Update on the use of calcium antagonists on hypertension - Nature

Journal of Human Hypertension (2002) 16 (Suppl 1), S114–S117  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh

Update on the use of calcium antagonists on hypertension R Hernańdez-Hernańdez1, M Velasco2, MJ Armas-Hernańdez1 and MC Armas-Padilla1 1

Clinical Pharmacology Unit, School of Medicine, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Venezuela; 2Clinical Pharmacology Unit, Vargas School of Medicine, Central University of Venezuela, Caracas, Venezuela

Calcium antagonists represent an important group of drugs for the treatment of hypertension; they are effective in the whole range of severity of the disease. Dihydropyridine derivatives are most frequently used, and can be used in association with other antihypertensive drugs; meanwhile phenylalkylamines and benzothiazepines are contraindicated in association with betablocker drugs. Calcium antagonists with slow starting effect and long duration of action are the choice for use in long-term antihypertensive treatment. This group of

drugs is specially indicated in elderly patients, in those with diabetes mellitus and in patients with coronary heart disease. Phenylalkylamines and benzothiazepine derivatives are also used in patients with supraventricular arrhythmias. This group of agents is as safe as diuretics, angiotensin-converting enzyme-inhibitors and beta-blocking drugs in the long-term treatment of hypertension. Journal of Human Hypertension (2002) 16 (Suppl 1), S114– S117. DOI: 10.1038/sj/jhh/1001355

Keywords: calcium antagonists; dihydropyridines

Introduction Drugs which block slow calcium channels or calcium antagonists are a group of agents with heterogeneous chemical structure, but with common properties to modulate the movement of calcium ions through the calcium selective channels that occurs in the membrane of excitable cells and smooth muscle fibres1,2 in relationship to voltagedependent channels.2 Calcium entrance to the cells activates the contractile system in the smooth muscle and cardiac fibre; on the contrary, reduction in the amount of intracellular calcium tends to reduce myocardial contraction force, and peripheral and coronary vasodilation, a basic mechanism of the clinical usage in hypertension and as anti-angina agents.3 Some calcium antagonists have the properties to impair the heart conductive system, mainly on the atria sinus and atria-ventricular nodes. These drugs are used mainly as antiarrhythmic agents to treat supraventricular arrhythmia; phenylalkylamines and benzothiazepines derivatives are in this group. There is a linear relationship between calcium antagonist plasma levels and their pharmacodynamic effect, such as antihypertensive effect.4

Correspondence: Dr R Hernańdez-Hernańdez, Unidad de Terapia Me´dica, Calle 55 entre Ave. PL Torres y Carrera 21, edif. El Bosque. Apto. A01, Barquisimeto, Venezuela E-mail: rhernan얀cantv.net

Calcium antagonist usage in hypertension Calcium antagonists reduce efficiently the increased arterial pressure in Caucasian and black patients,5 also in adults and in the elderly. Some prospective studies have shown that some calcium channel blockers, mainly nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same level as diuretics;6 other prospective studies are being carried out now, specially to elucidate a reduction not only in cardiovascular morbidity and mortality in hypertensive patients in general, but in the progression of atherosclerosis.7 Calcium antagonists are chemically and pharmacodynamically heterogeneous substances that have the common property of blocking the calcium channel-L entrance in the external cellular membrane; for instance in myocardic cells and vessel smooth muscular cells.5,8 Besides the chemical and pharmacodynamical heterogeneity, relevant pharmacokinetic heterogeneity among calcium antagonists also exists. This last one originated not only in the intrinsic properties of the substances, but also in galenic characteristics of different oral formulations. Chemical and pharmacodynamic heterogeneity of calcium antagonists are related to the location of the calcium channels that they can blockade with more intensity. Some substances act more on the calcium of heart channels than on the vascular ones (phenylalkylamines), others act more on the channels of the myocytes membranes of the resistance vessels (dihydropyridines), and others act pro-

Use of calcium antagonists on hypertension R Herna´ ndez-Herna´ ndez et al

portionately at the level of the heart and of the arterioles (benzothiazepines). Those derived from the phenylalkylamine and the benzothiazepines depress the automatism, conductivity, excitability and the contractility of the heart. For this reason, these pharmacological subclasses are useful in the treatment of certain supraventricular heart arrhythmias, and because they have these effects on the heart, they should not be used in hypertensive patients who have conditions such as bradycardia or evident heart failure, or if there is a possible predicable development of a heart failure, eg after a myocardium infarct. The decrease of arterial pressure caused by the dihydropyridines, substances which are eminently dilators of the resistance vessels, could activate reflectedly the sympathetic system, especially when given short-acting agents with rapid absorption. Among other consequences, the activity of the renin-angiotensin-aldosterone system and sympathetic system, are increased. Pharmacokinetic heterogeneity among the calcium antagonists and among different galenic formulations of the same substance in some cases (Table 1) is important in relationship to the efficacy and security of these drugs. A direct correlation exists between the blood level and the pharmacodynamic effect. When a calcium antagonist of the dihydropyridine type is absorbed quickly from the classic oral formulations, as with nifedipine and felodipine, increased plasma levels are generated over a short period of time and the arterial pressure descends in a rapid and marked way. This decrease

activates regulatory mechanisms, which include undesirable neurohormonal activations and an increment heart rate. For this reason dihydropyridine agents that have a slow beginning of action are preferred, be this intrinsically or due to their galenic formulation. Dihydropyridine calcium antagonists should be avoided for the chronic treatment in formulations that are absorbed rapidly, since they have been claimed to increase the risk of myocardium infarct9 and, comparatively with other pharmacological classes, increment mortality for other cardiovascular causes.10,11 The speed of the beginning of the action is variable from the duration of the action of the calcium antagonists on the arterial pressure. A recent meta-analysis has shown that the risk of myocardium infarct, of heart failure and of significant cardiovascular events in hypertensive patients treated with oral formulations of calcium antagonists with average and long action, was higher than in hypertensive patients in whom the arterial pressure was controlled at the same level with diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or clonidine.12 However other recent meta-analysis comparing effects of ACE inhibitors, calcium channel blockers and other antihypertensive drugs from results of prospectively designed overviews of randomised trials, arrive at the conclusion of strong evidence for the benefits of ACE inhibitors and calcium antagonists are provided by the placebo control trials, with weaker evidence of differences between treatment regimens or different drug classes.13

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Table 1 Calcium antagonists for the oral treatment of hypertension: substances, temporal course of the antihypertensive effect and doses Pharmacological subclass

Agent

Formulation

Post-ingestion antihypertensive effect Starta

Durationb

Total daily doses

No. of daily doses

Phenylalkylamines

Verapamil

Classic LRc RFd

Rapid Moderate Slow

Short Moderate Long

80–320 mg 120–240 mg 120–240 mg

2–3 1–2 1

Benzothiazepines

Diltiazem

Classic LRc

Rapid Slow

Short Long

120–360 mg 120–240 mg

2–3 1

Dihydropyridines

Amlodipine Felodipine Isradipine

Classic LRc Classic LRc

Slow Moderate Rapid Moderate

Long Moderate Long Long

2.5–10 mgf 2.5–10 mg 2.5–10 mg 5–10 mg

1 1 2 1

Lacidipine Manidipine Nifedipine

Classic Classic Classic LRc GITSe LRc Classic

Rapid Rapid Rapid Moderate Slow Moderate Rapid

Long Long Short Moderate Long Long Moderate

2–8 mg 10–20 mg 30– 40 mg 10– 40 mg 20–60 mg 10– 40 mg 20– 40 mg

1 1 3 2 1 1 2

Nisoldipine Nitrendipine

Start times: rapid = 5 h, moderate = 1.5–5 h, slow = ⬎5 h. Short: 6–8 h; moderate: ⭓8h ⭐24 h; long: ⭓24 h. c LR: long release. d RF: retard formulation. e GITS: gastro-intestinal therapeutic system or osmotic pump. f 5–20 mg: only in hypertension induced by pregnancy. a

b

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Calcium antagonists have demonstrated to exert certain antiatherosclerotic action in experimental and clinical situations.14 Dihydropyridine derivatives have some singular pharmacological effects in man. These medications normalise the high platelet aggregation observed in hypertensive patients when compared with normotensive ones, that action could contribute to reduce the atherosclerotic and thrombogenic risk.15–17 Also, they reduce the body weight modestly during a long treatment, possibly due to a sustained reflected sympathetic activation secondary to the vasodilatation that they might cause, also stimulus of beta-3 adreno-receptors.18,19 The longterm significance of these reports requires evaluation in specifically designed studies. The group of oral formulations considered to be safe and effective for long-term usage, are those that reduce the arterial pressure slowly after ingestion and maintain long duration of antihypertensive effect (Table 1), to be taken on a one-daily dose basis; also treatment compliance would be facilitated in this way, which is necessary to assure the effectiveness. In some cases, intrinsically longacting drugs can provide certain coverage beyond 24 h leading to control of the arterial blood pressure when a dose is omitted.20 Calcium antagonists are particularly useful in patients that have Prinzmetal angina and in coronary patients alone or in association with betablockers, but this association is restricted to usage of dihydropyridine agents. Table 2 shows the relevant adverse effects limiting calcium antagonist usage. Oedema, headache and body flushing are more frequent with dihydropyridines, constipation (verapamil), bradycardia, atriaventricular blockade and depression of the pump

heart function (phenylalkylamines and benzothiazepines). Black patients tend to develop hypertension of larger severity; also they have a higher risk of developing complications, mainly stroke and renal failure, in comparison with Caucasian patients.21,22 Addition of diabetes is particularly noxious in these patients.23,24 Consequently, the black patients require a more intense control of their hypertension. Monopharmacotherapy of hypertension in black patients, diuretics and calcium antagonists are, in general, more effective than the ACE inhibitors25 or AT-1-receptor blockers. Elderly patients have some biological characteristics that are important for the selection of antihypertensive medications and its doses.26 Diuretics and calcium antagonists are the drugs of choice in elderly patients with hypertension, especially those with isolated systolic hypertension27,28 accompanied with diabetes mellitus. Dihydropyridines types with non-rapid beginning of action and of long duration of effect have a good place in the treatment of hypertension in general. It is a convenient start therapy with low doses of these agents, usually half of the suitable dose for an adult, and to be increased according to response.

Conclusions Calcium antagonists represent an important group of drugs for treatment of hypertension; they are effective in the whole range of severity of the disease. Calcium antagonists are specially indicated in elderly patients, in diabetes mellitus and in patients with coronary heart disease. Also phenylalkyl-

Table 2 Calcium antagonists: some contraindications and some potential adverse effects Pharmaco-logical subclass

Dihydro-pyridines

a

Substance

Contraindications

Possible adverse effects

Verapamil

앫 First- or second-degree atrialventricular blockade 앫 Sick sinus syndrome 앫 Carotid sinus syndrome 앫 Heart rate in seated position smaller than 50 bpm 쐌 Heart failure

앫 Bradycardia 앫 Intraventricular conduction defect 앫 Headache 앫 Flushing 앫 Constipation 앫 Urinary retention

Diltiazem

앫 앫 앫 앫

Second- or third-degree A-V block Sick sinus syndrome Carotid sinus syndrome Heart frequency in seated position smaller than 50 bpm 쐌 Heart failure

앫 앫 앫 앫

Bradycardia Nauseas Headache Urinary retention

앫 Recurrent symptomatic supraventricular arrhythmias or clinically important 앫 Acute coronary syndromes (especially agents of rapid starting action) 앫 Heart failurea

앫 앫 앫 앫 앫

Tachycardia Peripheral edema Headache Flushing Gingival hypertrophy

Caution; amlodipine and felodipine have shown security during its usage in patients with heart failure.



amines and benzothiazepines derivatives for patients with supraventricular arrhythmias. This group of agents is as safe as diuretics, ACEinhibitors and beta-blocking drugs in the long-term treatment of hypertension.

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