Verapamil
Verapamil (brand names: Isoptin, Verelan, Verelan PM, Calan, Bosoptin, 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.[1] 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 4 antiarrhythmic, more effective than digoxin in controlling ventricular rate, and was approved by the United States
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 atrio-ventricular 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 that lines 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 hypertension and angina pectoris.
The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will 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.
Verapamil is also used intra-arterially to treat cerebral vasospasm. Verapamil has been used to treat cluster headaches, but it can also cause headaches as a side effect.
Pharmacokinetic details
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−1. 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 non-linear 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.
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.[6] It has on occasion been used to control mania in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid takingvalproic 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.
Side effects
Some possible side effects of the drug are headaches, facial flushing, dizziness, swelling, increased urination, fatigue, nausea, ecchymosis, lightheadedness, and constipation.
Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia.
Overdosage
Acute overdosage 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.
Uses in cell biology
Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein.[8] This is useful as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It's also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342.
Veterinary use
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given post-operatively in rabbits who have suffered trauma to abdominal organs to prevent formation of these intra-abdominal adhesions.
Potential use in the treatment of malaria
Recent resistance to the anti-malarial 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. It has been shown that verapamil, when used in combination with chloroquine, 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
Diltiazem
iltiazem is a non-dihydropyridine (non-DHP) member of the class of drugs known as calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types ofarrhythmia. It is also an effective preventive medication for migraine. It is a class 3 anti-anginaldrug, and a class IV antiarrhythmic. It is a common adulterant of cocaine seized in the UK
Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.
Mechanism
Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. Its pharmacological activity is somewhat similar to verapamil.
Potent vasodilator of coronary vessels.
Vasodilator of peripheral vessels. This reduces peripheral resistance and afterload.
Negative inotropic effect. Diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption.
Negative chronotropic effect. Diltiazem causes a modest lowering of heart rate. This effect is due to slowing of the SA (sinoatrial) node. It results in reduced myocardium oxygen consumption.
Negative dromotropic effect. By slowing conduction through the AV (atrioventricular) node, diltiazem increases the time needed for each beat. This results in reduced myocardium oxygen consumption by the body.
Nontherapeutic effects and toxicities
Reflex sympathetic response. Caused by the peripheral dilation of vessels and the resulting drop in BP; the response works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Undesirable effects of Diltiazem include hypotension, bradycardia,dizziness, flushing.
Indications
Angina:
§ Stable angina (exercise-induced) . Diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility
§ Variant angina. Diltiazem is effective due to its direct effects on coronary dilation.
§ Unstable angina (preinfarction, crescendo). Diltiazem may be particularly effective if the underlying mechanism is vasospasm.
Supraventricular tachycardias. Diltiazem appears to be as effective as verapamil in treating reentrant supraventricular tachycardia.
Hypertension. Because of its vasodilatory effects, diltiazem is useful for treating hypertension. Calcium channel blockers are well-tolerated, and especially effective in treating low-renin hypertension.
Contraindications and precautions
§ CHF. Patients with reduced ventricular function may not be able to counteract the inotropic and chronotropic effects of diltiazem, the result being an even higher compromise of function.
§ SA node or AV conduction disturbances. Use of diltiazem should be avoided in patients with SA or AV nodal abnormalities, because of its negative chronotropic and dromotropic effects
§ Low blood pressure. Patients with systolic blood pressures below 90 mm Hg should not be treated with diltiazem.
§ Wolff-Parkinson-White syndrome. Diltiazem may paradoxically increase ventricular rate in patients with WPW syndrome because of accessory conduction pathways.
Diltiazem is relatively contraindicated in the presence of sick sinus syndrome, atrioventricular node conduction disturbances, bradycardia, impaired left ventricle function, peripheral artery occlusive disease, chronic obstructive pulmonary disease, and Prinzmetal's angina.
Drug interactions
Beta-blockers
Intravenous diltiazem should be used with caution with beta-blockers, because while the combination is most therauputically beneficial, there are rare instances of dysrhythmia and AV node block.
Quinidine
Quinidine should not be used concurrently with calcium channel blockers because of reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes.
Miscellaneous
Inhibition of hepatic enzymes. Diltiazem and verapamil inhibit hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, possibly resulting in drug interactions.
Potential future indications
Diltiazem is prescribed off-label by doctors in the US
Recent research has shown that diltiazem is able to reduce cocaine cravings in drug-addicted rats.[17] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signalling in the brain. Diltiazem also enhances the analgesic effect ofmorphine in animal tests, without increasing respiratory depression,[19] and reduces the development of tolerance.[20]
Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with equal effectiveness. When applied topically, it is made into a cream form using either vaseline or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates.[21][22] Like all non-surgical treatments of anal fissure it does not address the long term problem of increased basal anal tone and does not decrease the subsequent recurrence rate that can vary between 40 to 60%.
Bepridil
Bepridil (trade name Vascor) is a calcium channel blocker once used to treat angina. It is no longer sold in the United States
It is nonselective.
It has been discussed as a possible option in the treatment of atrial fibrillation. It has been implicated in causing the ventricular arrythmia
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