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The major antihypertensive mechanism of calcium antagonists is by decreasing the systemic vascular resistance, modified by the counter-regulatory responses of the baroreflexes and the renin-angiotensin-aldosterone system. In severe hypertension, the concept that calcium overload of the vascular myocyte could precipitate or aggravate peripheral vasoconstriction provides a logical basis for the use of these agents as first choice therapy; nifedipine, especially, has been well tested. As monotherapy for mild to moderate hypertension each of the three first-generation agents compares well with beta-blockers. Calcium antagonists may have a special role in the therapy of certain patient groups (elderly, black) or in those subjects whose life style involves intense physical or mental exertion (hemodynamics better maintained than with beta-blockade) or in patients with early end-organ damage such as left ventricular hypertrophy or renal insufficiency. However, the goal blood pressure may not be reached during monotherapy so that drug combinations may be required. Further indications for these compounds are as follows. Verapamil and diltiazem are frequently used in supraventricular tachycardias including acute and chronic atrial fibrillation. In the arrhythmias of the Wolff-Parkinson-White syndrome, there is the potential danger of provocation of anterograde conduction. Further indications for calcium antagonists, still under evaluation, include congestive heart failure (controversial), hypertrophic cardiomyopathy (verapamil), primary pulmonary hypertension (high doses required), Raynaud's phenomenon (nifedipine and diltiazem effective), peripheral vascular disease (proof not yet documented), cerebral insufficiency and subarachnoid hemorrhage (nimodipine promising), migraine, exertional bronchospasm, renal disease, atherosclerosis (experimental), and primary aldosteronism (nifedipine inhibits aldosterone release). Second-generation agents include dihydropyridines, such as nitrendipine, nicardipine, felodipine, amlodipine, nisoldipine, nimodipine, and isradipine. From these will be selected agents that are longer acting and provide higher vascular selectivity. New preparations of existing agents include slow-release formulations of nifedipine, verapamil, and diltiazem. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine. Yet caution is required when calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as alpha-adrenergic blockers, beta-adrenergic blockers, digoxin, quinidine, and disopyramide.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Calcium channel antagonists. Part III: Use and comparative efficacy in hypertension and supraventricular arrhythmias. Minor indications. 315 29

Calcium channel blocking drugs are a chemically heterogenous group, so it might be expected that their effects on vascular smooth muscle, cardiac contractility, and conduction tissue may differ. However, the majority of adverse reactions are predictable from their pharmacological actions and may be conveniently grouped in the following categories: 1) vasodilatation, 2) negative inotropic effects, 3) conduction disturbances, 4) gastrointestinal effects, 5) metabolic effects, and 6) drug interactions. Vasodilatory symptoms, namely, dizziness, headaches, flushing sensation, and palpitation, are more likely with nifedipine. Peripheral edema is also common with nifedipine, but the mechanism is uncertain. For a given degree of vasodilation, the greatest negative inotropic effect is seen with verapamil first, diltiazem second, and nifedipine last. Calcium channel blocking drugs are contraindicated in hypertensive patients with second and third degree heart block, sick sinus syndrome, and severe heart failure. Verapamil and diltiazem have a significant effect on cardiac conduction, whereas nifedipine, in therapeutic doses, does not. Local gastrointestinal symptoms, such as nausea and constipation, are common with verapamil. None of the calcium channel blocking drugs have been reported to adversely affect lipid or protein metabolism. However, nifedipine, verapamil, and diltiazem in high doses may inhibit liberation of insulin. The significance of this finding needs to be explored further in hypertensive diabetics. Serum digoxin levels have been shown to increase after administration of verapamil and nifedipine, but there is no evidence that this change has any clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Side effects of calcium channel blockers. 328 Apr 92

We compared verapamil and propranolol hydrochloride for monotherapy of hypertension. Verapamil lowered blood pressure (BP) more effectively than propranolol in black and white patients. Verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites. Heart rate was reduced by 6.0 beats per minute by verapamil, and by 13.6 beats per minute by propranolol. In blacks, verapamil lowered systolic BP 16.9 vs 8.1 mm Hg for propranolol; verapamil reduced diastolic BP 12.8 vs 8.6 mm Hg for propranolol. In whites, verapamil lowered systolic BP 19.0 vs 12.7 mm Hg for propranolol; verapamil reduced diastolic BP 16.7 vs 12.3 mm Hg for propranolol. Increases in systolic BP were observed in 22% and 3.4% of patients receiving propranolol and verapamil, respectively. The PR interval was increased from 163.5 to 174.9 ms for verapamil vs 160.3 to 164.4 ms for propranolol. Constipation (15%) and headaches (10%) were most frequent complaints for verapamil vs fatigue (18%) and dizziness (7%) for propranolol. Changes in blood biochemistry values were of small magnitude. We conclude that verapamil monotherapy is a safe and effective means of achieving BP control in patients with essential hypertension.
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PMID:A comparison of verapamil and propranolol for the initial treatment of hypertension. Racial differences in response. 353 60

The antihypertensive effect of an oral slow release (retard) formulation of verapamil was evaluated in a negative (placebo) and positive (nifedipine) controlled study. After a run-in period of one week without antihypertensive therapy, 54 patients were classified as having mild to moderate hypertension (diastolic blood pressure 95-115 mm Hg) and assigned randomly to one of three groups (n = 18 each). These received one of the following treatments over 2 weeks: either placebo b.i.d., or a nifedipine retard preparation 20 mg b.i.d., or a verapamil retard preparation 240 mg b.i.d. Assessments of blood pressure were made at rest and during a standardized bicycle stress test. Data were recorded at baseline and at the end of each week. After one week of treatment, 1 patient receiving nifedipine and 14 patients receiving placebo dropped out of the study because their diastolic pressures were equal to or above the values before treatment. After two weeks of treatment, 13 of 18 patients on verapamil and 9 of 18 patients on nifedipine had resting diastolic pressures less than or equal to 90 mm Hg. Also systolic pressure and blood pressures during exercise were significantly lowered by both active drugs. Verapamil caused a fall in heart rate during rest and under maximal exercise. Undesired side effects from verapamil were constipation (6 of 18) and headache (1 of 18); those from nifedipine were flush or headache (5 each of 18); ankle edema, dizziness, or tachycardia were each reported by one patient. In comparison with placebo values, verapamil lengthened the atrioventricular conduction time (PQ-interval) significantly, however, PQ-interval did not exceed 0.24 s.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Controlled study on the treatment of hypertension with verapamil in retard form]. 390 62

In migraine patients the effect of calcium antagonists (flunarizine, verapamil and nifedipine) on both venous and pupillary neuromuscular functions, as well as on blood pressure have been evaluated. A single oral dose of flunarizine (10 mg) and verapamil infusion (50 micrograms/ml/min) increased venous compliance. Verapamil also counteracted dose-dependent dopamine induced venoconstriction. Nifedipine (10 mg orally) reduced mean arterial pressure in upright position in migraineurs but not in controls. In addition, chronic treatment with flunarizine (10 mg for 2 weeks) induced a transient miotic effect and a reduction of tyramine induced mydriasis. These findings demonstrated that calcium antagonists affect vascular and extravascular structures. It is postulated that, in migraine, calcium entry blockers may prevent exaggerated responses to catecholaminergic stimulation.
Cephalalgia 1985 May
PMID:Pupillary and vascular effects of calcium antagonists in migraine. 401 32

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels-namely, 80 mg thrice daily and 120 mg thrice daily-propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0.01) and in the prolongation of exercise test (P < 0.05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0.01).
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PMID:Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. 457 Jun 71

The pharmacokinetics, clinical efficacy, and adverse effects of three calcium-channel blocking agents--verapamil, nifedipine, and diltiazem--are reviewed. Verapamil, nifedipine, and diltiazem are absorbed well after oral dosing, but absolute bioavailability of each is reduced substantially by a first-pass effect. Each drug is metabolized extensively (verapamil and diltiazem to moderately active metabolites) by the liver. A substantial percentage of each drug is bound to plasma proteins, but the binding is of clinical importance only for nifedipine (92--98% protein bound). Intravenous verapamil has become the agent of first choice for treatment of acute paroxysmal supraventricular tachycardia (PSVT); use of chronic oral verapamil therapy for prophylaxis remains controversial. Verapamil and diltiazem have been evaluated with mixed results for atrial flutter and fibrillation. For treatment of myocardial ischemia, calcium-channel blockers may be of some value (possibly in combination with nitrates of B blockers). All three agents have been studied in patients with exertional angina with good results. Calcium-channel blockers appear to be equal with nitrates for treatment of variant angina. Patients with hypertropic cardiomyopathy have been treated with verapamil and nifedipine with promising results. Nifedipine has been effective for treatment of essential hypertension. Adverse effects of calcium-channel blockers have been relatively minor or infrequent. Diltiazem overall has the best side-effect profile, with adverse effects causing discontinuation of therapy in about 2--10% of patients; verapamil in intermediate (8--10%) and nifedipine the worst (17%) in this respect. The most common side effects generally are fatigue, headache, dizziness, skin rash, and peripheral edema. While they generally should be reserved for patients in whom more conventional therapy has failed (except those with PSVT), calcium-channel blockers appear to have a valid role as reserve agents for exertional and variant angina, cardiomyopathy, and hypertension.
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PMID:Update on calcium-channel blocking agents. 635 66

We conducted a double-blind, placebo-controlled crossover study of verapamil HCl in the prophylaxis of chronic migraine headaches. Verapamil significantly reduced both headache frequency and duration with few side effects. The drug may be useful for a segment of the migraine population refractory to other prophylactic agents or for those who cannot tolerate the side effects of other drugs.
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PMID:Verapamil in prophylactic therapy of migraine. 653 77

The effectiveness and safety of orally administered verapamil was tested in 11 patients with frequent paroxysmal supraventricular tachycardia. In a 4-month randomized, double-blind, placebo-controlled trial, the frequency of paroxysmal supraventricular tachycardia fell from 0.3 +/- 0.3 (mean +/- SD) to 0.1 +/- 0.1 episodes per day by patient diary (p less than 0.05) and from 0.7 +/- 0.7 to 0.3 +/- 0.5 episodes per day by Holter monitor (p less than 0.05) for placebo and verapamil treatment periods, respectively. Verapamil caused a decrease in the duration of paroxysmal supraventricular tachycardia (in minutes per day): placebo 27 +/- 51 by dairy, 67 +/- 111 by Holter; verapamil, 3 +/- 3 by diary, 1 +/- 2 by Holter (p less than 0.05). Five patients required a total of 35 pharmacologic cardioversions for sustained tachycardia: two during verapamil and 33 during placebo (p less than 0.001). No verapamil treatment period was shortened due to unacceptable paroxysmal supraventricular tachycardia, but five of 22 placebo treatment periods were shortened (p equal to 0.02). Verapamil was well-tolerated, causing mild constipation in five patients and headache in one. Oral verapamil is both safe and effective in the long-term treatment of patients with paroxysmal supraventricular tachycardia.
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PMID:Oral verapamil for paroxysmal supraventricular tachycardia: a long-term, double-blind randomized trial. 706 55

Two teenage girls with chronic paroxysmal hemicrania demonstrated dramatic yet incomplete improvement with indomethacin. Verapamil monotherapy provided nearly complete cessation of headaches.
Headache 1994 Apr
PMID:Adolescent chronic paroxysmal hemicrania responsive to verapamil monotherapy. 801 35


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