Part II

Cardio-Vascular
System
Heart failure
 • Pharmacotherapy aimed at:
↓ preload: diuretics, ACEIs, ARBs, and
venodilators
↓ afterload: ACEIs, ARBs, and arteriodilators
↑ contractility: digoxin, beta agonists, PDE III
inhibitors
Heart ↓ remodelling of cardiac muscle: ACEIs, ARBs,
spironolactone, beta blockers
failure • Whereas digoxin does not improve survival,
ACEIs, ARBs, beta blockers, and spironolactone
have been proven beneficial in CHF. ACEIs and
ARBs are currently drugs of choice for the
chronic management of CHF. Inotropes are
more beneficial in management of acute CHF.
 Mechanism
• Loop diuretics inhibit active chloride reabsorption and
Na /K ATPase in the ascending limb of the loop of Henle
with increased salt and water loss.

Loop Pharmacokinetics

diuretics – • Loop diuretics are well absorbed following oral

administration. Elimination is largely by renal excretion

furosemide with a small contribution by liver metabolism. These drugs

have a rapid onset and short duration of action.

(frusemide) Adverse effects

• Salt and water depletion can occur. May cause pre- renal
uraemia (increase in blood urea and creatinine
concentrations). Regular monitoring of serum potassium is
required.
Drug interactions
• Loop diuretics may potentiate the nephrotoxic and
ototoxic effects of aminoglycosides such as gentamicin.
NSAIDs may impair diuresis and provoke hyperkalaemia
and renal failure.
Potassium-sparing diuretics: amiloride, spironolactone

They act mainly on the distal tubule, inhibiting sodium/ potassium exchange.

Spironolactone is a mineralocorticoid receptor antagonist and acts by inhibiting

the effect of aldosterone on the distal tubule.

The adverse effect is hyperkalaemia and is particularly likely in patients with

impaired renal function.

Potassium-sparing diuretics (with the exception of spironolactone) should

generally be avoided in patients taking ACE inhibitors, as both agents raise
potassium and severe hyperkalaemia may occur especially in the presence of
renal failure.
Neuroendocri
ne
antagonists
ACE inhibitors

• ACE inhibitors are first line medical therapy in all patients with heart failure.
• The ACE not only converts angiotensin I to angiotensin II, but also degrades
bradykinin. Angiotensin II is a powerful vasoconstrictor. It stimulates
aldosterone and antidiuretic hormone release, enhances sympathetic
activity, causes renal sodium retention and can cause direct damage to
cardiac myocytes, increase myocardial fibrosis and stimulate vascular and
myocardial hypertrophy. Bradykinin is a powerful vasodilator and also has
anti-proliferative effects on smooth muscle and stimulates the production of
vasodilator prostaglandins and nitric oxide. ACE inhibitors produce both
arterial and venous dilatation. ACE inhibitors increase serum and total body
potassium by reducing aldosterone.
• Agents used include: Enalapril: 2.5–20 mg bd. Lisinopril: 2.5–40 mg/day.
Ramipril: 1.25–10 mg/day.
β-adrenoceptor antagonists

• The mechanism of action of beta-blockers in heart failure seems to

involve retarding or even reversing progressive ventricular dysfunction
due to excessive sympathetic activity. Currently, the most promising
results have been achieved with bisoprolol, carvedilol and extended
release metoprolol;
• About 5–10% of patients will deteriorate within the first few days of
receiving a beta-blocker and it may take 2–6 months for benefits to
become obvious.
• Dose
• Bisoprolol: Initially 1.25 mg/day; target dose 10 mg/ day.
• Carvedilol: Initially 3.125 mg bd; target dose 25 mg bd (50 mg bd if
body weight > 85 kg).
• Metoprolol CR/XL: Initially 12.5 mg/day; target dose 200 mg/day.
Angiotensin II antagonists

• By specifically blocking the AT1 receptor, an ARB effects vasodilation,

sodium and water excretion and reduced anti-diuretic hormone
secretion. Since bradykinin breakdown is not inhibited, adverse
effects seen with ACE inhibition such as cough and angio-oedema are
much less likely to occur.
• There is evidence that angiotensin II receptor antagonists or blockers
(ARBs) have comparable haemodynamic and neurohumoral effects to
those of ACE inhibitors in congestive heart failure (CHF). These drugs
also improve symptoms.
• An ARB should be used like an ACE inhibitor, i.e. initiated at a low
dose which should be increased gradually over a week’s period with
appropriate monitoring of renal function, potassium and for
symptoms of hypotension.
Aldosterone antagonists

• Elevated aldosterone levels in heart failure are associated with adverse

cardiac remodelling, ventricular arrhythmias and excess mortality. ACE
inhibitor therapy does not reliably suppress aldosterone production and what
has been termed ‘aldosterone escape’ occurs in up to 40% of patients with
heart failure.
• Spironolactone is a non-selective aldosterone antagonist and as such binds to
androgen and progesterone receptors and may produce gynaecomastia in
men and menstrual irregularities in women.
• Initiation and dose titration requires close monitoring of renal function and
potassium levels.
• Spironolactone: Initially 25 mg/day; target dose 50 mg/day.
• In practice an ARB is only added to heart failure therapy with an ACE inhibitor
and a beta-blocker if the patient is intolerant of an aldosterone antagonist.
Hydralazine and isosorbide Ivabradine
dinitrate

• The combination of hydralazine and • Ivabradine is a recently developed drug

isosorbide dinitrate was shown to which lowers heart rate by selectively
reduce mortality in patients with inhibiting the If channel within the
heart failure in a relatively small trial sinoatrial node.
conducted before the widespread use • A recent large randomised controlled
of ACE inhibitors and beta- blockers. trial in heart failure patients
• Recently, the same combination was demonstrated that when ivabradine was
shown to improve symptoms, reduce prescribed for patients with a resting
admission to hospital for worsening heart rate of greater than 70 beats per
heart failure minute on maximally tolerated therapy
with an ACE inhibitor (or ARB) and a
• Contraindications to use include beta-blocker, there was a significant
significant renal dysfunction and reduction in the combined primary end-
hypotension. Hydralazine may induce point of cardiovascular mortality and
a drug-induced lupus syndrome in heart failure hospitalizations, driven by
slow acetylators. the latter.
Drugs with a
positive
inotropic
effect
Digoxin

• Digoxin now has a limited role in patients with

heart failure in sinus rhythm, usually reserved
for those remaining symptomatic despite an
ACE inhibitor or ARB, beta-blocker and an
aldosterone antagonist
• In patients with sinus rhythm, digoxin has a
positive inotropic effect when given acutely.
• Digoxin has autonomic actions that may be
useful in heart failure.
• Toxicity may be judged by the occurrence of
side effects (anorexia, nausea).
 Mechanism

• Both drugs produce their inotropic effect by β1-

adrenoceptor stimulation of the myocardium.
Adrenocepto • Below 5 μg/kg per minute the major effect is to

r agonists: increase renal blood flow by stimulation of

dopamine receptors. As the dose is increased
dopamine in the 5–20 μg/kg per minute range both β1-
and α-adrenoceptor stimulant effects are seen
and with increased cardiac output and a modest
rise in blood pressure.
dobutamine Pharmacokinetics

• These drugs undergo rapid clearance.

Dopamine and dobutamine must be given
intravenously.
Adverse effects

• Tachyarrhythmias
Levosimendan

• Levosimendan is thought to act by sensitising the cardiomyocyte

contractile proteins to calcium, thus exerting a positive inotropic effect
without increasing intracellular calcium or cAMP concentration,
undesirable properties of adrenoceptor agonists and phosphodiesterase
inhibitors.
• Levosimendan also causes arterial vasodilatation, possibly by opening
ATP- dependent K+ channels in vascular smooth muscle.
• Preliminary clinical studies have confirmed that levosimendan has some
favourable haemodynamic effects in acute severe heart failure and may
improve symptoms.
Drugs affecting preload
Glyceryl trinitrate and isosorbide dinitrate

Intravenous nitrates effect a reduction in preload

(predominantly) and in afterload (at higher doses).

In acute heart failure they reduce systolic BP in addition to

left and right heart filling pressures and systemic vascular
resistance.

If systolic blood pressure is less than 110 mmHg then

intravenous nitrates must be used with caution to avoid
reducing central organ perfusion or exacerbating renal
dysfunction.
Drugs affecting
preload and
afterload
 This is a mixed venous and arteriolar
dilator also used for acute reduction of
blood pressure

Sodium
nitroprussi It must be given intravenously by
continuous infusion in a dose range of
de 25–125 μg/min.

This agent is particularly useful in acute

valvular insufficiency, such as mitral
incompetence following an acute infarct
or aortic incompetence in bacterial
endocarditis.
 Nesiritide is recombinant human b-
type natriuretic peptide which acts
as an arterial and venous dilator by
increasing intracellular cGMP.

Nesiritide Intravenous administration of

nesiritide reduces pulmonary
capillary wedge pressure, increases
cardiac output and has been shown
to reduce breathlessness in patients
with acute decompensated heart
failure.
Cardiac arrhythmia
Classificatio
n of anti-
arrhythmic
drugs
 Mechanism

• Flecainide slows conduction in the atria, His– Purkinje

system, accessory pathways and ventricles. In
therapeutic concentration it causes lengthening of the
PR and QRS intervals.
Pharmacokinetics

• Flecainide is well absorbed orally, and about 27% is

Class Ic excreted unchanged in the urine. The remainder
undergoes biotransformation to active metabolites. The

agents - average elimination half- life in normal subjects is 14

hours.

Flecainide Adverse effects

• It should be used with great care in patients with SA

disease, AV nodal disease or bundle branch block

Clinical use

• Flecainide is effective in the chemical cardioversion of

recent-onset atrial fibrillation, and in the maintenance
of sinus rhythm after cardioversion or in paroxysmal
atrial fibrillation. The drug is also used in the
prophylaxis of AV re-entry tachycardia in the Wolff–
Parkinson–White syndrome.
 This class Ic agent has additional minor beta-
blocking and calcium antagonist properties.

Class Ic Pharmacokinetics

agents – • Fast acetylators metabolise the drug rapidly to an active

metabolite, in contrast to slow acetylators.
Propafenon Adverse effects
e • The weak beta-blocking action may be of significance in
patients with asthma in whom the drug is
contraindicated. The calcium antagonist proper- ties also
render the drug unsuitable for patients with myasthenia
gravis.
Clinical use
• Propafenone is indicated for the prophylaxis of
paroxysmal atrial fibrillation or supraventricular
tachycardia.
Class II agents: β-adrenoceptor
antagonists

They may be used for the control of inappropriate

sinus tachycardia, or the prophylaxis of
paroxysmal atrial fibrillation or supraventricular
tachycardia.

Beta-blockers are ineffective in restoring sinus

rhythm in atrial fibrillation.

β-adrenoceptor antagonists reduce the risk of

sudden death in long-term therapy after MI and
in congestive heart failure.
Class III agents
 Amiodarone

Mechanism Pharmacokinet Adverse Clinical use

Amiodarone prolongs ics
After oral effects
pulmonary supraventricular and
the action potential administration, (alveolitis), hepatic ventricular
duration and effective considerable (hepatitis), arrhythmias.
refractory period in all accumulation occurs neurological (tremor, An oral loading dose
cardiac tissues. It is a in muscle and fat, ataxia), thyroid of 600–1200 mg/day
non-competitive α- and the therapeutic (hyper- or is given for 2 weeks,
and β-adrenoceptor action may take hypothyroidism), and then reduced to
antagonist. several weeks to testicular (orchitis) 100–400 mg/day.
develop fully. and cutaneous
Amiodarone is (photosensitivity).
metabolised in the
liver to
desethylamiodarone,
which is also
 Dronedarone is less lipophilic than amiodarone
and has a much shorter elimination half-life of 24
hours in comparison to several weeks.

Dronedarone has been implicated in the

Dronedaro development of severe liver damage and so
monthly monitoring of liver function tests for the
ne/ Sotalol first 6 months is recommended with periodic
monitoring thereafter. The dose of dronedarone
is 400 mg bd.

Sotalol is a non-selective beta-blocker, which also

possesses class II activity and thus prolongs
atrial and ventricular action potential duration
and refractory period.
Class IV agents
 Mechanism

• Verapamil inhibits the slow inward Ca2+ current. Its

anti-arrhythmic actions stem from decreasing AV
conduction.
Pharmacokinetics

• Bioavailability is only 10–20% owing to extensive first-

pass metabolism. It is eliminated by the kidneys.

Adverse effects
Verapamil • Constipation, nausea, dizziness and facial flushing.
• Verapamil has significant negative inotropic action,
and is contraindicated in heart failure

Clinical use

• Its effect on increasing AV block allows control of the

ventricular rate and is useful when adenosine is
ineffective or contraindicated in cardioversion of
supraventricular tachycardia.
 Mechanism

• Decrease ventricular rate in atrial fibrillation or flutter, by

decreasing AV conduction.
• Increase myocardial automaticity in high (toxic)
concentrations, or at ‘therapeutic’ concentrations if other
factors such as hypokalaemia are present.

Digitalis Adverse effects

• The common extracardiac adverse effects are anorexia,

glycosides nausea, diarrhoea, vomiting, fatigue or weak- ness. Less
commonly, neurological symptoms occur, including difficulty in

- Digoxin reading, confusion or even psychosis.

• The cardiac adverse effects may include depression of
automaticity or conduction resulting in sinus bradycardia, sinus
arrest, junctional rhythm or various degrees of AV block,
including complete heart block.
Clinical use

• The principal use of digoxin is in the control of ventricular rate

in atrial fibrillation, particularly when a return to sinus rhythm
is not expected (e.g. chronic mitral valve disease).
• Treatment of digoxin-induced arrhythmias is often difficult. The
digoxin should be withdrawn, and if hypokalaemia is present,
potassium chloride should be administered.
 Mechanism

• The adenine nucleoside, adenosine, acts via purinergic

receptors situated in the SA and AV nodes. Stimulation of
these receptors causes hyperpolarisation of the cells
resulting in suppression of automaticity and conduction. This

Adenine results in transient sinus bradycardia and AV block.

nucleotides Pharmacokinetics

• Adenosine is metabolised to the inactive inosine. The

- plasma half-life of adenosine is less than 10 seconds.

Adenosine Adverse effects

• Adenosine may precipitate bronchoconstriction in

asthmatics.
• Sometimes chest pain is experienced, which may be very
unpleasant but is transient.
Clinical use

• Adenosine is the drug of choice for the termination of

regular supraventricular tachycardias.
• Dosing of adenosine is by rapid intravenous bolus injection,
using a large or central vein, starting with a bolus of 3 mg.
Approach to the management of
thrombosis
 Aspirin

Pharmacology Pharmacokinet Clinical use Adverse

Aspirin acetylates and ics
Aspirin, in standard Low-dose aspirin has effects
Gastric erosions and
inactivates cyclo- formulation, is rapidly been shown to be GI bleeding,
oxygenase, a key absorbed from the clinically beneficial in Intracranial
enzyme in the upper GI tract acute myocardial haemorrhage,
platelet biosynthetic including both the infarction, unstable Exacerbation of
pathway for the pro- stomach and angina and acute asthma, Precipitation
aggregatory duodenum. ischaemic stroke; in of renal failure.
prostaglandin the secondary
thromboxane A2. prevention of arterial
Aspirin also inhibits thrombosis; and in
endothelial cyclo- prevention of arterial,
oxygenase, in this venous and coronary
case leading to a thrombosis in per-
reduction in sons at increased
prostacyclin risk.
Thienopyridines - Clopidogrel

Clopidogrel has an active metabolite that irreversibly

modifies the platelet ADP receptor, reducing the
aggregability of platelets for the remainder of their
lifespan.
Clopidogrel is at least as effective as aspirin in reducing
the risk of arterial thrombosis in patients with recent
myocardial infarction, recent ischaemic stroke, or chronic
peripheral arterial disease.
The combination of clopidogrel and aspirin is more
effective than aspirin alone (or anticoagulants) in
prevention of thrombosis following coronary angioplasty
with stenting.