CARDIAC PHARMACOLOGY
Drugs for systemic
hypertension and angina
James R Waller
Derek G Waller
Abstract
Drugs used for the treatment of hypertension and for management of
angina are discussed. Their major mechanisms of action, key pharmaco-
kinetic principles essential for their safe use, and important adverse ef-
fects are explained. Each class of drug is also given context for
effective clinical use.
Keywords Alpha-blockers; angina pectoris; beta-blockers; calcium
channel blockers; hypertension; nitrates; sinus node inhibitor;
vasodilators
Drugs for systemic hypertension
Drugs used for the management of hypertension manipulate
three systems that control systemic blood pressure: the auto-
nomic nervous system, the renin-angiotensin-aldosterone system
and locally acting vascular mediators (Figure 1).
Calcium channel blockers
Mechanisms: calcium channel blockers reduce blood pressure
largely by arterial vasodilatation, achieved by blocking the influx
of calcium via transmembrane L-type channels in the smooth
muscle cells of resistance vessels. These channels are also pre-
sent in the myocardium and blockade here causes a reduction in
heart rate and contractility, which contributes to the reduction of
systemic blood pressure.
Calcium channel blockers can be subdivided into the dihy-
dropyridine group (such as nifedipine and amlodipine) and the
non-dihydropyridines (Table 1), which bind to different sites on
L-type calcium channels. The different sub-unit structures of
these channels in vascular and cardiac tissue explain drug
selectivity; the dihydropyridines act mainly on vascular smooth
muscle, whereas verapamil and, to a lesser extent, diltiazem also
have important actions on the myocardium.1
Pharmacokinetics: most calcium channel blockers have short
half-lives and modified-release formulations are necessary for a
prolonged action. Amlodipine has a longer half-life of 1e2 days.
Adverse effects: dihydropyridines produce vasodilator effects,
such as flushing, headache, ankle oedema and reflex tachycardia.
James R Waller BSc MBBS MRCP is a Specialist Registrar in Cardiology at
the University Hospital Southampton NHS Foundation Trust,
Southampton, UK. Competing interests: none declared.
Derek G Waller BSc MBBS DM FRCP is a Consultant Cardiovascular
Physician at the University Hospital Southampton NHS Foundation
Trust, Southampton, UK. Competing interests: none declared.
MEDICINE 42:9
What’s new?
C Aliskiren, a direct renin inhibitor, is not recommended for use in
combination with an ACE inhibitor or angiotensin II receptor
antagonist due to a potential for deterioration in renal function
and hyperkalaemia
C Ivabradine is a specific sinus node inhibitor that slows heart
rate without negative inotropic actions. It is an alternative to a
b-blocker or a heart rate-limiting calcium channel blocker. It has
an additive anti-anginal action when given with a b-blocker, but
should be avoided with non-dihydropyridine calcium channel
blockers
C Ranolazine is a late sodium current inhibitor that relaxes the
myocardium in diastole and reduces myocardial oxygen de-
mand, while increasing intramyocardial coronary blood flow. It
does not have negative inotropic actions
Many of these (other than oedema) can be reduced by using a
modified-release formulation. By contrast, diltiazem and verap-
amil produce less vasodilatation but can cause bradycardia and
heart block, which is a greater risk when they are taken with a
b-blocker. Verapamil and diltiazem can exacerbate heart failure
owing to their negative inotropic effects, but many dihydropyr-
idines can also reduce myocardial contractility when left ven-
tricular function is impaired.
b-adrenoceptor antagonists (b-blockers)
Mechanism: b-adrenoceptor antagonists are competitive antago-
nists; they reduce blood pressure by decreasing cardiac output and,
indirectly, by reducing renin release, which results in vasodilata-
tion and decreased plasma volume.2 There are many different
b-blockers with differing pharmacological effects (Table 2).

b1-adrenoceptor selective (cardioselective) drugs (e.g.
atenolol, bisoprolol and metoprolol) show selectivity for
b1-adrenoceptors, although this decreases at higher doses.

Non-selective drugs (e.g. propranolol) are antagonists at
both b1- and b2-adrenoceptors. Both non-selective and b1-
selective drugs have the same effect on blood pressure.

Partial agonist activity at b-adrenoceptors (e.g. pindolol)
results in less resting bradycardia and some peripheral
vasodilation.

Vasodilator activity may also be produced by drugs with
antagonist action at a-adrenoceptors (e.g. labetalol and
carvedilol), or by those promoting endothelial nitric oxide
production (e.g. nebivolol). Vasodilatation may be ad-
vantageous when treating hypertension.3
Pharmacokinetics: lipophilic drugs, such as propranolol and
metoprolol, have good gut absorption and extensive liver meta-
bolism which varies greatly among individuals, so individualized
dosing is more important to maximize benefit. Their half-lives
are generally short, and modified-release formulations are usu-
ally preferred.
Hydrophilic drugs, such as atenolol, are less well absorbed
orally, but are excreted unchanged in the urine. They usually
give more predictable plasma concentrations and generally have
longer half-lives.
538 Ó 2014 Elsevier Ltd. All rights reserved.
 CARDIAC PHARMACOLOGY

Sites of action of drugs for the treatment of hypertension

Vasomotor centre
α2-Adrenoceptor agonists
Imidazoline receptor agonists

Sympathetic nerve terminals

Adrenergic neuron blockers1

Sympathetic ganglia
β-Adrenoreceptors on heart Ganglion blockers 1
β-Adrenoreceptor antagonists
Vascular smooth muscle
Diuretics
Angiotensin receptors α-Adrenoreceptors Vasodilators
on vessels on vessels Nitrovasodilators
ACE inhibitors α1-adrenoceptor Calcium channel openers
AT1 receptor antagonists antagonists
α1 antagonists
Adrenal cortex
ACE inhibitors
AT1 receptor antagonists

Kidney tubules Juxtaglomerular cells that release renin

Diuretics β-adrenoreceptor antagonists
ACE inhibitors Direct renin inhibitor

1
Classes of drug that are rarely used now. ACE, angiotensin-converting enzyme.
Adapted from Waller DG, Renwick AG and Hillier K. Medical Pharmacology and Therapeutics. 3rd edition.
Philadelphia: Saunders, 2010. With permission from Elsevier.

Figure 1

Adverse effects: b1-adrenoceptor antagonists can cause acute left
ventricular failure when given in large doses to people with
impaired left ventricular function. They can also exacerbate
intermittent claudication and Raynaud’s phenomenon, and
excessive bradycardia can lead to syncope.
b2-adrenoceptor antagonism can produce bronchospasm in
patients with asthma, a potential problem even with car-
dioselective drugs. This is rarely an issue in chronic obstructive
pulmonary disease, where there is little reversibility of the
airway narrowing. Gluconeogenesis in the liver is reduced,

Calcium channel blockers

Drug T1/2 (h) Modified release Negative inotropic effect Vasodilator Bradycardia Dose reduction Pregnancy Breastfeeding

Amlodipine 30e60 No No þþþ No L ?A,3 A

Felodipine 12e25 Yes No þþþ No L A
Isradapine 2e6 No þ þþþ No L ?A,3 A
Lacidipine 7e8 No þ þþþ No L ?A,3 A
Lercanidipine 3e5 No þ þþþ No L,R A A
Nicardipine 1e12 Yes þ þþþ No L,R ?A,3 A
Nifedipine 2e4 Yes þ þþþ No L ?A,3
Diltiazem 2e5 Yes þþ þþ Yes L,R A ?A
Verapamil 2e5 Yes þþþ þ Yes L A

T1/2, plasma half-life.

Modified-release: formulation available to prolong effect.
Negative inotropic effect: when present, avoid in heart failure.
Vasodilator: comparative degree of vasodilator action.
Bradycardia: reduces heart rate at rest and on exercise.
Dose reduction: reduce dose or avoid in liver (L) impairment, or reduce dose in renal (R) impairment.
Pregnancy: avoid (A), or avoid (?A) unless essential in third3 trimester as may inhibit labour.
Breastfeeding: manufacturer advises avoid (A) since no information available, or avoid (?A) unless no suitable alternative.

Table 1

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 CARDIAC PHARMACOLOGY

b-adrenoceptor antagonists
Drug T1/2 (h) Selectivity Vasodilator activity Dose reduction Pregnancy Breastfeeding

Acebutolol 7 Yes No R A 1,2 ?A

Atenolol 7 Yes No R A 1,2 ?A
Bisoprolol 11 Yes No L,R A 1,2
Carvedilol 6 No Yes L A 1,2
Celiprolol 5 Yes Yes R A 1,2 ?A
Labetalol 3 Yes Yes L,R
Metoprolol 3e10 Yes No L A 1,2
Nadolol 17e24 No No L,R A 1,2 ?A
Nebivolol 10 Yes Yes L,R A 1,2 ?A
Oxprenolol 2 No Yes L A 1,2
Pindolol 4 No Yes R A 1,2
Propranolol 4 No No L,R A 1,2
Timolol 2e5 No No L,R A 1,2

T1/2, plasma half-life.

Selectivity: b1-adrenoceptor selective (cardioselective).
Vasodilator activity: vasodilator action in addition to b-adrenoceptor antagonist action.
Dose reduction: avoid or reduce dose in liver (L) or renal (R) impairment.
Pregnancy: avoid (A) in first1 or second2 trimester.
Breastfeeding: possibly avoid (?A) as present in breast milk in quantities that may affect the infant.

Table 2

which in people with insulin-dependent diabetes can increase the
risk of hypoglycaemia while blocking the physiological signs
associated with hypoglycaemia.
Most b-blockers alter blood lipids by raising triglycerides and
decreasing HDL cholesterol. Central nervous system effects are
more prominent with lipophilic drugs that readily cross the blood
ebrain barrier, and can produce sleep disturbance, vivid dreams
and hallucinations.4
Sudden withdrawal should be avoided, especially in ischae-
mic heart disease, as upregulation of b-adrenoceptors with
chronic use can lead to increased catecholamine sensitivity with
tachycardia and palpitation.
The main interactions of b-blockers are with the calcium
channel blockers diltiazem and especially verapamil. The com-
binations can cause profound bradycardia and hypotension.
Angiotensin converting-enzyme (ACE) inhibitors and
angiotensin II receptor antagonists
In hypertension, these drugs produce arterial vasodilatation by
limiting the direct effects of angiotensin II on vascular smooth
muscle and its ability to increase sympathetic tone. They also
decrease the production of aldosterone, which promotes renal
salt and water loss.5 For further details, see later article on drugs
for heart failure (see also Drugs for Heart Failure and Arrhyth-
mias in Medicine 2014; 42(10)).
Direct renin inhibitors
Mechanism: Aliskiren is a selective renin inhibitor that competi-
tively binds to renin and blocks the generation of angiotensin I (and
therefore angiotensin II; Table 3). Unlike ACE inhibitors and angio-
tensin receptor antagonists, it does not cause a compensatory rise in
plasma renin and produces a more complete block of the pathway.6
Adverse effects: diarrhoea and cough are reported. When used
in combination with an ACE inhibitor or angiotensin II receptor
antagonist, renal function may deteriorate. Such combinations
are contraindicated in patients with renal impairment or
diabetes.
Diuretics
Thiazide diuretics, and less frequently loop and potassium-
sparing diuretics, are used to treat hypertension.7 Their mecha-
nism of action is likely to be twofold. There is an initial decrease
in intravascular volume, although compensatory mechanisms
are activated to reduce this effect over time. Their sustained
hypotensive action is by direct arterial dilatation, possibly by
decreasing calcium entry into the smooth muscle cells and by
stimulating local vasodilator prostaglandins. Thiazides, in
particular, reduce blood pressure at doses too low to cause
effective diuresis.8
Thiazide diuretics: in the kidney, thiazides inhibit Naþ/Cle co-
transporters in the proximal diluting segment of the distal con-
voluted tubule and early collecting duct. Their diuretic action is
less effective in renal impairment.9
Adverse effects: hyponatraemia and hypokalaemia can occur,
especially in the first 2 weeks of treatment; renal function and
electrolytes should be checked in within 2 weeks and less
frequently thereafter. Hyperuricaemia can occur, but does not
often cause clinical gout. Prolonged hypokalaemia leads to a
progressive, reversible impairment of glucose tolerance over
several months by inhibiting insulin release. Thiazides adversely
affect plasma lipids and this becomes more likely as the dose
increases.

MEDICINE 42:9 540 Ó 2014 Elsevier Ltd. All rights reserved.

 CARDIAC PHARMACOLOGY

hypertension, such as in renal failure or from the use of vaso-

Other antihypertensive drugs dilator drugs.

Drug T1/2 (h) Dose reduction Pregnancy Breastfeeding

Potassium-sparing diuretics: these are discussed in more detail
in the chapter on drugs for heart failure. Amiloride and tri-
Vasodilators
amterene are weak antihypertensive agents. Spironolactone is
Aliskiren 40 R A A
most useful for treatment of hyperaldosteronism, or as therapy
Hydralazine 4 L,R
for resistant hypertension.
Minoxidil 3e4 R A
Centrally acting antihypertensives
Centrally acting antihypertensives
Clonidine 20e25 A
Selective imidazoline receptor agonist
Methyldopa 1e2 L,R
Moxonidine 2e3 L,R A A
Mechanism: moxonidine stimulates imidazoline I1 receptors in
a-Adrenoceptor antagonists
the ventrolateral medulla, thereby decreasing sympathetic
Doxazosin 9e12 A
outflow and lowering blood pressure without a reflex tachycardia
Indoramin 5
(Table 3). It has a long duration of action.
Prazosin 3 L,R
Terazosin 12
Adverse effects: moxonidine can cause a dry mouth, nausea,
T1/2, plasma half-life. fatigue, dizziness and headache.
Dose reduction: reduce dose or avoid in liver (L) or renal (R) impairment.
Pregnancy: avoid (A). Centrally acting a2-adrenoceptor agonists
Breastfeeding: avoid (A).
Mechanism: methyldopa is a prodrug that is metabolized in the
nerve terminal to a neurotransmitter analogue, while clonidine
Table 3
acts directly on the receptors (Table 3). Potent agonist activity at
Loop diuretics: these are discussed in more detail in the chapter presynaptic a2-adrenoceptors in the brainstem decreases sym-
on drugs for heart failure. Because of their short duration of pathetic outflow and increases vagal activity. Methyldopa is most
action, they are not used as first-line therapy for hypertension, often used to treat hypertension in pregnancy, whereas clonidine
but may be useful if volume expansion contributes to the is rarely used.

Sites of action of drugs for the treatment of angina

Verapamil Nifedipine, nitrates,

Diltiazem potassium channel
β-Adrenoreceptor antagonists openers (nicorandil)

Arterial resistance
Reduced heart rate
– decreases: reflex –
and contractiity
tachycardia

Decreased afterload

Venous –
return Arterial resistance
decreases decreases: No reflex –
tachycardia

Reduces –
Diltiazem,
heart rate
Dilate venous verapamil
– Reflex
capacitance
tachycardia ivabradine
vessels

Nitrates

Adapted from Waller DG, Renwick AG and Hillier K. Medical Pharmacology and Therapeutics. 3rd edition.
Philadelphia: Saunders, 2010. With permission from Elsevier.

Figure 2

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 CARDIAC PHARMACOLOGY
Adverse effects: decreased sympathetic activity can result in
postural or exertional hypotension, which is less troublesome
with clonidine. Ejaculatory failure can affect some men. The
action of these drugs on the CNS can also cause sedation and
drowsiness, particularly with methyldopa.
Methyldopa can cause a reversible positive Coomb’s test,
though haemolytic anaemia is rare. Sudden withdrawal of
clonidine can cause reflex tachycardia, sweating and anxiety.
a-adrenoceptor antagonists (a-blockers)
Mechanism: a1-selective antagonists, such as doxazosin and
prazosin, act on post-synaptic a1-adrenoceptors to relax smooth
muscles in arterioles and venous capacitance vessels (Table 3).
Adverse effects: postural hypotension may be troublesome from
peripheral venous pooling. Headache, lethargy, dizziness,
nausea, and urinary frequency or incontinence, also occur.
Minoxidil
Mechanism: minoxidil opens ATP-sensitive potassium channels
in vascular smooth muscle, hyperpolarizing the cell membrane
and closing voltage-gated calcium channels. This leads to smooth
muscle relaxation and vasodilatation (Table 3).
Adverse effects: hirsutism restricts the use of minoxidil to men.
Activation of the renin-angiotensin-aldosterone system encour-
ages salt and water retention with peripheral oedema. Minoxidil
is a powerful vasodilator and can cause flushing, headache and a
reflex tachycardia with associated palpitation. Concurrent use of
an ACE inhibitor or a b-blocker and a loop diuretic is almost
always necessary to minimize adverse effects.
Hydralazine
Mechanism: hydralazine causes arterial vasodilatation by
smooth muscle relaxation, possibly by activation of guanylate
cyclase raising intracellular cGMP (Table 3). It is rarely used,
except to treat pre-eclampsia.
Adverse effects: hydralazine is extensively metabolized by
acetylation in the liver. Slow acetylators are at higher risk of
dose-related SLE-type syndrome, which can develop over months
and slowly resolves on withdrawal of the drug. Other adverse
effects, which are largely caused by vasodilatation, include
headaches, dizziness, flushing, and hypotension. Tachycardia
can result from reflex sympathetic activation.
Drugs for angina
Medications for angina generally aim to decrease myocardial
oxygen requirements, or increase blood supply to the myocar-
dium (Figure 2).10,11
Organic nitrates
Mechanism: the metabolites of glyceryl trinitrate (GTN) and
isosorbide mononitrate (ISMN) release nitric oxide, which acti-
vates enzymes in the vascular endothelium, and reduce the
availability of intracellular calcium in the vascular smooth
muscle (Table 4). Nitrates dilate venous capacitance vessels,
large systemic arteries and coronary arteries, which decreases
cardiac preload, decreases afterload and increases blood supply
MEDICINE 42:9
to ischaemic myocardium when there is coronary artery
vasoconstriction.12
Pharmacokinetics: GTN is rapidly absorbed in the gut but
metabolized to an inactive substance by first-pass metabolism. It is
well absorbed sublingually, and an aerosol spray is preferred to
tablets because of the longer storage time before efficacy is lost.
GTN works within a minute or so to relieve angina, and provides
prophylaxis for up to 30 minutes. The buccal tablet has a slower
release and longer duration, whereas a transdermal patch can
deliver the drug via a rate-limiting matrix across the skin to
maintain a stable blood concentration. Given by intravenous
infusion, it is short-acting, which can be useful for titrating the dose
against relief of pain when treating unstable angina.
ISMN is completely absorbed orally, does not undergo first-
pass metabolism, and provides a predictable and prolonged
response. A once-daily modified-release formulation is often
given.
Adverse effects: venodilatation can cause postural hypotension,
dizziness, syncope and a reflex tachycardia.1 The latter can be
limited by concurrent use of a b-blocker. Arterial dilatation can
cause headache and flushing. Tolerance to the therapeutic effects
of nitrates can occur with regular use, but can be limited by
ensuring a ‘nitrate low’ period each day.13 This is achieved by
asymmetric dosing (morning and lunchtime with the twice-daily
formulations) or by using a once-daily modified-release formu-
lation that allows plasma nitrate to fall after a few hours.
Transdermal patches should be removed for a few hours each
day. Hypotension can be exacerbated by concurrent treatment
with phosphodiesterase drugs used to treat impotence, such as
sildenafil.
b-adrenoceptor antagonists (beblockers)
Mechanism: b-blockers decrease myocardial oxygen demand by
reducing heart rate (particularly on exertion), reducing myocar-
dial contractility and lowering blood pressure. Diastole is also
lengthened, which gives more time for coronary perfusion and
increases myocardial oxygen supply. The additional vasodilator
action of some b-blockers makes an uncertain contribution to the
anti-anginal action of the drugs. Further details are given above.1
Calcium channel blockers
Mechanism: all calcium channel blockers produce arterial
vasodilatation, which reduces afterload and thus myocardial
oxygen demand, and can also relieve coronary artery spasm. The
non-dihydropyridine drugs, verapamil and diltiazem, also
decrease exercise heart rate and may be more effective than the
dihydropyridines as monotherapy for treatment of angina by
further decreasing oxygen demand. For details of these drugs, see
above.1
Potassium channel opener
Mechanism: nicorandil promotes vasodilatation in systemic and
coronary arteries by opening ATP-sensitive potassium channels,
increasing potassium efflux from smooth muscle cells (Table 4).
The resultant hyperpolarization of the cell membrane inhibits
opening of voltage-dependent calcium channels and relaxes
vascular smooth muscle. This is enhanced by the local
542 Ó 2014 Elsevier Ltd. All rights reserved.
 CARDIAC PHARMACOLOGY

Adverse effects: ranolazine also causes gastrointestinal distur-

Other anti-anginal drugs bance, lethargy, headaches and dizziness but does not depress
Drugs T1/2 (h) Dose Pregnancy Breast myocardial contractility. Lengthening of the QT interval on the
reduction feeding ECG can occur although it has not been associated with an
increased incidence of arrhythmia. ECG monitoring is advised,
Glyceryl trinitrate 1e3 min L,R C C especially if ranolazine is taken with other drugs that also
Isosorbide dinitrate 0.5e2 L,R A C lengthen the QT interval.17 A
Isosorbide mononitrate 3e7 L,R A C
Nicorandil 1 A A
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MEDICINE 42:9 543 Ó 2014 Elsevier Ltd. All rights reserved.