Drug Management of Heart Failure

Describe the physiology of Na, K and H2O renal excretion, including the renin-angiotensin-aldosterone system

• Renal Physiology: Reabsorption part 1
• Renal Physiology: Reabsorption part 2

Describe the drug strategies to enhance Na and H2O excretion (ACE inhibitors, aldosterone antagonists)

ACE inhibitors, such as enalapril and captopril, work by inhibiting angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. Since angiotensin II normally works on the arterioles to cause constriction and on the adrenal cortex to increase the release of aldosterone, inhibiting ACE causes vasodilation (and an increase in blood flow to the kidneys) and an increase in salt and water excretion (via the actions of aldosterone).

Angiotensin II and aldosterone can also be blocked directly. AT1 receptor blockers block the actions of angiotensin II (since AT1 receptors, confusingly enough, are the receptors for angiotensin II). These drugs tend to end with the suffix -sartan, such as irbesartan. Aldosterone antagonists such as spironolactone not only increase salt and water excretion, but also inhibit the myocardial remodelling that occurs during heart failure.

Describe the clinically important beta adrenoreceptor blockers

Beta-1 blockers can also be used to treat heart failure, as they can block cardiac modelling and also decrease the myocardial contractility (which in turn decreases the blood pressure). Furthermore, they can also slow the heart down, allowing more time for the ventricles to fill with blood (which is important in cases of diastolic heart failure). Most beta-blockers end with -olol, and include metoprolol and bisoprolol. Adverse effects of beta-1 blockers are mainly related to off-target activation of beta-2 receptors, and include bronchospasm (which is why beta-blockers tend to be avoided in people with asthma). There are also side-effects from having too much of a good thing, such as excessive slowing of the heart.

Describe the clinically important diuretics

I'll discuss diuretics in a later post, but essentially diuretics act on certain transporters in the tubule to decrease reabsorption and/or increase secretion of salts and water so that you pee more. The main types of diuretics include loop diuretics (e.g. frusemide), thiazides (e.g. hydrochlorothiazide), and aldosterone antagonists (e.g. spironolactone).

Describe how digoxin acts as antiarrhythmic agent and to increase cardiac contractility

Digoxin is an antiarrhythmic that is also used for heart failure. It works by blocking Na+/K+ pumps, thus reducing the gradients of sodium and potassium. Because it blocks the pumping out of sodium, it also has a downstream effect on Na+/Ca2+ exchangers, which bring in sodium to let calcium leave the cell. Because the Na+/Ca2+ exchangers are being affected, there is more intracellular calcium, which leads to more efficient contraction of myocytes and increased cardiac contractility.

Digoxin also has indirect effects on the heart via the vagus nerve. Digoxin stimulates the vagus nerve, causing an increase in parasympathetic stimulation and decreased heart rate. Therefore, digoxin is also good for treating supraventricular tachyarrhythmias (only the supraventricular ones as the ventricles don't get parasympathetic stimulation).

Even though digoxin can reduce heart rate, at toxic doses it can actually increase heart rate. Since digoxin blocks the Na+/K+ pump, there is a smaller potassium gradient and so less potassium leaves the cell during repolarisation. Therefore, the membrane becomes less polarised (i.e. less negative), making it easier to reach threshold during the next heartbeat.

Digoxin toxicity may also present with other symptoms, such as serious arrhythmias, nausea, confusion, and visual problems. Nausea and confusion are most commonly seen in elderly patients. Since digoxin relies a lot on the kidneys for excretion (~70% excretion via the kidneys), it is especially toxic in people with renal impairment. Digoxin is also especially toxic in people who are hypokalaemic, as potassium would ordinarily compete with digoxin for binding to the Na+/K+ ATPase.

Describe how nitrates may be used in heart disease

The actual mechanism of action of nitrates wasn't really discussed in this lecture, other than that they are vasodilators that can help in emergency situations by reducing afterload.