Nifedipine in hypertension

In true hypertensive emergencies, nifedipine capsules are contraindicated because of the unpredictability of the fall in arterial pressure. Given the seriousness of the adverse effects and the complete lack of outcome data, the routine use of short-acting nifedipine in hypertensive emergencies should be abandoned. Other slower and therefore probably safer CCBs can be used. 

Venkat-Raman G, FeehaUy J, EUiott HL, Griffin P, Moore RJ, Olubodun JO, Wilkinson R. Renal and haemodynamic effects of amlodipine and nifedipine in hypertensive renal transplant recipients. Nephrol Dial Transplant 1998 13(10) 2612-16. 

Ellrodt AG, Ault MJ, Riedinger MS, Murata GH. Efficacy and safety of sublingual nifedipine in hypertensive emergencies. Am J Med 1985 79(4A) 19-25. 

Groth H, Foerster EC, Neyses L, KuUimann U, Vetter H, Vetter W. Nifedipine beim hypertensiven Notfall und bei schwerer Hypertonic. [Nifedipine in hypertensive emergencies and severe hypertension.] Schweiz Rundsch Med Prax 1984 73(2) 45-9. 

Sunderji R, Shalansky KF, Beauchesne MF, Fung A. Is there a role for nifedipine in hypertensive urgencies Can J Hosp Pharm 1999 52 167-70. 

Napoli et al. [286] found that the nifedipine treatment of stroke-prone spontaneously hypertensive rats (SPSHR) suppressed the plasma and LDL oxidation and the formation of oxidation-specific epitopes and increased the survival of rats independently of blood pressure modification. Their results suggest that the protective effects of calcium blockers of dihydro-pyridine-type on cerebral ischemia and stroke may, at least in part, depend on their antioxidant activity. In vivo antioxidant effect of nilvadipine on LDL oxidation has been studied in hypertensive patients with high risk of atherosclerosis [287], It was found that there was a significant decrease in the level of LDL cholesterol oxidation in patients after nilvadipine treatment. 

Amlodipine and nifedipine are dihydropyridine calcium-channel blockers. Amlodipine differs from nifedipine in that it has a longer duration of action and can therefore be given once daily, unlike nifedipine. Both are indicated in hypertension and angina and tend to cause ankle oedema that does not respond to diuretic therapy. Neither amlodipine nor nifedipine are available as spray formulations. 

Spasmolytics. N-Butylscopolamine (p. 104) is used for the relief of painful spasms of the biliary or ureteral ducts. Its poor absorption (N.B. quaternary N absorption rate <10%) necessitates parenteral administration. Because the therapeutic effect is usually weak, a potent analgesic is given concurrently, e.g., the opioid meperidine. Note that some spasms of intestinal musculature can be effectively relieved by organic nitrates (in biliary colic) or by nifedipine (esophageal hypertension and achalasia). 

The 1,4-dUiydropyridines, for example, nifedipine, nicardipine and amlodip-ine, are a well-established class of anti-hypertensive drugs. They are photolabile, some markedly so, for example, nifedipine. In all cases, the major light degradation product is the resonance-stabilised, fuUy aromatic, pyridine analogue [38]. 

Data on the effect of calcium antagonists on cardiovascular disease risks in patients with hypertension are available from one moderate-to-large scale randomized, placebo-controlled trial. In the Systolic Hypertension in Europe (Syst-Eur) trial, nitrendipine-based therapy produced an approximate 10/5 mmHg reduction in SBP-DBP in patients with systolic hypertension and a 42% reduction in the risk of stroke. Similar results were observed in two large, nonrandomized, placebo-controlled trials (with alternate treatment assignment), i.e. the Shanghai Trial of Nifedipine in the Elderly and the Systolic Hypertension in China (Syst-China) trial. 

Calcium channel blockers with vasodilator effects, such as nifedipine, nicardipine, and nimodipine, will potentiate the effect of vasodilator effects of, e.g. halothane or isoflurane, potentiating any hypotension. This is especially obvious in hypertensive patients and when combined with similarly acting agents, such as sodium nitroprusside or nitroglycerin. Similarly, they also enhance the tendency of volatile anaesthetics to reduce hypoxic pulmonary vasoconstriction, which might exacerbate ventilation/perfusion mismatching during anaesthesia. 

In addition to angina, calcium channel blockers have well-documented efficacy in hypertension (see Chapter 11) and supraventricular tachyarrhythmias (see Chapter 14). They also show moderate efficacy in a variety of other conditions, including hypertrophic cardiomyopathy, migraine, and Raynaud s phenomenon. Nifedipine has some efficacy in preterm labor but is more toxic and not as effective as atosiban, an investigational oxytocin antagonist (see Chapter 17). 

Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine a 24-hour study. Br J Clin Pharmacol 2000 49(5) 423-7. 

Pontremoli R, Leoncini G, Parodi A. Use of nifedipine in the treatment of hypertension. Expert Rev Cardiovasc Ther. 2005 3 43-50. 

Stason WT3, Schmid CH, Niedzwiecki D, et al. Safety of nifedipine in angina pectoris a meta-analysis. Hypertension. 1999 3 3 (1) 24—31. 

Mibefradil is a tetralol derivative developed as a unique CCB. Its efficacy as an antihypertensive was demonstrated in phase III trials, where doses of 50 to 100 mg were compared to other CCBs (nifedipine SR, diltiazem CD, nifedipine GITS, amlodipine). Mibefradil was shown to be equally effective as or more effective than nifedipine SR, diltiazem CD, nifedipine GITS, or amlodipine in reducing blood pressure in mild to moderate hypertension. Average reductions of diastolic blood pressure of as much as 15 mmHg were seen with the 100-mg dose. It was also found to be effective in the treatment of chronic stable angina. Thus, it was indicated for use in hypertension and stable angina at doses of 50 or 100 mg once daily (15). 

Nifedipine (Fig. 7.1) is the lead compound which was first introduced for the treatment of coronary angina. However, its use in the treatment of hypertension was blunted by a short plasma half-life (in the range of 1.5-2 h) this led to the need for multiple daily administration, and consequently blood pressure control and patient compliance were not fully achieved. However, slow-release formulations - for example, the once-daily Nifedipine Oros - made possible the wide use of nifedipine in cardiovascular therapy. 

Both the NORDIL and INSIGHT trials (Lancet 2000 356 359-365,366-372) confirmed that a calcium chaimel blocker (diltiazem and nifedipine respectively) had the same efficacy as older therapies (diuretics and /or p-blockers) in hypertension with no evidence of increased sudden death. 

A retrospective cohort study in 5052 elderly subjects, of whom 451 were taking verapamil, diltiazem, or nifedipine, showed that these drugs were associated with a cancer risk of 1.72 (95% Cl = 1.27, 2.34), and there was a significant dose-response relation (8). A small risk of cancer (RR = 1.27 95% Cl = 0.98, 1.63) with calcium channel blockers was reported in a nested case-control retrospective study involving 446 cases of cancers in hypertensive patients (128). However, the authors concluded that this... 

Wachter RM. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987 147(3) 556-8. 

Schwartz M, Naschitz JE, Yeshurun D, Sharf B. Oral nifedipine in the treatment of hypertensive urgency cerebrovascular accident following a single dose. Arch Intern Med 1990 150(3) 686-7. 

Batra AK, Segall PH, Ahmed T. Pulmonary edema with nifedipine in primary pulmonary hypertension. Respiration 1985 47(3) 161-3. 

In the INSIGHT (Intervention as a Goal in Hypertension Treatment) study, a prospective, multicenter, double-blind study in 6321 hypertensive patients aged 55-80 years, long-acting nifedipine 30 mg was compared with co-amilozide (hydrochlorothiazide 25 mg plus amUoride 2.5 mg) (3). There were no differences between the two treatments in the primary end-points of cardiovascular death, myocardial infarction, heart failure, or stroke during follow-up for 4 years. 

Several reports have linked renal dysfunction with nifedipine. In a study of hypertensive diabetics with renal insufficiency, nifedipine increased proteinuria and worsened renal function (SEDA-16, 196). Others have reported mild reversible renal impairment in patients with chronic renal insufficiency taking nifedipine for angina or hypertension a biopsy in one of the patients, who had heavy proteinuria, showed focal and segmental glomerulosclerosis (30). Immune-complex nephritis was reported in a patient taking nifedipine, but the proteinuria persisted (and indeed worsened) on changing to verapamil (31). 

Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000 356(9227) 366-72. 

Rubio-Guerra AF, Vargas-Ayala G, Lozano-Nuevo JJ, Narvaez-Rivera JL, Rodriguez-Lopez L. Comparison between isosorbide dinitrate aerosol and nifedipine in the treatment of hypertensive emergencies. J Hum Hypertens 1999 13(7) 473-6. 

Nifedipine (10 to 20 mg t.i.d.) is indicated in vasospastic (Prinzmetal s or variant) angina. It may also be used in chronic stable angina (classical effort-associated angina) without vasospasm. Sustained release nifedipine (30 to 60 mg once daily) is used in hypertension. 

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