A Textbook of Clinical Pharmacology and Therapeutics

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 lidocainethat 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),
  lidocaineand 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 tachydys-
rhythmias (see Chapter 32), as well as hypertension. There are
three classes: dihydropyridines, benzothiazepines and pheny-
lalkylamines. Examples are listed in Table 28.2.

Use

Dihydropyridine calcium-channel blockers.Amlodipinehas 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.Amlodipineis
taken once daily. The daily dose can be increased if needed,

usually after a month or more. Slow-release preparations of

nifedipineprovide an alternative to amlodipine.

Mechanism of action

Calcium-channel blockers inhibit Ca^2 influx through volt-

age-dependentL-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 arte-

rial blood pressure.

Adverse effects

Calcium-channel blocking drugs are usually well tolerated.

• Short-acting preparations (e.g. nifedipinecapsules) cause
  flushing and headache. Baroreflex activation causes
  tachycardia, which can worsen angina. These
  formulations of nifedipineshould 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 verapamilexacerbates
  cardiac failure.


• Constipation is common with verapamil.

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. Amlodipineis renally eliminated and

has a half-life of two to three days and produces a persistent

antihypertensive effect with once daily administration.

DRUGSUSED TOTREATHYPERTENSION 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