but large acute doses reduced efficacy [62], Amiodarone decreased the ethanol level in rats that received alcohol chronically but its antiarrhythmic action was impaired.
  • ii) Disopyramide blocks sodium channels, prolongs repolarization and has negative inotropic effect. Concomitant disopyramide and ethanol administration had no effect on the total body clearance or halflife of disopyramide in a study ofhealthy volunteers [63], The renal clearance of disopyramide significantly increased, possibly from ethanol-induced diuresis [63], Chronic ethanol consumption may increase metabolism of disopyramide through enzyme induction.
  • iii) Phenytoin. At therapeutic dose, this agent effectively abolishes abnormal automaticity caused by digitalis-induced arrhythmias. Since subjects consuming ethanol metabolize phenytoin more rapidly than control subjects [64], prolonged excessive ethanol ingestion could result in seizures in an epileptic patient controlled on phenytoin. Whether a smaller amount of ethanol would affect phenytoin metabolism is unknown, but it is deemed unlikely [65],
  • iv) Procainamide has electrophysiologic and hemodynamic effects similar to quinidine except for weaker anticholinergic effects and is devoid of an alpha-adrenergic blocking effect. This agent has modest negative inotropic properties that are, however, less than those of quinidine. Although acute ethanol ingestion increases the acetylation of procainamide [66], the clinical significance of this clinical interaction is unknown. However, the acetylated metabolite (N-acetylprocainamide) may mitigate the clinical impact of this interaction, since its clinical activity is similar to the parent drug [67], The patient stabilized on procainamide should be monitored for an altered response following acute alcohol ingestion. Since chronic alcohol use has been reported to affect the volume of distribution of the drug and reduce the procainamide effectiveness [68], the net effect would appear to be a reduced efficacy.
  • v) Quinidine acts to inhibit sodium channel activity, blunt the rapid upstroke of the action potential and prolong its duration, and prolong the refractory period of the myocardium. In addition, vagal influence on the heart is weakened. In a rat model, the combined effects of ethanol and quinidine decreased the papillary muscle tension. The quinidine-induced prolongation of the absolute refractory and relative refractory periods were also diminished [69], As an additional interaction a syndrome of cocktail purpura has been reported in persons drinking a cocktail with quinine water [70,71], analogous to the increased bleeding tendency in patients taking oral quinidine while simultaneously using alcohol.

Anticoagulation

Coumadin and heparin (both fractionated and unfractionated) are the two most commonly used anticoagulants. Coumadin prevents the reduction of vitamin K epoxide in liver microsomes and induces a state analogous to vitamin K deficiency by competitively inhibiting the effects of vitamin K in the carboxylation of the vitamin K dependent plasma protein. Additionally, thrombin generation and clot formation are slowed by the biologic activity of the prothrombin complex proteins.

Ethanol-induced increases in the hypoprothrombinemic response to oral anticoagulants have been noted clinically for many years. It is clear that most patients on oral anticoagulants are not affected by moderate ethanol intake (e.g., 2 drinks per day or less) [72], Further, daily ingestion of 592 ml (20 oz) of table wine or 296 ml(10 oz) of fortified wine (20% alcohol) had no effect on the hypoprothrombinemic response to warfarin in healthy subjects [73], The ability of acute ethanol intoxication to enhance the hypoprothrombinemic response to oral anticoagulants may be due to inhibition of the anticoagulant metabolism. The apparent increase in warfarin metabolism in heavy drinkers when sober is presumed to be due to ethanol-induced stimulation of hepatic microsomal enzymes [74,75], Finally, the late stages of ethanol-induced hepatic damage can be accompanied by reduced hepatic production of vitamin K-dependent clotting factors [5,76], The interaction ofheparin with ethanol is not clearly defined. The metabolite of alcohol, acetaldehyde, was shown to augment the anticoagulating activity of heparin, but only when using an unphysiological dose of acetaldehyde [77],

Antiplatelet agents

Aspirin irreversibly inactivates cyclo-oxygenase in circulating platelets, thereby interrupting the endoperoxide/ thromboxane A2 pathway.

Ethanol appears to increase the gastrointestinal bleeding produced by aspirin. Both aspirin and ethanol individually damage the gastric mucosal barrier, and their combined use appears to result in additive or synergistic effects. Also, the ability of aspirin to prolong the bleeding time is enhanced by ethanol administration [77], No effect of aspirin on the single-dose kinetics of ethanol has been found, the peak concentration of aspirin being diminished by 25% [78],

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Beat The Battle With The Bottle

Beat The Battle With The Bottle

Alcoholism is something that can't be formed in easy terms. Alcoholism as a whole refers to the circumstance whereby there's an obsession in man to keep ingesting beverages with alcohol content which is injurious to health. The circumstance of alcoholism doesn't let the person addicted have any command over ingestion despite being cognizant of the damaging consequences ensuing from it.

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