Discuss the following:

(a)            verapamil.

(b)            triazolam.

(c)            ranitidine.

Suggested Answer:

(a)

Verapamil hydrochloride is a phenylalkylamine-derivative calcium-channel blocking agent. The principal physiologic action of verapamil is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.

Calcium plays important roles in the excitation-contraction coupling process of the heart and vascular smooth muscle cells and in the electrical discharge of the specialized conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium. Activation of these slow calcium channels contributes to the plateau phase (phase 2) of the action potential of cardiac and vascular smooth muscle cells. Verapamil blocks the influx of calcium ions through ‘L’ type voltage-gated channels. By inhibiting calcium influx, verapamil inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries.

Verapamil is an arterial vasodilator with some venodilator effect; it also has marked negative myocardial inotropic and chronotropic actions. Although verapamil rarely produces clinically important changes in the rate of sinoatrial (SA) node discharge or recovery time, the drug may reduce the resting heart rate and produce sinus arrest or SA block in patients with SA node disease (e.g., sick sinus syndrome). Verapamil also slows conduction and prolongs refractoriness in the atrioventricular (AV) node, thereby prolonging the AH (atria-His bundle) interval. This usually also results in PR-interval prolongation on ECG, which is correlated with plasma verapamil concentrations and may rarely cause second- or third-degree AV block.

About 90% of an oral dose of verapamil is rapidly absorbed from the GI tract. It undergoes substantial first-pass in the liver with a bioavailability of 65 – 80%. Verapamil has two stereoisomers, the (-) isomer being 10x more active than the (+) isomer but the former has a bioavailability of only 15% of the latter. It is 90% is bound to plasma proteins and it is widely distributed in the body tissues including the CNS, breast milk and across the placenta. Verapamil has a half-life of 4 – 6h and is rapidly and almost completely metabolized by the liver to at least 12 dealkylated or demethylated metabolites.

Verapamil is used IV in the management of supraventricular tachyarrhythmias, including rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias (PSVT) (e.g., those associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome)and temporary control of rapid ventricular rate in atrial flutter or fibrillation. IV verapamil also has been used for the treatment of ectopic or multifocal atrial tachycardia and junctional tachycardia in patients in whom left-ventricular dysfunction is not present. In atrial flutter or fibrillation, IV verapamil is used to temporarily control rapid ventricular rate, usually decreasing heart rate by at least 20%. The drug should not be used when atrial flutter or fibrillation  is associated with an accessory bypass tract (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome), since ventricular tachyarrythmias, including ventricular fibrillation, and cardiac arrest may be precipitated. Although approximately 70% of patients with atrial flutter and/or fibrillation respond to IV verapamil with a reduction in ventricular rate, the drug alone rarely converts atrial flutter or fibrillation to normal sinus rhythm.

The drug is used orally for the management of Prinzmetal variant angina and unstable and chronic stable angina pectoris, for the management of hypertension, for the prevention of recurrent PSVT, and in combination with a cardiac glycoside, to control ventricular rate at rest and during stress in patients with atrial flutter and/or fibrillation. In the management of unstable or chronic stable angina pectoris, verapamil appears to be as effective as beta-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates. In unstable or chronic stable angina pectoris, verapamil may reduce the frequency of attacks, allow a decrease in sublingual nitroglycerin dosage, and increase the patient’s exercise tolerance. Verapamil is used orally in the management of hypertension. The drug has been used as monotherapy or in combination with other classes of antihypertensive agents. Verapamil may be particularly useful in the management of hypertension in patients with low renin hypertension, patients with coexisting angina or supraventricular tachyarrhythmia (e.g., tachycardia), and patients in whom other hypotensive agents are not tolerated or are contraindicated. Verapamil has been used a adjunctive therapy in the management of hypertrophic cardiomyopathy. The drug is used to relieve cardiac manifestations (e.g., angina, dyspnea) and improve exercise capacity and quality of life associated with cardiomyopathy-induced outflow tract obstruction and also may alleviate and suppress concomitant supraventricular tachyarrhythmias.

The overall incidence of unwanted effects reported with verapamil ranges between 6 and 14% with constipation, headache, pruritus, mild nausea, nervousness and peripheral edema most common. Serious hypotension, bradycardia and asystole have been reported, usually with concomitant beta-blocker therapy. Because of its negative effects on myocardial conducting and contracting cells it should not be given to patients with bradycardia, second or third degree heart block, or patients with Wolff-Parkinson-White syndrome who have atrial flutter or fibrillation. Unlike beta-blockers, veramapil does not predispose to bronchospasm and is not contraindicated in patients with pulmonary disease.

The concurrent administration of dofetilide with verapamil may result in elevated levels and increased effects of dofetilide, including torsades de pointes. Verapamil may reduce the clearance of digoxin and may displace digoxin from its tissue binding sites. Amiodarone and digoxin increases the AV block. The neuromuscular blocking effect of non-depolarizing muscle relaxants may be extended, producing prolonged respiratory depression and apnea. If possible, avoid administration of non-depolarizing neuromuscular blocking agents to patients receiving verapamil. When both drugs must be given, carefully monitor respiratory function to avoid prolonged neuromuscular blockade. If needed, blockade may be reversed by giving edrophonium. Verapamil may inhibit the metabolism of quinidine, resulting in increased levels of quinidine. Also, both agents may slow A-V conduction and prolong the refractory period. Concurrent administration of quinidine and verapamil may result in hypotension. Verapamil may inhibit the metabolism of carbamazepine and cycloserine, increasing their toxic effects. veramapil may inhibit the metabolism of lovastatin and simvastatin at the P4503A4 isozyme. Concurrent administration of diltiazem or veramapil with lovastatin or simvastatin may result in elevated levels of lovastatin or simvastatin, which may result in rhabdomyolysis. Rifampicin increases the hepatic metabolism of verapamil and decreases its effects.

(b)

Triazolam (Halcion) is a benzodiazepine. Triazolam occurs as a white, crystalline powder. The drug is poorly soluble in water and soluble in alcohol. Triazolam tablets should be stored in tight, light-resistant containers at a controlled room temperature of 20—25°C.

Like other benzodiazepines, triazolam has anxiolytic, sedative and hypnotic actions. It acts by binding to a specific site on the GABA receptor / chloride channel complex, potentiating the effect of GABA by increasing the frequency of opening of the channel.

Triazolam is well absorbed orally. It has a half-life of 3h and is highly protein bound. It is extensively metabolized in the liver to active metabolites which prolongs its duration of action especially in the elderly.

The more frequent adverse side effects of triazolam are ataxia, dizziness, drowsiness, slurred speech, amnesia and excess of psychiatric reactions. Itraconazole and ketoconazole inhibits the metabolism of triazolam at cytochrome P450 and drug combinations involving both are contraindicated. The protease inhibitors also inhibit the metabolism of triazolam and other benzodiazepines. Concurrent administration may result in increased levels and clinical effects of the benzodiazepines, which may result in prolonged sedation and respiratory depression. The SSRIs, macrolide antibiotics like erythromycin and cimetidine also inhibit the hepatic metabolism of triazolam and should not be administered concurrently.

Triazolam shares the actions of other benzodiazepines and is used as a hypnotic agent in the short-term treatment of insomnia generally for periods not exceeding 7—10 days in duration. The failure of insomnia to remit after 7—10 days of triazolam therapy may indicate the presence of an underlying psychiatric and/or medical condition. Continued use of the drug for longer than 2—3 weeks usually is not indicated and should be undertaken only upon further evaluation of the patient. The possibility that insomnia may be a symptom of an underlying condition for which there may be a more specific treatment should be considered.

(c)

Ranitidine is a histamine H₂-receptor antagonist chemically based on a furan ring. Ranitidine competitively inhibits the action of histamine on the H₂ receptors of parietal cells, reducing gastric acid secretion under daytime and nocturnal basal conditions and also when stimulated by food, insulin, amino acids, histamine, or pentagastrin. Ranitidine has been shown to be 3—13 times as potent on a molar basis as cimetidine in inhibiting stimulated gastric acid secretion. However, it does not have any hormonal or reproductive side effects and it does not inhibit the activity of cytochrome P450.

Ranitidine is rapidly absorbed from the GI tract following oral administration and from parenteral sites following IM injection; however, following oral administration, the drug undergoes extensive first-pass metabolism. Ranitidine is widely distributed throughout the body and is 10—19% protein bound. It has a half-life of 2 – 3h. Ranitidine is metabolized in the liver to ranitidine N-oxide, desmethyl ranitidine, and ranitidine S-oxide. It is excreted principally in the urine via glomerular filtration and tubular secretion.

Reversible headache, which may be severe, has been reported with ranitidine therapy. Malaise, dizziness, insomnia and vertigo have been reported less frequently. Reversible mental confusion, agitation, mental depression, and hallucinations have occurred, mainly in debilitated geriatric patients. Constipation, nausea, vomiting, and abdominal discomfort have occurred in patients receiving ranitidine. Rash, which may be pruritic, urticarial or maculopapular are rare side effects. Hepatitis, which may or may not be accompanied by jaundice, has occurred occasionally in individuals receiving ranitidine and is usually reversible. Reversible blurred vision suggestive of a change in accommodation has occurred rarely in patients receiving ranitidine. As with other histamine H₂-receptor antagonists, cardiac arrhythmias have occurred rarely in patients receiving ranitidine. Bradycardia, sometimes associated with dyspnea, has occurred. Interactions with other drugs are few. Ranitidine increases stomach pH which reduces the dissolution and absorption of the itraconazole and ketoconazole thereby decreasing their clinical effectiveness.

Ranitidine is used orally for the treatment of active duodenal or gastric ulcer, gastroesophageal reflux disease, or endoscopically diagnosed erosive esophagitis, and as maintenance therapy for duodenal or gastric ulcer. Ranitidine is used parenterally in hospitalized patients with intractable duodenal ulcer. Ranitidine bismuth citrate is used in combination with clarithromycin for the treatment of Helicobacter pylori infection in adults with active duodenal ulcer.