Drug Treatments for Cardiovascular Disease: Ischaemic Heart Disease and Heart Failure

Question 1

What is the mechanism of action of Digoxin?

Answer 1

It inhibits the Na+/K+ ATPase (sodium pump), binds to the extracellular K+ binding site, increases intracellular Na+, leads to Na+/Ca2+ exchange, and increases intracellular Ca2+ and inotropy.

Question 2

Does Digoxin decrease blood pressure like most HF medications?

Answer 2

No

Question 3

What side effect is associated with Digoxin?

Answer 3

It can cause almost every arrhythmia known, especially with hypokalemia.

Question 4

What is the specific antidote for Digoxin?

Answer 4

Digibind

Question 5

What is the pathophysiology of heart failure?

Answer 5

It involves LV contractility, increased cardiac output, increased LA/PV pressures, increased PA/RV/RA pressures, increased venous return (preload), renin/angiotensin/aldosterone activation, renal Na+ and H2O retention, sympathetic activation, pulmonary edema, and peripheral edema.

Question 6

What are the therapeutic targets for heart failure drugs?

Answer 6

LV contractility, cardiac output, increased LA/PV pressures, increased PA/RV/RA pressures, increased venous return (preload), renin/angiotensin/aldosterone activation, renal Na+ and H2O retention, sympathetic activation, contractility, pulmonary edema, and peripheral edema.

Question 7

What are the therapeutic targets for angina drugs?

Answer 7

The main therapeutic targets for angina drugs include relieving chest pain (angina) by improving blood flow to the heart, reducing myocardial oxygen demand, and preventing or reducing the frequency of angina attacks.

Question 8

What is the mechanism of action of loop diuretics?

Answer 8

Loop diuretics, such as furosemide and bumetanide, act on the Na/K/Cl cotransporter in the thick ascending limb of the Loop of Henle. They block the Cl- channel of the cotransporter, leading to increased loss of Na+, K+, Cl-, and water.

Question 9

What are loop diuretics primarily used for?

Answer 9

Loop diuretics are used to clear peripheral edema and are also used intravenously for acute pulmonary edema.

Question 10

What are some side effects of loop diuretics?

Answer 10

Side effects of loop diuretics include dehydration, renal impairment, hypokalemia (low potassium levels), hyponatremia (low sodium levels), hypocalcemia (low calcium levels), hypomagnesemia (low magnesium levels), hyperuricemia (high uric acid levels causing gout), and auditory nerve damage (especially at high doses and in the presence of renal impairment).

Question 11

What ions are lost due to the action of loop diuretics?

Answer 11

Loop diuretics cause loss of Na+, K+, Ca2+, Mg2+, and Cl- ions.

Question 12

What are the hemodynamic effects of ACE inhibitors?

Answer 12

ACE inhibitors cause arteriolar dilation, which leads to decreased afterload. They also cause venodilation, resulting in decreased preload. ACE inhibitors decrease aldosterone and ADH levels, leading to a reduction in fluid retention. They can increase LA pressure.

Question 13

What is the mechanism of action of ACE inhibitors?

Answer 13

ACE inhibitors block the conversion of angiotensin I (AT-I) to angiotensin II (AT-II) and also break down bradykinin. They decrease the levels of AT-II and increase the levels of bradykinin.

Question 14

What are some examples of ACE inhibitors?

Answer 14

Examples of ACE inhibitors include Captopril (first ACE inhibitor), Enalapril, Lisinopril, Ramipril, and Perindopril (once-daily dosing).

Question 15

What are the side effects of ACE inhibitors?

Answer 15

Side effects of ACE inhibitors may include a dry cough (due to bradykinin accumulation in the lungs), renal impairment, hyperkalemia (high potassium levels), and they are commonly given with a diuretic. ACE inhibitors are also used for hypertension.

Question 16

What is the mechanism of action of angiotensin II receptor antagonists (ARBs)?

Answer 16

ARBs block the action of angiotensin II (AT-II) on the AT1 receptor, thereby preventing its effects.

Question 17

What are some examples of ARBs?

Answer 17

Examples of ARBs include Candesartan (most commonly used in heart failure), Valsartan (used in a fixed-dose combination), and Losartan (a core drug and an alternative for patients intolerant of ACE inhibitors).

Question 18

How do ARBs compare to ACE inhibitors in terms of side effects?

Answer 18

ARBs have a similar side-effect profile to placebo and are associated with a decreased incidence of dry cough compared to ACE inhibitors.

Question 19

What is the mechanism of action of aldosterone antagonists?

Answer 19

Aldosterone antagonists block the upregulation of Na+ channels in the distal convoluted tubules (DCT) by aldosterone.

Question 20

What are some examples of aldosterone antagonists?

Answer 20

Examples of aldosterone antagonists include Spironolactone and Eplerenone (which has fewer side effects).

Question 21

In which conditions do aldosterone antagonists provide prognostic benefit?

Answer 21

Aldosterone antagonists have prognostic benefits in very poor left ventricular (LV) function and post-myocardial infarction (MI), especially when acute heart failure is present.

Question 22

What are the side effects of Spironolactone?

Answer 22

Side effects of Spironolactone include impaired renal function, hyperkalemia (high potassium levels), and gynecomastia (due to its structural similarity to estrogen).

Question 23

How does the adrenergic system relate to heart failure?

Answer 23

Positive inotropes (drugs that increase cardiac contractility) that act on the adrenergic system are uniformly associated with increased mortality in heart failure. They can cause malignant arrhythmias, catecholamine cardiotoxicity, structural/functional changes in cardiac myocytes, LV dilation, adverse remodeling, increased LV systolic dysfunction, and some of them act as pressors, leading to vasoconstriction and increased afterload. They also activate the renin-angiotensin-aldosterone system (RAAS).

Question 24

What are the different types of adrenoceptors in the adrenergic system?

Answer 24

The adrenoceptors in the adrenergic system include α1, β1, α2, and β2 receptors.

Question 25

What are the effects of stimulation of β1 adrenoceptors?

Answer 25

Stimulation of β1 adrenoceptors leads to an increase in heart rate, contractility, and renin release.

Question 26

What are the effects of stimulation of β2 adrenoceptors?

Answer 26

Stimulation of β2 adrenoceptors causes vasodilation, bronchodilation, and gluconeogenesis. It also leads to vasodilation, increased sweating, bladder sphincter closure, and decreased release of norepinephrine (NA) and acetylcholine (ACh).

Question 27

What are the effects of beta-blockers in chronic heart failure?

Answer 27

Beta-blockers slow down the heart rate (aiming for a heart rate of less than 70 bpm), increase diastolic filling time, reduce afterload (lower blood pressure), reduce renin release, and decrease the activation of the renin-angiotensin-aldosterone system (RAAS). Beta-blockers do not affect contractility once the patient is stabilized, and they have a substantial mortality benefit in chronic heart failure (e.g., Carvedilol shows a 35% reduction in mortality).

Question 28

What is the molecular action of beta-receptors?

Answer 28

Beta-receptors activate adenylate cyclase through G-protein-dependent activation. This leads to an increase in cyclic AMP (cAMP) levels and activates protein kinase A. Depending on the cell type, it can either increase or decrease intracellular calcium levels. In cardiac muscle, it increases contractility and causes structural changes. In arterial and bronchial smooth muscle, it leads to relaxation.

Question 29

What are the effects of beta-blockers?

Answer 29

Beta-blockers decrease the force and rate of contraction in the heart, lower blood pressure, and can cause bronchoconstriction in the lungs. They also reduce blood supply to muscles, skin, and the penis. Common side effects include fatigue, bradycardia, breathlessness, increased asthma symptoms, fatigue and claudication in the arterioles, cold hands/feet, and erectile dysfunction.

Question 30

Which types of beta-blockers are commonly used in heart failure?

Answer 30

In heart failure, b1 selective beta-blockers are commonly used. Examples include Bisoprolol (most commonly used in the UK), Metoprolol, and Carvedilol (which has a strong clinical trial evidence base).

Question 31

What is the mechanism of action of Ivabradine?

Answer 31

Ivabradine slows the heart rate by blocking the If channel in the SA node, resulting in reduced pacemaker activity.

Question 32

What is the mechanism of action of Sacubitril?

Answer 32

Sacubitril is a neprilysin inhibitor, which prevents the breakdown of natriuretic peptides, leading to increased levels of these peptides. It is used in combination with Valsartan in a fixed-dose combination for the treatment of heart failure.

Question 33

What is the mechanism of action of Dapagliflozin?

Answer 33

Dapagliflozin inhibits glucose reabsorption by the kidney, leading to increased urinary excretion of glucose. It is used for the treatment of heart failure.

Question 34

What are the principles of treatment for angina?

Answer 34

The principles of treatment for angina include reducing oxygen demand by reducing force and rate of contraction, slowing cardiac metabolism, reducing cardiac workload, reducing preload and afterload, and increasing oxygen supply by dilating coronary arterioles. Revascularization procedures may also be considered.

Question 35

What are some drugs used for the treatment of angina?

Answer 35

Drugs used for the treatment of angina include beta-blockers, calcium channel blockers, nitrates, and other medications such as Ivabradine, Nicorandil, and Ranolazine.

Question 36

What are the different formulations of nitrates?

Answer 36

Nitrates are available in various formulations, including glyceryl trinitrate (spray for angina attacks and prophylaxis before exercise), slow-release tablets such as isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) for preventing angina, and intravenous forms of GTN/ISMN that can be titrated against pain in unstable angina.

Question 37

What are the effects of nitrates on blood vessels?

Answer 37

Nitrates deliver nitric oxide (NO) to tissues, which primarily dilates veins significantly and dilates arterioles to a lesser extent. This leads to a reduction in preload (venous dilation) and afterload (arteriolar dilation) and promotes coronary artery and arteriole dilation, ultimately reducing cardiac workload.

Question 38

What is the mechanism of action of nitrates?

Answer 38

Nitrates activate guanylyl cyclase via the release of nitric oxide (NO). This leads to an increase in cyclic guanosine monophosphate (cGMP) levels, which inhibits myosin light chain kinase. Inhibition of myosin phosphorylation results in vascular smooth muscle relaxation. The L-type voltage-gated calcium channel and the calcium-calmodulin complex are involved in this process.

Question 39

How does NO affect myosin light chain kinase?

Answer 39

NO inhibits myosin light chain kinase, which reduces myosin phosphorylation. This ultimately leads to relaxation of vascular smooth muscle.

Question 40

What are some side effects of nitrates?

Answer 40

Side effects of nitrates include vasodilation-related effects such as headaches, hypotension/dizziness, and the potential for syncope with GTN use. Nitrate tolerance can also occur, leading to a rapid loss of effectiveness with continuous use. To counteract this, “nitrate holidays” or the use of slow-release preparations may be employed.

Question 41

What are some examples of dihydropyridine calcium channel blockers?

Answer 41

Examples of dihydropyridine calcium channel blockers include Nifedipine (the first one developed), Amlodipine (most commonly used in the UK), Felodipine, and Diltiazem (used for beta-blocker intolerance). Verapamil is also a calcium channel blocker but is not a dihydropyridine.

Question 42

What is the molecular mechanism of calcium channel blockers?

Answer 42

Calcium channel blockers block the L-type voltage-gated calcium channel, resulting in a decrease in intracellular calcium levels. This leads to smooth muscle relaxation in arterioles, a decrease in force of contraction in cardiac muscle, and a decrease in heart rate in the SA and AV nodes.

Question 43

How do dihydropyridine calcium channel blockers (e.g., Amlodipine) and non-dihydropyridine calcium channel blockers (e.g., Diltiazem, Verapamil) differ in their balance of actions?

Answer 43

Dihydropyridine calcium channel blockers predominantly cause vasodilation, while having a lesser effect on cardiac contractility and heart rate. Non-dihydropyridine calcium channel blockers, such as Diltiazem and Verapamil, have more pronounced effects on cardiac contractility and heart rate, in addition to vasodilation.

Question 44

What are some other uses of nitrates?

Answer 44

Nitrates are also used in the treatment of hypertension, Raynaud’s syndrome, and certain arrhythmias.

Question 45

What causes ankle swelling as a side effect of nitrates?

Answer 45

Nitrates preferentially dilate pre-capillary arterioles, which impairs the function of the pre-capillary sphincter. This leads to increased hydrostatic pressure and net filtration, resulting in ankle swelling.

Question 46

What are some other side effects of nitrates?

Answer 46

Other side effects of nitrates may include palpitations due to reflex tachycardia, constipation, flushing, headache, and exacerbation of heart failure.

Question 47

What are some other drugs used for the treatment of angina?

Answer 47

Other drugs used for the treatment of angina include Ivabradine, which inhibits the If channel in the SA node and slows the heart rate without reducing contractility. Nicorandil opens ATP-sensitive K channels and has nitrate-like action. Ranolazine has metabolic effects.

Question 48

What drugs are used in the treatment of heart failure?

Answer 48

The treatment of heart failure involves the use of ACE inhibitors (such as Ramipril) or AR-II blockers (such as Losartan), beta-blockers (such as Bisoprolol), aldosterone antagonists (such as Spironolactone), loop diuretics (such as Furosemide), and cardiac glycosides (such as Digoxin).

Question 49

What drugs are commonly used for the secondary prevention of ischemic heart disease?

Answer 49

For secondary prevention of ischemic heart disease, antiplatelet drugs like Aspirin and Clopidogrel, ACE inhibitors (such as Ramipril) or AR-II blockers (such as Losartan), and statins (such as Atorvastatin) are commonly used. Blood pressure control is also optimized.

Question 50

What drugs are commonly used for the treatment of angina in ischemic heart disease?

Answer 50

Beta-blockers (such as Bisoprolol), calcium channel blockers (such as Diltiazem, Verapamil, and Amlodipine), and nitrates (such as GTN spray and Isosorbide mononitrate) are commonly used for the treatment of angina in ischemic heart disease.