Cardiovascular Drugs

1. Anti-arrhythmic Drugs
2. Anti-Hypertensive Drugs
3. Drugs to treat Heart Failure
4. Drugs to treat Angina
5. Quiz

• Anti-arrhythmic drugs treat arrhythmias (abnormal heart rhythms or rates) and vary with the type of arrhythmia. They include class I to IV anti-arrhythmics, adenosine, digoxin and atropine.
• ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, alpha blockers and beta blockers are used in the treatment of hypertension.
• ACEi, ARB, diuretics and beta blockers are used in the treatment of heart failure.

There are many types of drugs that are used to treat cardiovascular diseases. This article will briefly go through the different types of cardiac drugs and what they can be used for.

Anti-Arrhythmic Drugs

See the article on ECG Pathology for more detail on arrhythmias to appreciate how anti-arrhythmics work. The goal of anti-arrhythmics is to control the rate and rhythm of the heart.

There are four basic classes of anti-arrhythmic drugs:

Class I: Drugs that block voltage sensitive sodium channels. E.g. Lidocaine (used intravenously).

• This class of drug blocks sodium channels in open or inactive states (a use-dependent block: the faster the heart beats, the more channels are blocked).
• Damaged myocardium can spontaneously depolarise causing arrhythmias, particularly ventricular arrhythmias. Lidocaine works by blocking sodium channels after an action potential (AP), therefore preventing the initiation of another AP.
• The lidocaine dissociates rapidly (in well under one second). This means that the drug is bound for long enough to prevent inappropriate depolarisations, and will dissociate in time for the next AP. This allows the myocardium to depolarise normally, and the heart can beat efficiently.
• Can be used as a local anaesthetic as well as an anti-arrhythmic.

Class II: Drugs that antagonise (block) β-adrenoreceptors, the receptors that adrenaline and noradrenaline act on. E.g. atenolol and bisoprolol.

• Block sympathetic action by blocking β₁-receptors in the heart to slow the heart rate (negative chronotropy, meaning a slower rate) (see Control of Cardiac Output for more information on autonomic control of the heart). Blocking the β1-receptors causes reduced heart rate due to:
  • Decreased slope of the pacemaker potential (the slow rise in voltage between beats) in the sinoatrial (SA) node, the heart’s natural pacemaker, increases the time taken to initiate an action potential.
  • Slows conduction in the atrioventricular (AV) node, the electrical relay between the atria and the ventricles, to increase the time between the depolarisation of the atria and ventricles.
• Use:
  • Supraventricular tachycardia (SVT, a fast heart rhythm that starts above the ventricles) and atrial fibrillation (a fast, irregular rhythm from the atria), to protect the ventricles from high atrial rates via its effect on slowing AV conduction. For atrial fibrillation, NICE advises either a standard beta-blocker (one other than sotalol) or a rate-limiting calcium channel blocker (diltiazem or verapamil) as the first drug for controlling the heart rate.
  • Following a myocardial infarction (as sympathetic activity is often increased after a myocardial infarction).
  • Reduce myocardial ischaemia by reducing oxygen demand.
  • Heart failure (see the section on drugs to treat heart failure below).

Class III: Drugs that block potassium channels E.g. amiodarone.

• Blocking potassium channels prolongs the action potential and lengthens the absolute refractory period (the time when the cell cannot fire again). This helps prevent re-entry (an electrical signal looping round and re-exciting the heart) and abnormal rhythms. A longer refractory period stops another action potential from firing too soon. However, these drugs can themselves cause arrhythmias (they can be pro-arrhythmic).
• Amiodarone is a relatively 'dirty' drug (one that acts on many targets) as it has actions other than blocking potassium channels. Some of these other actions make it more effective at treating arrhythmias, but also give side effects.
• Uses:
  
  • Amiodarone is used for many types of arrhythmia, particularly when other drugs are ineffective or not suitable. It is started in hospital or under specialist supervision. It can cause serious side effects affecting the eyes, heart, lungs, liver, thyroid gland, skin and nerves.
  • Treat tachycardia (a fast heart rate) associated with Wolff-Parkinson-White syndrome (an extra electrical pathway between the atria and ventricles). Verapamil (in atrial flutter, a fast regular rhythm from the atria, or fibrillation) and digoxin (in supraventricular arrhythmias) are contraindicated (must not be given) when such an accessory pathway is involved. The BNF notes that digoxin can still be used in infancy.
  • Suppress ventricular arrhythmias post myocardial infarction.

Class IV: Calcium channel blockers (CCBs) E.g verapamil, diltiazem.

• CCBs target calcium-initiated muscle contraction. CCBs can affect vascular smooth muscle and/or cardiac muscle:
  • CCBs can act on the myocardium to decrease the slope of the action potential at the SA node and decrease AV node conduction by blocking calcium channels. This leads to negative inotropic (weaker contraction) and negative chronotropic (slower heart rate) effects.
  • CCBs can also block calcium channels on smooth muscle cells to reduce contraction. This leads to the dilation of blood vessels to reduce total peripheral resistance (TPR, the resistance the blood vessels offer to blood flow).
• There are three main groups of CCBs, and they are grouped by their effects on cardiac and smooth muscle:
  • Benzothiazepines (e.g. diltiazem) mainly act on the heart to give negative inotropic and chronotropic effects. 
  • Phenylalkylamines (e.g. verapamil) act on the heart to give negative inotropic and chronotropic effects, and also have a small effect on vasculature to cause vasodilation and reduce total peripheral resistance.
  • Dihydropyridines (e.g. amlodipine) mainly act on the peripheral vasculature to reduce total peripheral resistance. For this reason, they are not used as an anti-arrhythmic, and used more in hypertension, which is discussed later.
• Benzothiazepines and phenylalkylamines can be used to treat arrhythmias and angina (chest pain from reduced blood flow to the heart muscle) due to their effects on the heart. Verapamil and diltiazem are called rate-limiting CCBs because they slow the heart rate. They should be avoided in heart failure with reduced ejection fraction (HFrEF, where the left ventricle pumps out too little blood).

Other anti-arrhythmic drugs include:

Adenosine 

Adenosine is made naturally in the body (it is endogenous). It can be given intravenously (I.V.) and it acts on A₁ adenosine receptors to enhance potassium conductance and hyperpolarise cells (make the inside of the cell more negative, so it is harder to fire). Its action against supraventricular tachycardia (SVT) is a transient slowing or block of conduction through the AV node, interrupting re-entry circuits that depend on AV nodal conduction. The patient will feel like their heart has stopped when adenosine is given so should be warned before administration of the drug to prevent unneeded anxiety. Adenosine can be used to terminate re-entrant supraventricular tachycardia. It is contraindicated (must not be given) in several conditions, including asthma, chronic obstructive lung disease and second- or third-degree AV block (when impulses are partly or completely blocked at the AV node) unless a pacemaker is fitted.

Cardiac Glycosides e.g. digoxin

Digoxin causes increased vagal activity (more activity in the vagus nerve, which slows the heart). This slows AV node conduction and slows the heart rate. Digoxin also blocks the Na/K ATPase pump (the pump that moves sodium out of cells and potassium in), resulting in increased intracellular Na⁺ (sodium inside the cell). This decreases the activity of the sodium-calcium exchanger (NCX) which causes an increase in intracellular Ca²⁺. This results in more Ca²⁺ stored in the sarcoplasmic reticulum (the muscle cell’s internal calcium store), therefore more Ca²⁺ is released in contraction. Ultimately this leads to an increased force of contraction during an action potential.

Uses include reducing the ventricular rate in atrial fibrillation, particularly in patients with heart failure, and controlling certain arrhythmias in this context.

Atropine 

Atropine is a muscarinic antagonist (it blocks the acetylcholine receptors of the parasympathetic nervous system) that blocks vagal activity to speed up AV node conduction and increase heart rate. It is used mainly to treat vagal bradycardia (a slow heart rate caused by activity of the vagus nerve) when the patient is symptomatic e.g. if they're feeling dizzy or fainting.

Anti-Hypertensive Drugs

See the article on Hypertension for more information on the condition in order to appreciate how anti-hypertensive drugs act. The main goal for managing hypertension is to reduce BP by reducing TPR (total peripheral resistance) and blood volume. NICE guidance (NG136) chooses the first drug by age, family origin and type 2 diabetes. An ACE inhibitor or ARB is offered to people with type 2 diabetes, and to people aged under 55 who are not of Black African or African–Caribbean family origin. A calcium channel blocker is offered to people without type 2 diabetes who are aged 55 or over or who are of Black African or African–Caribbean family origin.

Angiotensin Converting Enzyme Inhibitors (ACEi) e.g. Ramipril, Lisinopril

These drugs inhibit the action of ACE, reducing the amount of angiotensin II (a hormone that narrows blood vessels and raises blood pressure) formed. ACEi don’t completely prevent angiotensin II formation as some conversion is carried out by an alternative pathway. However, ACEi do greatly reduce the degree of formation, enough to give a therapeutic benefit. 

Use of ACEi reduces the effect of the renin-angiotensin-aldosterone system (RAAS), resulting in:

• Vasodilation
• Reduced aldosterone release (aldosterone is a hormone that makes the kidney keep salt and water)
• Reduced ADH (antidiuretic hormone) release

RAAS is discussed in more detail in the article on Hypertension.

ACEi therefore help to treat hypertension as they decrease the TPR and help to increase fluid loss. This also helps treat heart failure because it reduces the heart's workload.

ACEi have a common side effect of a dry cough. This is because ACE also breaks down bradykinin (a chemical messenger that widens blood vessels and can trigger cough) in the lungs. Inhibiting ACE allows bradykinin to build up in the lungs which causes a dry cough. This can make patients stop taking the drug, especially as hypertension is a mostly silent condition, i.e. the drug causes symptoms when there were none previously. Patients with this side effect may be switched to an angiotensin receptor blocker (ARB). Less commonly, ACEi cause angioedema (swelling of the face, lips and tongue). Kidney function and blood electrolytes (such as potassium) are checked before starting an ACEi and monitored during treatment. ACEi should not be used in pregnancy unless absolutely necessary.

Angiotensin Receptor Blockers (ARBs) e.g. Losartan, Candesartan

Used in both the treatment of hypertension and heart failure. They block angiotensin receptor 1 which prevents angiotensin II from binding. This leads to a reduced effect of angiotensin II. ARBs essentially have the same effects as ACEi, however one difference is that the ACE enzyme is not affected. This means that ACE can still break down bradykinin and therefore cough is much less frequent with ARBs than with ACEi, although it can still occur. ARBs are used in patients who cannot tolerate ACEi, for example because of cough. NICE also advises considering an ARB in preference to an ACEi for adults of Black African or African–Caribbean family origin. An ACEi and an ARB should not be combined.

Calcium Channel Blockers (CCBs) e.g. Amlodipine, Lercandidipine, Verapamil

CCBs from the dihydropyridine group are mainly used in the treatment of hypertension due to the effect on the peripheral vasculature to reduce TPR. The other two classes, which include verapamil, are less commonly used in hypertension due to their effects on heart rate and cardiac conduction.

The three groups of CCBs are discussed earlier in this article in the section on anti-arrhythmics. 

Diuretics - Thiazide-like and thiazide groups e.g. Indapamide (thiazide-like) and Bendroflumethiazide (thiazide)

Diuretics are used in the treatment of both hypertension and heart failure. For hypertension, NICE advises a thiazide-like diuretic such as indapamide in preference to a conventional thiazide such as bendroflumethiazide. People whose blood pressure is already well controlled on bendroflumethiazide can continue it. In heart failure, loop diuretics are used to relieve fluid overload (see the heart failure section below).

Diuretics increase fluid loss from the body therefore lowering BP, making them useful in the treatment of hypertension. By lowering fluid levels in the body, diuretics reduce preload (the stretch on the ventricles before they contract). The lower blood pressure also reduces afterload (the pressure the ventricles must overcome to eject blood). This helps to reduce the demand on the heart. Therefore, diuretics can also be used in heart failure.

• Aldosterone antagonists e.g. Spironolactone
• This group of drugs are another type of diuretic, and are especially used in the treatment of hypertension caused by hyperaldosteronism (too much of the hormone aldosterone). These drugs block aldosterone receptors, therefore reducing the reabsorption of sodium and water from the kidney to reduce BP.
• NICE suggests considering low-dose spironolactone as an add-on drug in resistant hypertension, when blood pressure stays high despite an ACEi or ARB, a CCB and a thiazide-like diuretic, and blood potassium is 4.5 mmol/L or less. It carries a risk of hyperkalaemia (high blood potassium), so potassium and kidney function are monitored.

Alpha-Adrenoreceptor Blockers e.g. doxazosin and prazosin

Selectively antagonise α₁-receptors causing vasodilation and decreasing the total peripheral resistance, therefore lowering BP.

Beta-Adrenoreceptor Blockers e.g. atenolol and bisoprolol

Beta-blockers are used as an add-on in hypertension and are not usually the first drug tried. For example, NICE suggests considering a beta-blocker (or an alpha-blocker) as a fourth-step drug for resistant hypertension, when blood potassium is above 4.5 mmol/L.

Beta blockers are discussed earlier in this article in the section on anti-arrhythmics. The mechanism of action is the same.

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