A Textbook of Clinical Pharmacology and Therapeutics

mean pressure, but also to reduce the rate of rise of the arterial
pressure wave.

Classification of β-adrenoceptor antagonists

β-Adrenoceptors are subdivided into β 1 -receptors (heart),
β 2 -receptors (blood vessels, bronchioles) and β 3 -receptors
(some metabolic effects, e.g. in brown fat). Cardioselective
drugs (e.g. atenolol, metoprolol, bisoprolol, nebivolol)
inhibitβ 1 -receptors with less effect on bronchial and vascular
β 2 -receptors. However, even cardioselective drugs are haz-
ardous for patients with asthma.
Some beta-blockers (e.g. oxprenolol) are partial agonists
and possess intrinsic sympathomimetic activity. There is little
hard evidence supporting their superiority to antagonists for
most indications although individual patients may find such a
drug acceptable when they have failed to tolerate a pure
antagonist (e.g. patients with angina and claudication).
Beta-blockers with additional vasodilating properties are
available. This is theoretically an advantage in treating
patients with hypertension. Their mechanisms vary. Some
(e.g.labetolol,carvedilol) have additional α-blocking activity.
Nebivololreleases endothelium-derived nitric oxide.

Mechanism of action

β-Adrenoceptor antagonists reduce cardiac output (via nega-
tive chronotropic and negative inotropic effects on the heart),
inhibit renin secretion and some have additional central
actions reducing sympathetic outflow from the central nerv-
ous system (CNS).

Adverse effects and contraindications

• Intolerance– fatigue, cold extremities, erectile dysfunction;
  less commonly vivid dreams.


• Airways obstruction– asthmatics sometimes tolerate a
  small dose of a selective drug when first prescribed, only
  to suffer an exceptionally severe attack subsequently, and
  β-adrenoceptor antagonists should ideally be avoided
  altogether in asthmatics and used only with caution in
  COPD patients, many of whom have a reversible
  component.


• Decompensated heart failure–β-adrenoceptor antagonists
  are contraindicated (in contrast to stable heart failure,
  Chapter 31).


• Peripheral vascular disease and vasospasm–β-adrenoceptor
  antagonists worsen claudication and Raynaud’s
  phenomenon.


• Hypoglycaemia–β-adrenoceptor antagonists can mask
  symptoms of hypoglycaemia and the rate of recovery is
  slowed, because adrenaline stimulates gluconeogenesis.


• Heart block–β-adrenoceptor antagonists can precipitate or
  worsen heart block.


• Metabolic disturbance–β-adrenoreceptor antagonists
  worsen glycaemic control in type 2 diabetes mellitus.

Pharmacokinetics

β-Adrenoceptor antagonists are well absorbed and are only

given intravenously in emergencies. Lipophilic drugs (e.g.

propranolol) are subject to extensive presystemic metabolism

in the gut wall and liver by CYP450. Lipophilic beta-blockers

enter the brain more readily than do polar drugs and so

190 HYPERTENSION

Table 28.1:Examples of β-adrenoceptors in clinical use

Drug Selectivity Pharmacokinetic features Comment

Propranolol Non-selective Non-polar; substantial presystematic First beta-blocker in clinical use

metabolism; variable dose requirements;

multiple daily dosing

Atenolol β 1 -selective Polar; renal elimination; once Widely used; avoid in renal failure

daily dosing

Metoprolol β 1 -selective Non-polar; cytochrome P450 Widely used

(2D6 isoenzyme)

Esmolol β 1 -selective Short acting given by i.v. infusion; Used in intensive care unit/theatre

renal elimination of acid metabolite (e.g. dissecting aneurysm)

Sotalol Non-selective Polar; renal elimination A racemate: the D-isomer has class

(L-isomer) III anti-dysrhythmic actions (see

Chapter 31)

Labetolol Non-selective Hepatic glucuronidation Additional alpha-blocking and

partialβ 2 -agonist activity. Used in

the latter part of pregnancy

Oxprenolol Non-selective Hepatic hydroxylation/glucuronidation Partial agonist