Cardiac dysfunction and treatment

Congestive cardiac failure

Congestive cardiac failure (CCF) is the combined failure of both the left and right sides of the heart. The incidence of cardiac failure in the UK is between 1 and 5 per 1000 per year, and doubles for each decade of life after the age of 45.

CCF occurs when the cardiac output does not meet the needs of the tissues. This is thought to be due to defective excitation–contraction coupling, with progressive systolic and diastolic ventricular dysfunction.

Some of the causes, symptoms and signs of acute and chronic cardiac failure are given in Figure 2.7 as can be seen above.

The characteristics of left and right ventricular failure are listed in Figure 2.8 as can be seen below:

The body attempts to compensate for the effects of CCF by two processes:

  • extrinsic and
  • intrinsic.

Extrinsic cardiac compensation

Extrinsic cardiac compensation mechanisms aim to maintain cardiac output and blood pressure.

The reflex pathway is as follows:

hypotension leads to activation of baroreceptors (receptors responding to changes in pressure) and this activation of baroreceptors lead to increased sympathetic activity which in turn leads to increased an increased in  heart rate and vasoconstriction.

Vasoconstriction leads to increased cardiac contractility and vascular tone leads to increased arterial pressure.

However, the greater the resistance (arterial pressure) against which the heart must pump, the greater the reduction in both the ejection fraction and the perfusion of the tissues.

The reduced perfusion of the kidneys activates the renin–angiotensin system (RAS), leading to renin secretion and subsequent elevation of plasma angiotensin II and aldosterone level.

Angiotensin II causes peripheral vasoconstriction and aldosterone
increases sodium retention, leading to increased water retention, oedema and an increased preload.

Intrinsic cardiac compensation

The increased cardiac preload leads to incomplete emptying of the ventricles and an increase in end-diastolic pressure. The heart eventually fails, owing to the massive increase in myocardial energy requirements.

Drugs used in heart failure

Cardiac glycosides

Prototypical cardiac glycosides are digoxin and digitoxin. The drugs in this class shift the Frank–Starling ventricular function curve to a more favourable position (Fig. 2.9).

Chemically, cardiac glycosides have an aglycone steroid nucleus (the pharmacophore) that causes
positive inotropic. An unsaturated lactone ring is responsible for cardiotonic activity and by adding
additional sugar moieties the potency and pharmacokinetic distribution can be modulated.

Positive inotropic actions of cardiac glycosides improve the symptoms of CCF but there is no evidence they have a beneficial effect on the long-term prognosis of patients with CCF.

Mechanism of action

Cardiac glycosides act by inhibiting the membrane Naþ/Kþ ATPase pump.

This increases intracellular Naþ concentration, thus reducing the sodium gradient across the membrane and decreasing the amount of calcium pumped out of the cell by the Naþ/Ca2þ exchanger during diastole.

Consequently, the intracellular calcium
concentration rises, thus increasing the force of cardiac contraction and maintaining normal blood pressure.

In addition, cardiac glycosides alter the electrical activity of the heart, both directly and indirectly. At therapeutic doses they indirectly decrease the heart rate, slow atrioventricular (AV) conductance and shorten the atrial action potential by stimulating vagal activity.

This is useful in atrial fibrillation. At toxic doses they indirectly increase the sympathetic activity of the heart, and cause arrhythmias, including heart block. The direct effects are mainly due to loss of intracellular potassium,
and are most pronounced at high doses.

The resting membrane potential is reduced, causing enhanced automaticity slowed cardiac conduction, and increased atrioventricular node (AVN) refractory period.

The increased cytosolic calcium concentration may reach toxic levels thereby saturating the sarcoplasmic
reticulum sequestration mechanism and causing oscillations in calcium owing to calcium-induced calcium release. This results in oscillatory after-potentials and
subsequent arrhythmias.

In addition, cardiac glycosides have a direct effect on a-adrenoceptors, causing vasoconstriction and a consequent increase in peripheral vascular resistance, which is further enhanced by a centrally mediated increase in sympathetic tone.

Route of administration

  • Oral: cardiac glycosides are administered through the mouth.

Indications

  • Heart failure, supraventricular
    arrhythmias.

Contraindications

Cardiac glycosides are contraindicated in the following conditions:

  • Heart block, hypokalaemia associated with the use of diuretics (the lack of competition from potassium potentiates the effects of cardiac glycosides on the Na+/K+ ATPase pump).

Adverse effects

Arrhythmias, anorexia, nausea
and vomiting, visual disturbances, abdominal pain and diarrhoea.

Therapeutic notes

The cardiac glycosides have a very
narrow therapeutic window, and toxicity is therefore relatively common. If this occurs, the drug should be withdrawn and, if necessary, potassium supplements and antiarrhythmic drugs administered.

For severe intoxication, antibodies specific to cardiac glycosides are available.

Dangerous drug interaction

Cardiac glycosides + loop diuretics = potassium loss, arrhythmias.

Phosphodiesterase inhibitors

Examples of phosphodiesterase (PDE) inhibitors include enoximone and milrinone. These have been developed as a result of the many adverse effects and
problems associated with cardiac glycosides. There is no evidence that these improve the mortality rate.

Mechanism of action of phosphodiesterase inhibitors

The type III PDE isoenzyme is found in myocardial and vascular smooth muscle.

Phosphodiesterase is responsible for the degradation of cAMP; thus, inhibiting this enzyme raises cAMP levels and causes an increase in myocardial contractility and vasodilatation.

Cardiac output is increased,
and pulmonary wedge pressure and total peripheral resistance are reduced, without much change in heart rate or blood pressure.

Route of administration

Phosphodiesterase inhibitors are administered through intravenous route.

Indications

PDE inhibitors are given for severe
acute heart failure that is resistant to other drugs.

Adverse effects

Nausea and vomiting, arrhythmias,
liver dysfunction, abdominal pain, hypersensitivity.

b-Adrenoceptor agonists

Examples of b-adrenoceptor agonists (p. 35) include dobutamine and dopamine.

They are used intravenously in CCF emergencies.

Note:

Drugs with proven mortality benefits in cardiac failure should be remembered.

They are b-adrenoceptor
antagonists, angiotensin-converting enzyme (ACE) inhibitors, nitrates with hydralazine and spironolactone.

Diuretics

The main diuretic drug classes are:

  • Thiazides
  • Loop diuretics
  • Spironolactone.

Diuretics inhibit sodium and water retention by the kidneys, and so reduce oedema due to heart failure.

Venous pressure and thus cardiac preload are reduced, increasing the efficiency of the heart as a pump.

Spironolactone appears to have a beneficial effect in cardiac failure at doses lower than it would be expected to function as a diuretic.

Angiotensin-converting-enzyme inhibitors (ACEIs)

ACEIs will be discussed as a fresh article in Exlude.com. We will put a link here to enable your read more about it when we publish it.

Nitrates

Nitrates will be discussed as a fresh and whole article in Exlude.com under anginal drugs. We will put a link here to enable your read more about it when we publish it.

Vasodilating drugs

An example of vasodilating drugs us Hydralazine.

Arrhythmias

The most common cause of sudden death in developed countries is arrhythmia and it usually results from underlying cardiovascular pathology such as
atherosclerosis.

Myocardial ischaemia is one of the most important causes of arrhythmias, and occurs when a coronary artery becomes occluded, thus preventing sufficient
blood from reaching the myocardium.

Accumulation of endogenous biological mediators, including potassium, cAMP, thromboxane A2 and free radicals, is believed to initiate arrhythmias.

Reperfusion after coronary occlusion is necessary for tissue recovery and prevention of myocardial necrosis,
but spontaneous resumption of coronary flow is often itself a cause of arrhythmia.

Arrhythmias have been defined according to their appearance on the electrocardiogram (ECG) by the Lambeth Conventions. These include:

  • Ventricular: premature beats, tachycardia, fibrillation and torsades de pointes.
  • Atrial: premature beats, tachycardia, flutter and fibrillation.

The two main mechanisms by which cardiac rhythm becomes dysfunctional are:

  • Abnormal impulse generation (automatic or triggered).
  • Abnormal impulse conduction.

Abnormal impulse generation
Automatic—Automatic abnormal impulse generation is likely to cause sinus and atrial tachycardia, and ventricular premature beats. It can be:

  • Enhanced: pathological conditions, such as ischaemia, may effect nodal and conducting tissue so their
    inherent pacemaker frequency is greater than that of the SAN. Ischaemia causes partial depolarization of tissues (owing to a decrease in the activity of the
    electrogenic sodium pump) and catecholamine release, thus enhancing the automaticity of the slow pacemakers (AVN, Purkinje fibres, bundle of His) and often giving rise to an ectopic focus triggering the development of a premature beat.
  • Abnormal: A premature beat may also develop in atrial or ventricular tissue, which are not normally
    automatic. Triggered—Forms of triggered abnormal impulse generation are:

    • Early after-depolarizations (EADs): These are likely to cause torsade de pointes and reperfusioninduced arrhythmias. EADs are triggered during repolarization, i.e. phase 2 or 3, of a previously normal impulse. They may result from a decrease in the delayed rectifier Kþ current and are associated with abnormally long action potentials. They are therefore more likely to occur during bradycardia and class III antiarrhythmic drug treatment.
    • Delayed after-depolarizations (DADs): DADs are triggered once the action potential has ended, i.e. during phase 4, of a previously normal impulse. DADs usually result from cellular calcium overload, associated with ischaemia, reperfusion and cardiac glycoside intoxication.

Abnormal impulse conduction

Heart block—Heart block is likely to cause ventricular premature beats and results from damage to nodal
tissue (most commonly the AVN) caused by conditions such as infarction. AV block may be first, second or third
degree, manifesting itself from slowed conduction to complete block of conduction, where the atria and
ventricles beat independently.

Re-entry—Re-entry is likely to cause ventricular and atrial tachycardia and fibrillation, atrial flutter and Wolff–Parkinson–White syndrome. Re-entry is of two types, circus movement and reflection:

  • Circus movement: An impulse re-excites an area of the myocardium recently excited and after the refractory period has ended. This usually occurs in a ring of tissue in which a unidirectional block is present, preventing anterograde conduction of the impulse, but allowing retrograde conduction of
    the same impulse. This results in its continuous circulation, termed circus movement. The time taken
    for the impulse to propagate around the ring must exceed the refractory period; thus, administration of drugs that prolong the refractory period will
    interrupt the circuit and terminate re-entry.
  • Reflection: Occurs in non-branching bundles within which electrical dissociation has taken place. Owing to this electrical dissociation, an impulse can return over the same bundle.

Antiarrhythmic drugs

Antiarrhythmic drugs are classified according to a system devised by Vaughan Williams in 1970, and later
modified by Harrison. A summary of the effects of the different classes of drug is given in Figure 2.10 as seen in the image below.

Class I

All class I drugs block the voltage-dependent sodium channels in a dose-dependent manner. Their action
resembles that of local anaesthetics.

All class I drugs have the following effects:

  • They prolong the effective refractory period (terminate re-entry).
  • They convert unidirectional block to bidirectional block (prevent re-entry).
Class Ia

Examples of class Ia drugs include quinidine, procainamide and disopyramide.

Class Ia drugs affect atrial muscle, ventricular muscle, the bundle of His, the Purkinje fibres and the AVN.

Mechanism of action: Class Ia drugs block voltagedependent sodium channels in their open (activated) or refractory (inactivated) state.

Their effects are to slow phase 0 (increasing the effective refractory period) and phase 4 (reducing automaticity), and to prolong action potential duration.

Route of administration—Oral, intravenous. Consult the British National Formulary (BNF).

Indications— Ventricular, supraventricular arrhythmias.

Contraindications— Heart block, sinus node dysfunction, cardiogenic shock, severe uncompensated heart failure.

Procainamide should not be given to patients with systemic lupus erythematosus.

Adverse effects—Arrhythmias, nausea and vomiting, hypersensitivity, thrombocytopenia and agranulocytosis.

Procainamide can cause a lupus-like syndrome, and disopyramide causes hypotension.

Class Ib

Examples of class Ib drugs include lidocaine, mexiletine and phenytoin.

Mechanism of action—Class Ib drugs exert their effects in several ways.

These include:

  • Blocking voltage-dependent sodium channels in their refractory (inactivated) state, i.e. when depolarized, as occurs in ischaemia.
  • Binding to open channels during phase 0, and dissociating by the next beat, if the rhythm is normal, but abolishing premature beats.
  • Decreasing action potential duration.
  • Increasing the effective refractory period.

Route of administration—Lidocaine is administered intravenously, and mexiletine and phenytoin either
orally or intravenously.

Indications—Ventricular arrhythmias following myocardial infarction. Phenytoin is used in epilepsy.

Contraindications—Class Ib drugs should not be given to patients with SA disorders, AV block and porphyria.

Adverse effects—Hypotension, bradycardia, drowsiness and confusion, convulsions and paraesthesia
(pins and needles).

Lidocaine may cause dizziness and respiratory depression; mexiletine may cause nausea and vomiting, constipation, arrhythmias and hepatitis; and phenytoin may cause nausea and vomiting and peripheral neuropathy.

Class Ic

Flecainide is the only drug used from class Ic.

Mechanism of action—Flecainide blocks sodium channels in a fashion similar to the class Ia and Ib drugs, but shows no preference for refractory channels. This
results in a general reduction in the excitability of the myocardium.

Route of administration—Oral, intravenous.

Indications—Ventricular tachyarrhythmias.

Contraindications—Heart failure, history of myocardial infarction.

Adverse effects—Dizziness, visual disturbances, arrhythmias.

Class II

Examples of class II drugs include propranolol, atenolol and pindolol.

Class II drugs are b-adrenoceptor antagonists (atenolol is b1 selective). They have been shown to prevent sudden death after myocardial infarction by 50% (although this is believed to be due to prevention of cardiac rupture as opposed to prevention of ventricular
fibrillation).

Class III

Examples of class III drugs include bretylium, amiodarone, sotalol and ibutilide.

Mechanism of action—All class III drugs used clinically are potassium-channel blockers. They prolong cardiac action potential duration (increased QT interval
on the ECG), and prolong the effective refractory period.

Amiodarone also blocks sodium and calcium channels, i.e. slows phases 0 and 3, and blocks a- and b-adrenoceptors. Sotalol is a b-adrenoceptor antagonist with class III activity.

Route of administration—Bretylium is administered intravenously whereas amiodarone and sotalol are administered orally or intravenously.

Indications—Class III drugs are given for ventricular and supraventricular arrhythmias.

Contraindications—Bretylium should not be given to patients with phaeochromocytoma; amiodarone
should not be given to those with AV block, sinus bradycardia or thyroid dysfunction.

Adverse effects—Class III drugs can cause arrhythmias, especially torsades de pointes. Bretylium may cause
hypotension, nausea and vomiting, whereas amiodarone may cause thyroid dysfunction, liver damage, pulmonary
disorders, photosensitivity and neuropathy.

Class IV

Examples of class IV drugs include verapamil and diltiazem.

Class IV drugs are calcium antagonists that shorten phase 2 of the action potential, thus decreasing action
potential duration. They are particularly effective in nodal cells, where calcium spikes initiate conduction.
Details of the drugs are given in the section on antianginal drugs.

Other antiarrhythmics

The cardiac glycosides and adenosine are agents used in arrhythmias, but which do not fit into the four classes described.

Adenosine

Adenosine is produced endogenously, and acts upon many tissues, including the lungs, afferent nerves and
platelets.

Mechanism of action—Adenosine acts at A1 receptors in cardiac conducting tissue and causes myocyte hyperpolarization. This acts to slow the rate of rise of an action potential, and brings about delay in conduction.

Route of administration—Intravenous.

Indications—Paroxysmal supraventricular tachycardia. Aids diagnosis of broad and narrow complex
supraventricular tachycardia.

Contraindications—Second- or third-degree heart block, sick sinus syndrome.

Adverse effects—Transient facial flushing, chest pain, dyspnoea, bronchospasm. Side-effects are very short lived, often lasting less than 30 seconds.

Angina pectoris

Angina is associated with acute myocardial ischaemia, and results from underlying cardiovascular pathology.
When coronary flow does not meet the metabolic needs of the heart, a radiating chest pain results. This is angina pectoris.
Stable or classic angina is due to fixed stenosis of the coronary arteries, and is brought on by exercise and stress.

Unstable angina (crescendo angina) can
occur suddenly at rest, and becomes progressively worse, with an increase in the number and severity of attacks.

The following conditions can all cause unstable angina:

  • Coronary atherosclerosis
  • Coronary artery spasm
  • Transient platelet aggregation and coronary thrombosis
  • Endothelial injury causing the accumulation of vasoconstrictor substances
  • Coronary vasoconstriction following adrenergic
    stimulation.

Variant angina (Prinzmetal’s angina) occurs at rest, at the same time each day and is usually due to coronary
artery spasm. It is characterized by an elevated ST segment on the ECG during chest pain, and may be accompanied by ventricular arrhythmias.

Note:

The drugs used in stable angina pectoris are b-adrenoceptor antagonists, nitrates, calcium antagonists, antiplatelets and potassium-channel activators.

Antianginal drugs

Treatment of angina aims to dilate coronary arteries to allow maximal myocardial perfusion, decrease the
heart rate to minimize oxygen demands of the myocardium, lengthen diastole when cardiac perfusion occurs and to prevent platelets from aggregating and
forming platelet plugs.

Acute attacks of angina are treated with:

  • Sublingual nitrates.

In the hospital setting, acute anginal pain is treated with an opiate.

Stable angina is treated with:

  • Long-acting nitrates
  • Antiplatelet agents
  • b-Adrenoceptor antagonists
  • Calcium antagonists
  • Potassium-channel activators.

Unstable angina is a medical emergency, and requires hospital admission.

Unstable angina is treated with:

  • Antiplatelets: aspirin, clopidogrel, dipyridamole and the glycoprotein IIb/IIIa inhibitors.
  • Heparin/low-molecular-weight heparin.
  • Standard antianginal drug regimen.

Organic nitrates

The organic nitrates, glyceryl trinitrate (GTN), isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN), can relieve angina within minutes.

Mechanism of action—Most nitrates are prodrugs, decomposing to form nitric oxide (NO), which activates guanylyl cyclase, thereby increasing the levels of cyclic guanosine monophosphate (cGMP).

Protein kinase G is activated and contractile proteins are phosphorylated.
Dilatation of the systemic veins decreases preload and thus the oxygen demand of the heart, while dilatation
of the coronary arteries increases blood flow and oxygen delivery to the myocardium.

Route of administration—Sublingual, oral (modified release), transcutaneous patches. GTN can be given by intravenous infusion.

Indications—Organic nitrates are given for the prophylaxis and treatment of angina, and in left ventricular failure.

Contraindications—Organic nitrates should not be given to patients with hypersensitivity to nitrates, or those with hypotension and hypovolaemia.

Adverse effects—Postural hypotension, tachycardia, headache, flushing and dizziness.

Therapeutic notes—To avoid nitrate tolerance, a drugfree period of approximately 8 hours is needed.

b-Adrenoceptor antagonists (b-blockers)

Examples of b-blockers include propranolol, atenolol, bisoprolol and metoprolol. b-Adrenoceptors are found in many tissues, though the b1-adrenoceptor is found predominantly in the heart, and the b2-adrenoceptor is found mainly in the smooth muscle of the vasculature. Some overlap
does exist.

Different b-blockers have different affinity for the two types of adrenoceptor. Propranolol is non-selective,Bhaving equal affinity for both the b1- and b2-adrenoceptors. Atenolol, bisoprolol and metoprolol have greater
affinity for the b1-adrenoceptor and are therefore more ‘cardiac-specific’. Some b-blockers even appear to havebpartial agonistic effects at b-adrenoceptors, as well asbantagonistic effects.

Mechanism of action—The aim of using
b-adrenoceptor antagonists in cardiac disease is to block b-adrenoceptors in the heart.

This has the effect of causing a fall in heart rate (slowing of phase 4; in systolic blood pressure, in cardiac contractile activity and in myocardial oxygen demand.

Route of administration—Oral, intravenous.

Indications—Angina, post-myocardial infarction, arrhythmias, hypertension, thyrotoxicosis, glaucoma, anxiety.

Contraindications—Non-selective b-blockers (e.g. propranolol) must not be given to asthmatic patients.

At high doses b1-adrenoceptor antagonists lose their selectivity, and should be used with caution in those
with asthma.

Other contraindications for b-blockers include bradycardia, hypotension, AV block and CCF.

Adverse effects—Bronchospasm, fatigue and insomnia, dizziness, cold extremities (b2-adrenoceptor effect), bradycardia, heart block, hypotension and decreased
glucose tolerance in diabetic patients.

Calcium-channel blockers

There are two types of calcium-channel blocker (CCBs):

  • Rate-limiting CCBs (verapamil).
  • Dihydropyridine CCBs (short acting nifedipine or long acting felodipine).

Mechanism of action—Rate-limiting. CCBs block L-type calcium channels found in the heart and in the vascular smooth muscle, thereby reducing calcium entry into cardiac and vascular cella.

This decrease in intracellular calcium reduces cardiac contractility and causes vasodilatation, which results in several effects: reduced preload due to the reduced venous pressure; reduced afterload due to the reduced arteriolar pressure; increased coronary blood flow;
reduced cardiac contractility and thus reduced myocardial oxygen consumption; and a decreased heart rate.

High doses of these drugs affect AVN conduction.

Dihydropyridines block L-type calcium channels in vascular cells. They do not affect cardiac contractility or AVN conduction, and the beneficial effects are
due to increased coronary flow and peripheral vasodilatation.

Route of administration—Oral.

Indications—Prophylaxis and treatment of angina and hypertension.

Dihydropyridines are especially useful in angina associated with coronary vasospasm, with the long-acting dihydropyridines being particularly useful for hypertension management. Verapamil and diltiazem are given for supraventricular arrhythmias, and nifedipine for Raynaud’s syndrome (peripheral vasoconstriction).

Contraindications—CCBs should not be given to patients in cardiogenic shock.
Dihydropyridines are contraindicated in advanced aortic stenosis. Verapamil and diltiazem should not be given to patients in severe heart failure (owing to their negative inotropic action), to those taking b-blockers (risk of AV block and impaired cardiac output), and those with severe bradycardia.

Adverse effects—Verapamil and diltiazem may cause hypotension, rash, bradycardia, CCF, heart block and constipation.

Dihydropyridines may cause hypotension, rash, tachycardia, peripheral oedema, and flushing and
dizziness.

Note:

There are three classes of calcium-channel blockers.

Two of them act mostly on the heart (verapamil and diltiazem) and the other acts mostly on peripheral vascular tone (nifedipine).

Concurrent use of a b-adrenoceptor antagonist and a calcium-channel
blocker could result in profound bradycardia.

Potassium-channel activators

Nicorandil is the only licensed drug in this class.

Mechanism of action—Nicorandil acts to activate the potassium channels of the vascular smooth muscle.

Once activated, potassium flows out of the cells, causing hyperpolarization of the cell membrane. The hyperpolarized
membrane inhibits the influx of calcium, and therefore inhibits contraction; the overall effect is relaxation of the smooth muscle and vasodilatation.

Route of administration—Oral.
Indications—Angina prophylaxis.

Contraindications—Cardiogenic shock, left ventricular failure, hypotension.
Adverse effects—Headache, cutaneous vasodilatation, nausea and vomiting.

Note:

The overall aim of symptom management in angina: dilate coronary arteries to allow maximal myocardial
perfusion; to decrease the heart rate to minimize oxygen demands of the myocardium, and lengthen diastole when cardiac perfusion occurs; and to prevent platelets from aggregating and forming platelet plugs.

In addition to this, reversible risk factors need to be addressed to limit the progression of the disease.

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