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|Mol. mass||454.602 g/mol|
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Verapamil (brand names: Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Calaptin, Covera-HS) is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class-IV antiarrhythmic, more effective than digoxin in controlling ventricular rate and was approved by the U.S. Food and Drug Administration (FDA) in March 1982.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
Acute overdose is often manifested by nausea, asthenia, bradycardia, dizziness, hypotension, and cardiac arrhythmia. Plasma, serum, or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50-500 μg/l in persons on therapy with the drug, but may rise to 1–4 mg/l in acute overdose patients and are often at levels of 5–10 mg/l in fatal poisonings.
Uses in cell biology
Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein. This is useful, as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It is also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342. Radioactively labelled verapamil and positron emission tomography can be used with to measure P-glycoprotein function.
Mechanism and uses
Verapamil's mechanism in all cases is to block voltage-dependent calcium channels. In cardiac pharmacology, calcium channel blockers are considered class-IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrioventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias.
Calcium channels are also present in the smooth muscle lining blood vessels. By relaxing the tone of this smooth muscle, calcium channel blockers dilate the blood vessels. This has led to their use in treating high blood pressure and angina pectoris. The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like verapamil dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts.
In animal trials, verapamil also inhibits thioredoxin-interacting protein, the protein that leads to the death of pancreatic beta cells that produce insulin, and thus causes diabetes. This may allow the reversal of types I and II diabetes.
Given orally, 90–100% of verapamil is absorbed, but due to high first-pass metabolism, bioavailability is much lower (10–35%). It is 90% bound to plasma proteins and has a volume of distribution of 3–5 l/kg. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a nonlinear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis. It is excreted in human milk. Because of the potential for adverse reaction in nursing infants, nursing should be discontinued while verapamil is administered.
Verapamil has been reported to be effective in both short-term and long-term treatment of mania and hypomania. Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect. It has on occasion been used to control mania in pregnant patients, especially in the first three months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium (which has a small but significant incidence of causing cardiac malformation), verapamil is usable as an alternative, albeit presumably a less effective one.
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given postoperatively in rabbits which have suffered trauma to abdominal organs to prevent formation of these adhesions. Such effect was not documented in another study with ponies.
Potential use in the treatment of malaria
Recent resistance to the antimalarial drug chloroquine has hindered the treatment of malaria in Southeast Asia, South America, and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. When used in combination with chloroquine, verapamil enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.
Potential use in the treatment of diabetes
Recent research has shown verapamil to be an effective treatment for diabetes in animal models. Verapamil helps treat diabetes by limiting TXNIP expression. Human trials are expected to begin in 2015.
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