Pharmacology 9a – Drugs of the Heart

Anil Chopra

  1. To be able to describe the mechanisms regulating heart rate and contractility that are therapeutic targets in the heart
  2. To be able to describe the determinants of myocardial oxygen supply and demand and how these are favourably influenced by
  3. Beta blockers
  4. Organic nitrates and potassium channel openers
  5. Calcium antagonists
  6. To know the major adverse effects of:
  7. Beta blockers
  8. Organic nitrates and potassium channel openers
  9. Calcium antagonists
  10. To know the basis of the Vaughan Williams classification and understand its limitations
  11. Know the major uses of and be able to describe the mechanisms of action of:
  12. Adenosine
  13. Verapamil
  14. Amiodarone
  15. Digoxin and cardiac glycosides
  16. To be able to describe the mechanisms of action of cardiac inotropes and their clinical uses

Control of Heart Rate and Contractility

Sympathetic Control of HR and Contractility:

Increased force of contraction – positive inotropic effects

Increased HR – positive chronotropic effect

Increased automaticity

Repolarisation and restoration of function following cardiac depolarisation

Reduced cardiac efficiency – oxygen consumption increased mores than cardiac work

Effects largely due to β1 activation

β1 activation stimulates adenyl cyclase → increased cAMP → increased intracellular Ca+ due to effects on L-type calcium channels. Also stimulates Na/K ATPase in cardiac Myocytes

Parasympathetic Control of HR and Contractility:

Cardiac slowing and reduced automaticity

Inhibition of Av conductance

Increased preload (venous return) increases force of contraction

Increased afterload (arterial circulation impedance) reduces stroke volume

Determinants of myocardial oxygen supply and demand

Myocardial ischaemia arises from an imbalance in oxygen supply and demand

Oxygen Supply:

  • Blood flow
  • O2 saturation
  • HR

Oxygen Demand:

  • HR
  • Preload
  • Afterload
  • Contractility

»Beta-blockers prevent sympathetic effects on the heart, reduce demand and so reduce angina

»Organic nitrates act as venodilators, reduce venous return and preload and so reduce cardiac work (Frank-Starling)

»Potassium channel openers open KATP channels and so act as NO donors causing venodilation and arterial dilation

»Calcium antagonists inhibit L-type calcium channels causing arterial dilation causing reduced afterload and so reduced cardiac work

Beta blockers

Names

Atenolol (β1 selective),

propranolol (β1 & β2 non selective)

Uses

•Angina–myocardial ischaemia

•Post myocardial infarction

•Cardiac dysrhythmias

•Chronic heart failure

•Hypertension (4th line of treatment – β1 antagonists preferred).

•Also thyrotoxicosis, glaucoma, anxiety states, migraine prophylaxis, benign essential tremor

Mode of Action

The sympathetic nervous system acts on the heart by using noradrenaline to innervate β1 adrenoceptors on the cardiac monocyte and cause an increase in heart rate and contractility.This is done by producing cyclic AMP from ATP which in turn results in an increase in Ca2+ in the cell.

Beta blockers act by competitivelyblocking these β1 receptors and so:

–Reduce cardiac output

–reduce renin release by the kidney

–diminish noradrenaline release by sympathetic nerves,

–lipophilic agents (e.g. propranolol) exert central sympatho-inhibitory actions.

Side Effects

Because beta-blockers also affect β2 receptors, their use may result in:

–Worsening of cardiac failure

–Bradycardia (heart block)

–Bronchoconstriction

–Hypoglycaemia (in diabetics on insulin)

–Increased risk of new onset diabetes

–Fatigue

–Cold extremities and worsening of peripheral arterial disease

–impotence

–CNS effects (lipophilic agents) e.g. nightmares

Nitrates

Names

Glyceryl trinitrate, Isosorbide mononitrate

Uses

•Angina

•Acute and chronic heart failure (nitrates - symptoms)

•BP control during anaesthesia (nitrates

Mode of Action

Act through an effect on Frank-Starling relationship to reduce preload (stroke volume increases with venous return) and mainly cause venodilation. They cause the release nitric oxide in smooth muscle cells and stimulate guanylate cyclase. This increases venous capacitance and so decreases venous return.

It also has slight antiplatelet function, causes vasodilation of the coronary artery, (increases O2 supply)and reduces systemic arterial resistance.

Nitrates however undergo “first pass” metabolism by the liver (its concentration is greatly reduced before it reaches the systemic circulation). Therefore Glyceryl trinitrate, given sublingually (under the tongue) has a half life of 5 minutes and is used for rapid angina relief. For longer lasting effects, it is given via a transdermal patch or Isosorbide mononitrate is used

Side Effects & Pharmacokinetics

•Hypotension, headaches and flushing as a result of vasodilation

•Glyceryl trinitrate is explosive.

•Patients can develop tolerance to nitrates– i.e. a loss of effect and benefit – this is avoided by eccentric (asymmetric) dosing.

Pharmacokinetics:

•Extensive first pass metabolism

•Often administered as sub-lingual tablet or spray for rapid angina relief

•Longer duration of action via transdermal patches

Potassium Channel Openers:

Name - nicorandil

Mode of Action

Open KATP channels and also act as NO donors. Cause venodilation and arterial dilation

Side effects - hypotension and headaches

Calcium Antagonists

Names

Verapamil, Diltiazem, amlodipine

Uses

  • Hypertension (mainly dihydropyridines)
  • Angina
  • Verapamil is used to treat paroxysmal superventricular tachyarrhythmias (SVT) and atrial fibrillation (assuming no abnormal conduction pathways).

Mode of Action

There are 2 classes of calcium antagonists:

Phenylalkylamines- (Verapamil) and benzothiazepines (Diltiazem) reduce Ca2+ entry into cardiac and smooth muscle cells.

Dihydropyridines (amlodipine) reduces Ca2+ entry into just smooth muscle cells.

The inhibition of the Ca2+ ions into the cells results in a negative inotropic effect(weakening of force of contraction) and also inhibits conduction through the AV node.

»Bind to L-type calcium channels and prevent Ca2+ entry

»Ca2+ causes increased force of contraction in the heart and vessel

»Drugs giving cardiac and smooth muscle actions bind to channels in heart and vessels, smooth muscle acting drugs only bind in the vessels and not the heart

»Vasodilation predominantly affects arterial supply

Side Effects

Verapamil

•Bradycardia and AV block

•Worsening of heart failure

•Constipation

Dihydropyridines

•Ankle Oedema

•Headache / Flushing

•Palpitations

Dysrhythmias

-Common: affect around 700 000 people in UK.

-Treatment involves reduction of sudden death, prevention of strokes and symptom alleviation.

-Involve both brady- & tachycardia and are classified according to site of origin e.g.

  • Supraventricular arrhythmias (e.g. amidoarone, verapamil)
  • Ventricular arrhythmias (e.g. flecainide, lidocaine).
  • Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).

The Vaughan-Williams classification of anti-arrhythmic drugs

This is a system used to classify where drugs act, (however many drugs do not fit into any one category). The graph shows whereabouts in the cardiac cycle the various drugs act:

Class / Mechanism of action
I / Sodium channel blockade
II / Beta adrenergic blockade
III / Prolongation of repolarisation ('Membrane stabilisation', often mainly due to potassium channel blockade)
IV / Calcium channel blockade

Name

Adenosine

Uses

Given intravenously to terminate superventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil.

Mode of Action

It acts of A1 (adenosine) receptors on the cardiac muscle tissue causing them to hyperpolarise and therefore slow the conduction through the AV node.

Side Effects

Chest pain, shortness of breath, dizziness and nausea

Names

Amiodarone

Uses

An effective antidysrhythmic useful for a number of superventricular and ventricular tachyarrhythmias.

Mode of Action

Blocks multiple ion channels and possible anti-thyroid functions.

Side Effects

-Has a long half-life (10-100 days) and therefore accumulates in the body.

-photosensitive skin rashes

-hypo- or hyper-thyroidism

-pulmonary fibrosis

-corneal deposits

-neurological and gastrointestinal disturbances

Names

Digoxin and cardiac glycosides

Uses

  • Slowing down ventricular rate in atrial fibrillation.
  • Symptom relief in chronic heart failure

Mode of Action

Digoxin inhibits Na-K-ATPase (Na/K pump) resulting in increased intracellular Na+ which in turn increases intracellular Ca2+ via Na+/Ca2+ exchange. It also stimulates the vagus nerve and therefore results in reduced conduction rate through the AV node.

Side Effects

Dysrhythmias (e.g. AV conduction block, entopic pacemaker activity)

Clinically important interactions with drugs that reduce excretion and tissue binding e.g. amiodarone, verpamil, and drugs that reduce plasma K+e.g. diuretics.

Name

Ivabradine

Uses

Angina

NOT TO BE USED IN:

•severe bradycardia / sick sinus syndrome / 2-3rd degree heart block

•cardiogenic shock

•recent myocardial infarction

Mode of Action

Blocks If channel (f is for “funny”) – a Na/K channel important in the sinoatrial node resulting in a reduction in heart rate.

Cardiac Inotropes

Names

Dobutamine

Uses

Acute heart failure. (e.g. after cardiac surgery or in cardiogenic or septic shock).

Mode of Action

They are β1 receptor agonists and so increase the force of cardiac contraction but do not have a significant effect on heart rate.

Heart Failure:

Serious condition with high mortality

Heart does not fulfil needs or does so only at raised filling pressures – causing oedema, fluid retention and fatigue

Due to ischaemic heart disease, hypertension, cardiomyopathy or a combination

ACE inhibitors, beta blockers and spironolactone (aldosterone antagonist) shown to improve survival