A Textbook of Clinical Pharmacology and Therapeutics

186 HYPERTENSION
Cardiac output may be increased in children or young
adults during the earliest stages of essential hypertension, but
by the time hypertension is established in middle life the predominant
haemodynamic abnormality is an elevated peripheral
vascular resistance. With ageing, elastic fibres in the aorta
and conduit arteries are replaced by less compliant collagen
causing arterial stiffening and systolic hypertension, which is
common in the elderly.
The kidney plays a key role in the control of blood pressure
and in the pathogenesis of hypertension. Excretion of salt and
water controls intravascular volume. Secretion of renin influences
vascular tone and electrolyte balance via activation of the
renin–angiotensin–aldosterone system. Renal disease (vascular,
Heart
Peripheral resistance Kidneys
Figure 28.2: Arterial blood pressure is controlled by the force of
contraction of the heart and the peripheral resistance (resistances
in parallel though various vascular beds). The fullness of the
circulation is controlled by the kidneys, which play a critical role
in essential hypertension.
Heart
β-Blockers
(‘B’ drugs)
Kidney tubules
Diuretics (‘D’ drugs)
ACE inhibitors
Angiotensin
receptor blockers
‘A’ drugs
Sympathetic ganglia
parenchymal or obstructive) is a cause of arterial hypertension.
Conversely, severe hypertension causes glomerular sclerosis,
manifested clinically by proteinuria and reduced glomerular filtration,
leading to a vicious circle of worsening blood pressure
and progressive renal impairment. Renal cross-transplantation
experiments in several animal models of hypertension, as well
as observations following therapeutic renal transplantation in
humans, both point to the importance of the kidney in the
pathogenesis of hypertension.
The sympathetic nervous system is also important in the
control of blood pressure, providing background α receptormediated
vasoconstrictor tone and β receptor-mediated cardiac
stimulation. Sympathetic activity varies rapidly to adjust for
changes in cardiovascular demand with alterations in posture
and physical activity. It is also activated by emotional states
such as anxiety, and this can result in ‘white-coat’ hypertension.
A vasoconstrictor peptide, endothelin, released by the
endothelium contributes to vasoconstrictor tone. Conversely,
endothelium-derived nitric oxide provides background active
vasodilator tone.
Cardiovascular drugs work by augmenting or inhibiting
these processes, see Figure 28.3. The main such drugs for treating
hypertension can usefully be grouped as:
A angiotensin-converting enzyme inhibitors (ACEI) and
angiotensin AT 1 receptor antagonists (sartans);
B beta-adrenoceptor antagonists;
C calcium channel antagonists;
D diuretics.
Vasomotor centre
α 2-Adrenoceptor agonists
(e.g. clonidine)
Imidazoline receptor agonists
(e.g. moxonidine)
Vascular smooth muscle
ACE inhibitors
(‘A’ drugs)
Angiotensin receptor blockers
Calcium channel blockers (‘C’ drugs)
Diuretics (‘D’ drugs)
α1-Blockers (e.g. doxazosin)
Adrenal cortex
ACE inhibitors
Angiotensin receptors blockers
(‘A’ drugs)
Mineralocorticoid antagonists
Juxtaglomerular cells
β-blockers (‘B’ drugs)
Renin inhibitors
Figure 28.3: Classes of
antihypertensive drugs and their
sites of action.