Clinical Pharmacology and Therapeutics

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
partial β 2 -agonist activity. Used in
the latter part of pregnancy
Oxprenolol Non-selective Hepatic hydroxylation/glucuronidation Partial agonist
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)
inhibit β 1 -receptors with less effect on bronchial and vascular
β 2 -receptors. However, even cardioselective drugs are hazardous
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.
Nebivolol releases endothelium-derived nitric oxide.
Mechanism of action
β-Adrenoceptor antagonists reduce cardiac output (via negative
chronotropic and negative inotropic effects on the heart),
inhibit renin secretion and some have additional central
actions reducing sympathetic outflow from the central nervous
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