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Article by Dr. Thomas Burnell and Bethany Turner
Questions by Dr. Jenny Hubball
Next Lesson - Murmurs
Abstract
- Use of anti-arrhythmic drugs vary depending on the type of arrhythmia, but include class I-IV anti-arrhythmics, alongiside adenosine, digoxin and atropine.
- ACEi, ARB, CCB, diuretics, alpha and beta blockers are used in the treatment of hypertension.
- ACEi, ARB, diuretics and beta blockers are used in the treatment of heart failure.
Core
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.
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).
- Damaged myocardium can spontaneously depolarise causing arrhythmias e.g. atrial fibrillation. Lidocaine works in this condition by blocking sodium channels after an action potential (AP), therefore preventing the initiation of another AP.
- The lidocaine dissociates in <0.5ms. 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 can 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 β-adrenoreceptors E.g. atenolol and bisoprolol.
- Block sympathetic action by blocking β1-receptors in the heart to slow the heart rate (negative chronotropy) (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 in the SA node increases the time taken to initiate an action potential.
- Slows conduction in the AV node to increase the time between the depolarisation of the atria and ventricles.
- Use:
- Supraventricular tachycardia to protect the ventricles from high atrial rates via its effect on slowing AV conduction.
- Following a myocardial infarction (as sympathetic activity is often increased after a myocardial infarction).
- Reduce myocardial ischaemia by reducing oxygen demand.
- Heart failure.
Class III: Drugs that block potassium channels E.g. amiodarone.
- Blocking potassium channels prolongs the action potential and lengthens the absolute refractory period to slow the heart rate. This prevents another action potential, however these drugs can actually be pro-arrhythmic.
- Amiodarone is a relatively 'dirty' drug as it has actions other than blocking potassium channels. Some of these other actions make it more effective at treating arrythmias, but also give side effects.
- Uses:
- Can be used to treat most arrhythmias, however it is not first line in most cases due to the side effects.
- Treat tachycardia associated with Wolff-Parkinson-White syndrome.
- Supress 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 and negative chronotropic 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.
- There are three main groups of CCBs, and they are grouped by their effects on cardiac and smooth muscle:
- Benzothiazapines (e.g. diltiazem) mainly act on the heart to give negative inotropic and chronotropic effects.
- Phenylalkamines (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.
- Benzothiazapines and phenylalkamines can be used to treat arrhythmias and angina due to their effects on the heart.
Other anti-arrhythmic drugs include:
Adenosine
Adenosine is an endogenous substance that can be given I.V. which acts on α1-receptors to enhance potassium conductance and hyperpolarise cells. This hyperpolarisation inhibits the movement of calcium and essentially 'resets' the SA node. 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 supra-ventricular tachycardia.
Cardiac Glycosides e.g. digoxin
Digoxin causes increased vagal activity. This slows AV node conduction and slows the heart rate. Digoxin also blocks the Na/K ATPase pump, resulting in increased intracellular Na+. 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, therefore more Ca2+ is released in contraction. Ultimately is leads to an increased force of contraction during an action potential.
Uses include reducing ventricular rates in supraventricular tachycardias, and controlling arrhythmias in patients with heart failure.
Atropine
Atropine is a selective muscarinic antagonist that blocks vagal activity to speed up AV node conduction and increase heart rate. It is used mainly to treat vagal bradycardia when the patient is symptomatic e.g. if they're feeling dizzy or fainting.
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 and blood volume.
Angiotensin Converting Enzyme Inhibitors (ACEi) e.g. Ramipril, Lisinopril
These drugs inhibit the action of ACE, reducing the amount of angiotensin II formed. ACEi don’t completely prevent angiotensin II formation as some conversion is carried out by an alternative pathway. However, ACEi’s do massively reduce the degree of formation to a therapeutic benefit.
Use of ACEi reduces the effect of the RAAS system, resulting in:
- Vasodilation
- Reduced aldosterone release
- Reduced ADH 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 as it reduces the hearts workload.
ACEi have a common side effect of a dry cough. This is as ACE also breaks down bradykinin in the lungs. Inhibiting ACE allows bradykinin to build up in the lungs which causes a dry cough. This can alter compliance with treatment, especially as hypertension is a mostly silent condition i.e. the drug induces symptoms when there were none previously. Patients with this side effect may be switched to an angiotensin receptor blocker.
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 dry cough is not a side effect of ARBs. ARBs are used in patients who cannot tolerate ACEi.
Calcium Channel Blockers (CCBs) e.g. Amlodipine, Lercandidipine, Verapamil
CCBs from the dihydropiridine group are mainly used in the treatment of hypertension due to the effect on the peripheral vasculature to reduce TPR. The other two classes are not generally used in hypertension.
The three groups of CCBs are discussed earlier in this article in the section on anti-arrhythmics.
Diuretics – Thiazide group e.g. Indapamide and Bendroflumethiazide
Diuretics are used in the treatment of both hypertension and heart failure. Thiazides are used in hypertension.
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, the preload and afterload are reduced which 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. These drugs block aldosterone receptors, therefore reducing the reabsorption of sodium and water from the kidney to reduce BP.
- They can also be used as an adjunct along with ACEi or ARBs in primary hypertension.
Alpha-Adrenoreceptor Blockers e.g. doxazosin and prazosin
Selectively antagonise α1-receptors causing vasodilation and decreasing the total peripheral resistance, therefore lowing BP.
Beta-Adrenoreceptor Blockers e.g. atenolol and bisoprolol
Beta blockers are used as an add on in hypertension and are not generally first line.
Beta blockers are discussed earlier in this article in the section on anti-arrhythmics. The mechanism of action is the same.
Heart failure is an inability of the heart to meet the demands of the body. See the article on Heart Failure for more information abut the condition.
The main goal in managing heart failure is to reduce the strain on the heart and increase cardiac output to meet the body's needs.
Cardiac Glycosides e.g. digoxin
Mainly used in treatment of HF with arrhythmia. This is because digoxin is an anti-arrhythmic, and also has actions to slow HR and increase contractility.
Digoxin is discussed earlier in this article in the section on anti-arrhythmics. The mechanism of action is the same.
β-Adrenoreceptor Agonists – e.g. dobutamine.
Dobutamine is a selective β1-receptor agonist that stimulates receptors at the SA node, AV node and ventricular myocytes. This has positive inotropic and positive chronotropic effects, therefore dobutamine is used in acute but reversible HF, and cardiogenic shock.
Beta-Blockers – e.g. bisoprolol, carvedilol
Used in patients with chronic and stable HF as they:
- Reduce sympathetic influences to the heart allowing the heart rate to decrease, thus allowing it to fill more in diastole leading to an increased cardiac output.
- Stabilise the electrical conduction in the heart to help prevent arrhythmias.
- Blunt the RAAS by inhibiting renin release.
Beta blockers are discussed earlier in this article in the sections on anti-arrhythmics and hypertension. The mechanism of action on the heart is the same.
Loop Diuretics – e.g. furosemide and bumetanide
Diuretics are discussed earlier in this article in the sections on anti-arrhythmics and hypertension. The general effects of diuretics are the same.
The goal in managing angina is to reduce the pain during exacerbations. This is mainly done with GTN spray during acute episodes.
Nitrates are used in treatment of angina. Nitrates release NO2 ions which are converted to nitric oxide. NO activates guanylyl cyclase causing an increase in cGMP in the vascular smooth muscle. This causes muscle relaxation, especially in veins. The vasodilation lowers preload which decreases the workload of the heart. The heart fills less so it contracts less forcefully meaning the myocardium has a lower oxygen demand which relieves symptoms.
- Glyceryl Trinitrate (GTN) spray is used when patients have an acute episode of angina pain. GTN is sprayed under the tongue, and quickly takes effect to reduce the patient’s symptoms. Flushing and headache are common when used due to the vasodilation.
Edited by: Dr. Ben Appleby
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