A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

DRUGS USED TO TREAT HYPERTENSION 191
Table 28.2: Examples of calcium-channel blocking drugs in clinical use
Class Drug Effect on Adverse effects Comment
heart rate
Dihydropyridine Nifedipine q Headache, flushing, Slow-release preparations
ankle swelling
for once/twice daily use
Amlodipine 0 Ankle swelling Once daily use in
hypertension, angina
Nimodipine q Flushing, headache Prevention of cerebral vasospasm after
subarachnoid haemorrhage
Benzothiazepine Diltiazem 0 Generally mild Prophylaxis of angina, hypertension
Phenylalkylamine Verapamil p Constipation; marked See Chapter 32 for use in
negative inotropic action dysrhythmias. Slow-release preparation
for hypertension, angina
central nervous system side effects (e.g. nightmares) occur more
commonly. Polar (water-soluble) beta-blockers (e.g. atenolol)
are excreted by the kidneys and accumulate in patients with
renal impairment/failure.
Drug interactions
• Pharmacokinetic interactions: β-adrenoceptor antagonists
inhibit drug metabolism indirectly by decreasing hepatic
blood flow secondary to decreased cardiac output. This
causes accumulation of drugs such as lidocaine that have
such a high hepatic extraction ratio that their clearance
reflects hepatic blood flow.
• Pharmacodynamic interactions: Increased negative inotropic
and atrioventricular (AV) nodal effects occur with
verapamil (giving both intravenously can be fatal),
lidocaine and other negative inotropes.
C DRUGS
CALCIUM-CHANNEL BLOCKERS
Drugs that block voltage-dependent Ca 2 channels are used to
treat angina (see Chapter 29) and supraventricular tachydysrhythmias
(see Chapter 32), as well as hypertension. There are
three classes: dihydropyridines, benzothiazepines and phenylalkylamines.
Examples are listed in Table 28.2.
usually after a month or more. Slow-release preparations of
nifedipine provide an alternative to amlodipine.
Mechanism of action
Calcium-channel blockers inhibit Ca 2 influx through voltage-dependent
L-type calcium channels. Cytoplasmic Ca 2
concentrations control the contractile state of actomyosin.
Calcium-channel blockers therefore relax arteriolar smooth
muscle, reduce peripheral vascular resistance and lower arterial
blood pressure.
Adverse effects
Calcium-channel blocking drugs are usually well tolerated.
• Short-acting preparations (e.g. nifedipine capsules) cause
flushing and headache. Baroreflex activation causes
tachycardia, which can worsen angina. These
formulations of nifedipine should be avoided
in the treatment of hypertension and never used
sublingually.
• Ankle swelling (oedema) is common, often troublesome,
but not sinister.
• The negative inotropic effect of verapamil exacerbates
cardiac failure.
• Constipation is common with verapamil.
Use
Dihydropyridine calcium-channel blockers. Amlodipine has been
compared directly with a diuretic (chlortalidone) and an ACEI
(lisinopril), in a very large end-point trial (ALLHAT) and as a
basis for treatment in another large trial, ASCOT. It is a good
choice, especially in older patients and Afro-Caribbeans,
although more expensive than chlortalidone. Amlodipine is
taken once daily. The daily dose can be increased if needed,
Pharmacokinetics
Calcium-channel antagonists are absorbed when given by
mouth. Nifedipine has a short half-life and many of its
adverse effects (e.g. flushing, headache) relate to the peak
plasma concentration. Slow-release preparations improve its
profile in this regard. Amlodipine is renally eliminated and
has a half-life of two to three days and produces a persistent
antihypertensive effect with once daily administration.