CHF AND ARRHYTHMIAS PHARMACOLOGY

ANTIARRHYTHMICS

Due to the lack of evidence of improved survival for any antiarrhythmic drug in patients without life-threatening arrhythmias, and the proarrhythmic properties of many antiarrhythmic agents, including those in Class IA, the use of antiarrhythmic drugs should be reserved for patients with life-threatening ventricular arrhythmias.

Because of the differences in pharmacological activity of the various antiarrhythmic drugs, they are classified according to the mechanisms that they target.

CLASS I ANTIARRHYTHMICS 

-Block the transmembrane influx of sodium (Na+)

-Subdivided into three classes:

1) Class 1A (eg, quinidine, procainamide, disopyramide):

-Broad-spectrum antiarrhythmics

-Intermediate in binding kinetics to Na+ channel receptors

-Slow conduction velocity, prolong the refractory period, and decrease automaticity

-Indicated to treat ventricular and supraventricular arrhythmias

2) Class 1B (eg, mexiletine):

-Bind to and dissociate quickly from Na+ channel receptors

-Have little effect on conduction velocity

-Decrease refractory period and automatocity 

-More effective in treating ventricular arrhythmias

3) Class 1C (eg, flecainide, propafenone):

-Bind to and dissociate slowly from Na+ channel receptors

-Potent effects on slowing ventricular conduction

-Refractory period left unchanged

-Used to treat both ventricular and supraventricular arrhythmias

-Limited by the risk of proarrhythmias

CLASS II ANTIARRHYTHMICS 

-Composed of β-blockers (eg, acebutolol, propranolol)

-Inhibit β-adrenergic receptors in the heart

-Slow conduction velocity, prolong the refractory period, and decrease automaticity

-Useful in treating re-entrant arrhythmias involving the atrioventricular (AV) node and in controlling ventricular rates in atrial fibrillation or flutter

CLASS III ANTIARRHYTHMICS (eg, dofetilide, amiodarone, sotalol)

-Block potassium channels in the heart causing an increase in action potential duration (increased QT interval) and a reduction in normal automaticity 

-Increase in refractoriness makes them effective in treating re-entry

-Amiodarone and sotalol also have β-blocking properties that contribute to efficacy

-Used to treat ventricular arrhythmias (particularly life-threatening arrhythmias resistant to other treatments)

CLASS IV ANTIARRHYTHMICS 

-Composed of calcium channel blockers (eg, diltiazem, verapamil)

-Block calcium channels in slow response tissue of the sinus and AV nodes 

-Slow conduction velocity, prolong the refractory period, and decrease automaticity 

-Used to treat automatic or re-entrant tachycardias that arise from sinoatrial and AV nodes

CONGESTIVE HEART FAILURE (CHF)

CHF is a condition in which the heart fails to pump blood at a rate proportionate to the metabolic needs of the body. 

Goals of therapy:

-Improve patient's quality of life

-Reduce symptoms

-Reduce hospitalizations

-Slow the progression of the disease

-Prolong survival

RENIN-ANGIOTENSIN SYSTEM ANTAGONISTS

-Cause arterial vasodilation resulting in decreased afterload and increased stroke volume and cardiac output

-Prevent Na+ and water retention, potentiating the effect of diuretics 

-Decrease sympathetic nervous system activity

1) ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEIs) (eg, ramipril, lisinopril)

-Block angiotensin II and aldosterone production

-More potent arterial than venous dilators

-Reduce bradykinin degradation thereby increasing production of vasodilator substances (nitric oxide, prostaglandin I2)

-"ACE escape" (an increase in circulating angiotensin II) can result with chronic therapy

-Start with low dose to avoid abrupt drop in blood pressure

-Bradykinin-mediated side effects: cough, angioedema

2) ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs) (eg, candesartan, valsartan)

-Block angiotensin II receptor subtype AT1

-May provide more potent reduction of the effects of angiotensin II than ACEIs

-Does not appear to affect bradykinin (however, angioedema has been reported with ARBs)

-Preferred alternative in patients who cannot tolerate ACEIs

DIURETICS (For more information on diuretics see the Edema section)

-Recommended for all patients with evidence of fluid retention

-Reduce extracellular fluid volume and ventricular filling pressure

-Response often impaired in patients with CHF

-The use of spironolactone, an aldosterone antagonist, has been beneficial in patients with moderate to severe heart failure

CARDIAC GLYCOSIDES (eg, digoxin)

-Positive inotropic effect due to inhibition of Na+,K+-ATPase

-Control ventricular rate response to atrial fibrillation

-Neurohumoral effects: block sympathetic activation and reduce renin release

-Narrow therapeutic index (monitor for toxicity)

-No longer considered first-line treatment 

β-BLOCKERS (eg, metoprolol, carvedilol)

-Improve left ventricular structure and function, decrease chamber size, and increase ejection fraction

-Reduce the incidence of sudden death

-Recommended therapy in patients with ejection fraction <35% in conjunction with ACEIs or ARBs, and diuretics

-Should be initiated at low doses and increased slowly because of the potential to worsen symptoms and ventricular function

-May be necessary to adjust diuretic regimen because of increased fluid retention

-Increase in exercise tolerance seen with metoprolol

NITRATES & HYDRALAZINE 

-Nitrates are venodilators that produce reductions in preload

-Hydralazine is a direct-acting vasodilator that reduces afterload and increases stroke volume and cardiac output

-Combination therapy (nitrate + hydralazine) should be considered in patients with renal dysfunction who cannot tolerate ACEIs

by

Akshaya Srikanth

Pharm.D Intern

Hyderabad, India