CARDIOVASCULAR PHARMACOLOGY - COMPLETE STUDY NOTES
Based on: Drugs for Heart Failure, Anti-Hypertensive Drugs, Anti-Anginal & Anti-Arrhythmic Drugs, Coagulation Modifier Drugs
Professor G. Gurgenidze
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SECTION 1 - MECHANISM OF HEART FAILURE
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Heart failure is a disorder in which the heart loses its ability to pump blood efficiently throughout the body, resulting in decreased cardiac output. The heart can fail because of increased workload to overcome pressure or volume overload, or because it simply becomes too weak to maintain adequate output.

When cardiac output falls, the body activates several compensatory mechanisms, but these compensations eventually become harmful. The first compensatory change involves venous return and preload. Because cardiac output is reduced, blood volume remains in the ventricle after each beat, stretching the myocardial fibers. The heart initially tries to use this stretch to contract more forcefully through the Frank-Starling mechanism, but over time the muscle becomes overstretched and weakens further.

The second compensatory change involves afterload, which is the resistance against which the heart must pump blood. As the body tries to maintain blood pressure despite falling cardiac output, it increases systemic vascular resistance, forcing the already-failing heart to work even harder against higher resistance.

The third change involves myocardial contractility and heart rate. The fall in cardiac output causes a drop in blood pressure, which activates baroreceptors and triggers the sympathetic nervous system. This leads to tachycardia and increased catecholamine release. While this temporarily maintains output, chronic sympathetic overactivation is directly toxic to heart muscle cells and causes further damage over time.

The fourth change involves salt and water retention. The reduced cardiac output decreases renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS). Angiotensin causes sodium and water retention, increasing blood volume and worsening the fluid overload that the failing heart already cannot handle.

Myocardial remodeling is the long-term structural change that occurs in heart failure. It involves progressive alteration of ventricular size and shape. The increased workload causes hypertrophy initially, but eventually leads to loss of myocytes, interstitial fibrosis, and dilation of the ventricle. This remodeling makes the heart progressively less efficient. The key mediators driving this remodeling are angiotensin II, aldosterone, and catecholamines.


SECTION 2 - THERAPEUTIC OBJECTIVES IN HEART FAILURE
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The treatment of heart failure has two primary goals. The first is to relieve symptoms by reducing the fluid overload, which means reducing preload and decreasing congestion in the lungs and periphery. The second and more important goal is to prevent further deterioration and reduce mortality, which means preventing ongoing cardiac remodeling and protecting the heart muscle from further damage.

Drug therapy in heart failure targets several mechanisms. Positive inotropic drugs increase the force of contraction and improve cardiac output. Diuretics remove excess fluid and reduce preload. ACE inhibitors and ARBs reduce both preload and afterload and, most importantly, prevent cardiac remodeling. Beta-blockers prevent the harmful effects of chronic sympathetic overactivation. Vasodilators like nitrates reduce preload and afterload to lessen the burden on the heart.


SECTION 3 - ORDER OF THERAPY IN HEART FAILURE
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The standard approach to treating chronic heart failure begins with ACE inhibitors as the first-line drug, given together with diuretics. ACE inhibitors form the cornerstone of heart failure therapy because they not only reduce blood pressure and ease the heart's workload, but they also actively prevent and reverse cardiac remodeling. Beta-blockers are added next, and while they seem counterintuitive in a failing heart, they are vital for long-term protection. Diuretics, particularly loop diuretics, are used to control fluid retention and relieve symptoms. Cardiac glycosides like digoxin are added when symptoms persist despite the above drugs, or when the patient also has atrial fibrillation.


SECTION 4 - ACE INHIBITORS
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ACE inhibitors include drugs such as captopril, enalapril, and lisinopril. Their mechanism of action involves inhibiting the enzyme that converts angiotensin I to angiotensin II. By doing this, they reduce levels of angiotensin II in the blood, which leads to arterial dilation and reduced afterload, as well as venous dilation and reduced preload. They also reduce aldosterone secretion, which decreases sodium and water retention.

ACE is also the enzyme responsible for breaking down bradykinin, a peptide that causes vasodilation by stimulating nitric oxide production. When ACE is inhibited, bradykinin accumulates. This elevated bradykinin contributes to vasodilation, which is beneficial, but it is also responsible for the most common side effect of ACE inhibitors, which is dry cough. The cough occurs because elevated bradykinin irritates the airways, and it affects around 10 to 15 percent of patients.

In heart failure, ACE inhibitors prevent cardiac remodeling by blocking angiotensin II, which is one of the main drivers of ventricular hypertrophy and fibrosis. By blocking this, ACE inhibitors prevent further loss of myocytes and interstitial fibrosis, effectively slowing down the progression of heart failure and improving survival.

The adverse effects of ACE inhibitors include dry cough as the most common, angioedema as a rare but serious and potentially life-threatening reaction involving swelling of the face, lips, and throat, hypotension especially after the first dose, hyperkalemia because reduced aldosterone means less potassium excretion, and renal impairment. ACE inhibitors are absolutely contraindicated in pregnancy because they are foetopathic - they cause abnormal fetal kidney development and can be fatal to the fetus.

The advantages of ACE inhibitors include the fact that they do not cause postural hypotension, electrolyte disturbances, feeling of weakness, hyperuricemia, or adverse effects on lipid profiles. They are also protective in diabetic nephropathy because they reduce intraglomerular pressure by dilating the efferent arteriole of the glomerulus, slowing progression to end-stage kidney disease.

The uses of ACE inhibitors include all grades of hypertension as a first-line drug, chronic heart failure especially with left ventricular dysfunction, diabetic nephropathy, and post-myocardial infarction to prevent remodeling.


SECTION 5 - ARBs (ANGIOTENSIN RECEPTOR BLOCKERS)
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ARBs include losartan, valsartan, candesartan, telmisartan, olmesartan, and irbesartan. All drugs in this class end in the suffix "-sartan." Losartan is the prototype and most commonly referenced drug. Valsartan is the ARB combined with sacubitril to form the ARNI drug used in advanced heart failure.

ARBs work by blocking the AT1 receptor, which is where angiotensin II exerts its effects. By blocking this receptor, ARBs prevent vasoconstriction, aldosterone release, and sodium retention just like ACE inhibitors do. However, the key difference is that ARBs do not affect the ACE enzyme itself, so bradykinin levels remain normal. This means ARBs do not cause dry cough, which is the most important practical difference between the two drug classes.

The main indication for ARBs in heart failure is as an alternative when the patient cannot tolerate ACE inhibitors, which is most often due to the dry cough. ARBs provide the same hemodynamic benefits - reducing preload, reducing afterload, and preventing cardiac remodeling - without causing cough. They are also contraindicated in pregnancy just like ACE inhibitors. Angioedema can very rarely occur with ARBs as well, though it is far less common than with ACE inhibitors.


SECTION 6 - DIFFERENCE BETWEEN ACE INHIBITORS AND ARBs
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Both ACE inhibitors and ARBs block the renin-angiotensin system and produce similar clinical benefits in heart failure and hypertension. The fundamental difference lies in where they act in the pathway. ACE inhibitors block the enzyme that makes angiotensin II, so they prevent angiotensin II from being formed. ARBs allow angiotensin II to be formed but block the receptor through which it acts.

Because ACE inhibitors block bradykinin breakdown, they raise bradykinin levels, which is beneficial for vasodilation but causes dry cough and angioedema as side effects. ARBs have no effect on bradykinin, so they do not cause these side effects. This makes ARBs better tolerated. However, some research suggests that the elevated bradykinin from ACE inhibitors may contribute additional cardiovascular protection beyond just blocking angiotensin II. Both drug classes are contraindicated in pregnancy, and neither should be combined with each other due to the risk of serious adverse effects.


SECTION 7 - BETA-BLOCKERS
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Beta-blockers work by blocking beta-adrenergic receptors, reducing the effects of catecholamines like adrenaline and noradrenaline on the heart and blood vessels. By blocking beta-1 receptors in the heart, they reduce heart rate, reduce the force of contraction, reduce cardiac output, and reduce blood pressure.

In heart failure, the use of beta-blockers seems paradoxical because they reduce the heart's pumping function. The reason they are used is that in heart failure, the sympathetic nervous system is chronically overactivated, and the resulting high catecholamine levels are directly toxic to cardiac myocytes. Prolonged exposure to high catecholamines causes apoptosis (death) of heart muscle cells, fibrosis, and progressive remodeling that worsens heart failure over time. Beta-blockers block this harmful effect, prevent further structural damage, and reduce mortality. The key rule is that they must be started at a very low dose and titrated up very slowly, because starting at a high dose can cause acute worsening of heart failure by suddenly reducing an already-compromised cardiac output.

The beta-blockers preferred in heart failure are carvedilol, metoprolol, and bisoprolol because they have additional vasodilating properties that offset the initial reduction in cardiac output.

In angina, beta-blockers reduce myocardial oxygen demand by slowing the heart rate, reducing contractility, and lowering blood pressure. They are the first-line treatment for chronic stable angina because they reduce the frequency and severity of attacks and improve exercise tolerance. Cardioselective agents like atenolol and metoprolol are preferred over non-selective ones like propranolol.

In hypertension, beta-blockers are one of the four main classes of antihypertensive drugs.

The contraindications of beta-blockers include asthma and COPD because non-selective beta-blockers block beta-2 receptors in the bronchi, causing bronchoconstriction. They are also relatively contraindicated in diabetes because they can mask the symptoms of hypoglycemia such as tachycardia and tremor. They should not be used in severe peripheral vascular disease because they reduce blood flow to the limbs. They are contraindicated in heart block and severe bradycardia. Cardioselective beta-blockers like atenolol and metoprolol are safer in asthma and diabetes compared to non-selective ones because they primarily act on the heart, though even these can lose selectivity at high doses.

Beta-blockers must never be used in variant (Prinzmetal's) angina because the coronary spasm that causes this condition is partly mediated by unopposed alpha-receptor activity. When beta-2 receptors in coronary vessels are blocked, there is no opposing vasodilation, and the spasm worsens.


SECTION 8 - DIURETICS
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Diuretics are drugs that increase urine output and help remove excess fluid from the body. They are used in heart failure to relieve fluid congestion, and in hypertension to reduce blood volume and blood pressure.

Loop diuretics are the most potent diuretics available. Furosemide is the prototype, with others being bumetanide, torsemide, and ethacrynic acid. They work by inhibiting the sodium-potassium-chloride cotransporter (Na+-K+-Cl- symport) in the thick ascending limb of the Loop of Henle in the kidney. This prevents reabsorption of sodium and chloride, resulting in large amounts of dilute urine. Because they act on the Loop of Henle where a large proportion of sodium reabsorption occurs, they are highly potent. In heart failure, loop diuretics are the first choice in acute heart failure because they act quickly and can dramatically reduce pulmonary congestion. A major side effect is hypokalemia (low potassium), because the increased flow of sodium to the collecting duct causes more potassium to be excreted. This is clinically important because hypokalemia worsens digoxin toxicity.

Thiazide diuretics like hydrochlorothiazide and chlorthalidone are milder diuretics. They work by inhibiting the sodium-chloride cotransporter (Na+-Cl- symport) in the distal convoluted tubule. They are used for mild-to-moderate hypertension and chronic management of fluid retention. They are less potent than loop diuretics but are very useful for long-term blood pressure control.

Potassium-sparing diuretics include two subgroups. Spironolactone and eplerenone are competitive aldosterone antagonists - they block the aldosterone receptor in the collecting duct, preventing aldosterone from promoting sodium retention and potassium excretion. Amiloride directly blocks the sodium channels in the collecting duct without involving aldosterone. All these drugs retain potassium while still promoting sodium and water excretion. They are weak diuretics on their own but are frequently combined with loop or thiazide diuretics to prevent potassium loss.

Spironolactone has a special role in heart failure beyond just being a diuretic. Aldosterone in heart failure not only causes sodium retention but also stimulates fibroblasts to lay down collagen in the heart, causing myocardial fibrosis. By blocking aldosterone receptors, spironolactone prevents this fibrosis and cardiac remodeling, which is why it has been shown to reduce mortality in heart failure independently of its diuretic effect.


SECTION 9 - VASODILATORS AND VENODILATORS - ORGANIC NITRATES
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Organic nitrates are prodrugs that release nitric oxide (NO) after entering the body. The NO activates the enzyme soluble guanylyl cyclase, which converts GTP to cyclic GMP (cGMP). The increased cGMP causes dephosphorylation of the myosin light chain and a reduction in cytosolic calcium, which leads to relaxation of smooth muscle in blood vessel walls.

The most important action of organic nitrates is venodilation, which reduces preload. At low doses, nitrates preferentially dilate veins (capacitance vessels), causing peripheral pooling of blood in the venous system. This reduces the amount of blood returning to the heart (venous return), which decreases the filling pressure of the ventricle (end-diastolic volume). This reduced preload means the heart wall has less tension and needs less oxygen, which relieves angina. At higher doses, nitrates also dilate arterioles, reducing afterload.

Nitrates also have an important coronary redistribution effect. They preferentially dilate large epicardial coronary arteries rather than smaller resistance arterioles. This is significant because in ischemia, blood flow is redirected from the ischemic subendocardial zones toward better-supplied areas. Nitrates reverse this by dilating the large arteries and redistributing flow back to the ischemic zones. This is unique to nitrates - many other vasodilators can cause "coronary steal" by dilating small vessels and actually worsening ischemia.

There are three main organic nitrates. Glyceryl trinitrate (GTN or nitroglycerin) is given sublingually for acute angina attacks. It is given sublingually because if swallowed, it undergoes massive first-pass metabolism in the liver where nearly 100 percent is destroyed before reaching the bloodstream. The sublingual route avoids the liver entirely - drug is absorbed directly into the systemic circulation through the rich venous plexus under the tongue. This gives an onset of 1 to 3 minutes. GTN has a half-life of only 1 to 5 minutes and a duration of action of 20 to 30 minutes, making it ideal for acute use. It is also available as an IV infusion for acute MI and acute left ventricular failure, and as a transdermal patch for chronic use.

Isosorbide dinitrate (ISDN) can be given both sublingually for acute attacks and orally for chronic prophylaxis. When given orally, it undergoes significant first-pass metabolism in the liver, but it is converted to isosorbide mononitrate, which is the active metabolite. Its sublingual onset is slightly slower than GTN at 2 to 5 minutes, and its duration is longer at 1 to 2 hours sublingually and 4 to 6 hours orally.

Isosorbide mononitrate (ISMN) is already the active metabolite, so it does not require conversion in the liver. It has almost 100 percent oral bioavailability and predictable blood levels. It is given only orally for chronic prophylaxis of angina and is not suitable for acute attacks. It is the preferred form for long-term management because of its reliable and consistent absorption.

The adverse effects of organic nitrates include headache as the most common side effect, caused by vasodilation of meningeal blood vessels. At higher doses they cause postural hypotension, facial flushing, and reflex tachycardia. Nitrates must never be combined with phosphodiesterase type 5 inhibitors such as sildenafil (Viagra). Sildenafil prevents the breakdown of cGMP while nitrates increase cGMP production - together they cause a massive and potentially fatal drop in blood pressure.

Nitrate tolerance develops with continuous use. The blood vessels become desensitized to the drug's effects. This is prevented by giving a daily nitrate-free interval of 8 to 12 hours, usually overnight, during which the vessels recover their sensitivity. Sudden withdrawal after prolonged use should be avoided as it can cause rebound coronary spasm.

The uses of organic nitrates include acute angina attacks (GTN sublingual is first-line), chronic prophylaxis of stable angina, acute coronary syndromes, evolving myocardial infarction, acute left ventricular failure and pulmonary edema, and esophageal spasm.


SECTION 10 - UNSTABLE ANGINA AND THROMBUS
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The three types of angina are stable angina, variant angina, and unstable angina. Stable angina is caused by a fixed atherosclerotic plaque that narrows a coronary artery. Symptoms occur predictably during exertion when oxygen demand increases but supply cannot meet it through the narrowed vessel. Rest relieves it within 15 minutes. This type makes up about 90 percent of angina cases.

Variant angina, also called Prinzmetal's or vasospastic angina, is caused by sudden spasm of a coronary artery rather than a fixed blockage. It occurs at rest or during sleep and is unpredictable. Less than 10 percent of cases. The treatment of choice is calcium channel blockers (especially diltiazem) and nitrates, both of which relax coronary smooth muscle. Beta-blockers are contraindicated in variant angina because blocking beta-2 receptors removes their vasodilating influence on the coronary vessels, leaving alpha-receptor-mediated vasoconstriction unopposed, which can worsen the spasm.

Unstable angina is caused primarily by thrombus formation. An atherosclerotic plaque in a coronary artery becomes unstable and ruptures or fissures. This exposes the underlying collagen and tissue factor to the bloodstream, which activates platelets and the coagulation cascade. A platelet plug forms first (white thrombus), followed by a fibrin clot (red thrombus). This causes partial occlusion of the coronary artery, which produces ischemia even at rest. Unstable angina is therefore part of the spectrum called Acute Coronary Syndrome, along with NSTEMI and STEMI.

If the thrombus in unstable angina grows and partially occludes the artery causing damage to the innermost (subendocardial) layer of the heart muscle, it becomes an NSTEMI (non-ST elevation myocardial infarction). The troponin level in the blood rises, indicating myocyte damage, but there is no ST elevation on the ECG because the full thickness of the heart muscle is not involved. If the thrombus completely occludes the artery and cuts off blood supply to the full thickness (transmural) of the myocardium, it becomes a STEMI (ST elevation myocardial infarction), which is the most dangerous form. If this is not treated immediately, the patient can die from ventricular fibrillation or cardiogenic shock.

Because unstable angina is caused by thrombus, its treatment includes antiplatelet drugs (aspirin plus clopidogrel) to prevent further platelet aggregation, anticoagulants (heparin) to prevent clot extension, nitrates to relieve vasospasm and ischemia, and beta-blockers to reduce oxygen demand. If it progresses to STEMI, urgent reperfusion with thrombolytics or percutaneous coronary intervention (PCI/angioplasty) is required.


SECTION 11 - DIGOXIN (CARDIAC GLYCOSIDE)
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Digoxin is a cardiac glycoside derived from the Digitalis plant species. It is the most important drug in this class and is used in both heart failure and arrhythmias.

The mechanism of action of digoxin begins with its inhibition of the Na+-K+ ATPase pump on cardiac muscle cells. This pump normally moves sodium out of the cell and potassium into the cell. When digoxin inhibits it, sodium accumulates inside the cell. This intracellular sodium buildup reduces the activity of the sodium-calcium exchanger, which normally moves calcium out in exchange for sodium entering. With less sodium gradient to drive calcium out, calcium also accumulates inside the cell. The increased intracellular calcium is what causes the positive inotropic effect - greater calcium availability means stronger cross-bridge cycling between actin and myosin, resulting in a more forceful contraction.

The most important outcome of digoxin's action is that it increases the force of contraction (positive inotropic effect) while simultaneously slowing the heart rate (negative chronotropic effect) and slowing conduction through the AV node (negative dromotropic effect). The slowing of heart rate occurs through increased vagal (parasympathetic) tone rather than direct effects on the SA node. This makes digoxin uniquely useful because most positive inotropes tend to increase heart rate, which is harmful, whereas digoxin improves contractility while actually slowing the rate.

Digoxin corrects heart failure by increasing force of contraction, which improves cardiac output. Better cardiac output improves renal blood flow, relieving oliguria and aiding fluid excretion. Improved tissue perfusion relieves peripheral edema and symptoms of congestion.

The therapeutic uses of digoxin include heart failure with atrial fibrillation (it is particularly useful when diuretics and ACE inhibitors have failed to control symptoms), atrial fibrillation (for rate control), and atrial flutter.

The adverse effects of digoxin are numerous. In the CNS it causes disorientation, hallucinations, and visual disturbances, most classically an aberration of color perception where the patient sees a yellow-green tinge to everything (xanthopsia). Nausea and vomiting are common early signs of toxicity. Cardiac toxicity from prolonged use or overdose includes bradycardia, various arrhythmias, and heart block.

Digoxin toxicity is worsened by hypokalemia. This is because potassium and digoxin compete for the same binding site on the Na+-K+ ATPase pump. When potassium levels in the blood are low, there is less competition, and digoxin binds more easily and more powerfully. This means even a normal blood level of digoxin becomes toxic when potassium is low. This is clinically critical because loop diuretics, which are frequently used alongside digoxin in heart failure, cause urinary potassium loss, predisposing the patient to hypokalemia and thereby to digoxin toxicity.

The treatment of digoxin toxicity involves first checking and correcting serum potassium. The specific antidote is digoxin immune Fab, which are antibody fragments that bind to digoxin molecules in the blood and tissues, neutralizing them.


SECTION 12 - OTHER INOTROPIC AGENTS
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Dobutamine and dopamine are both beta-1 agonists used as inotropes in acute heart failure. Dobutamine acts selectively on beta-1 receptors in the heart, increasing force of contraction and cardiac output with minimal effect on blood pressure. Dopamine has dose-dependent effects across different receptors. At low doses it acts on dopamine receptors in the kidney, increasing renal blood flow and urine output - useful when the patient has oliguria. At moderate doses it stimulates beta-1 receptors like dobutamine, improving cardiac output. At high doses it stimulates alpha receptors, causing vasoconstriction and raising blood pressure - used when the patient is in cardiogenic shock with severe hypotension. Dobutamine is preferred when you want to improve cardiac output without raising blood pressure, while dopamine is preferred when low blood pressure is also a concern.

Milrinone is a bipyridine drug that inhibits phosphodiesterase type 3 (PDE3). PDE3 is the enzyme that breaks down cAMP inside cardiac cells. When milrinone inhibits this enzyme, cAMP accumulates, which activates protein kinase A, which opens calcium channels, allowing more calcium into the cell. More calcium means stronger contraction. Milrinone also causes vasodilation because it inhibits PDE3 in vascular smooth muscle too, reducing afterload. The difference between milrinone and digoxin is that milrinone works through cAMP and directly opens calcium channels, while digoxin works by inhibiting the Na+-K+ ATPase pump and raises calcium indirectly through the sodium-calcium exchanger. Both increase intracellular calcium and improve contractility but through entirely different pathways.


SECTION 13 - ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR (ARNI)
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The ARNI is sacubitril combined with valsartan, sold under the brand name Entresto. It combines two mechanisms in one drug. Valsartan is an ARB that blocks the AT1 receptor and prevents angiotensin II effects. Sacubitril inhibits the enzyme neprilysin, which normally breaks down natriuretic peptides like ANP and BNP, bradykinin, and angiotensin. By inhibiting neprilysin, levels of natriuretic peptides increase, which causes vasodilation, promotes sodium excretion in the urine (natriuresis), and reduces cardiac remodeling. The combined effect of blocking AT1 while simultaneously raising beneficial natriuretic peptides makes this drug more effective than ACE inhibitors or ARBs alone in reducing hospitalizations and mortality in heart failure with reduced ejection fraction. Current guidelines recommend replacing ACE inhibitors or ARBs with ARNI in eligible heart failure patients who can tolerate it.


SECTION 14 - ANTIHYPERTENSIVE DRUGS
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Hypertension is defined as persistently elevated blood pressure at or above 140/90 mmHg. In 85 to 90 percent of patients, no specific identifiable cause is found - this is called primary or essential hypertension. In the remaining 10 to 15 percent, a specific cause can be identified, such as renal artery stenosis or pheochromocytoma - this is called secondary hypertension.

Blood pressure is determined by cardiac output and peripheral vascular resistance. Antihypertensive drugs work by targeting one or both of these components through different mechanisms.

The four main classes of antihypertensive drugs are diuretics, beta-blockers, ACE inhibitors or ARBs, and calcium channel blockers.

Diuretics reduce blood volume, which reduces cardiac output and blood pressure. Thiazides like hydrochlorothiazide are the most commonly used antihypertensives in this class. Loop diuretics are used when there is associated heart failure or severe hypertension with fluid overload. Potassium-sparing diuretics are used as add-on therapy.

Beta-blockers reduce heart rate and cardiac output, lowering blood pressure. They are mild antihypertensives but are especially useful when the patient has both hypertension and angina, or hypertension and heart failure, or hypertension and arrhythmia, because they treat all these conditions simultaneously. Cardioselective beta-blockers like metoprolol and atenolol are the most widely used. Non-selective ones like propranolol are less preferred because of their side effects in asthma and diabetes. Drugs like carvedilol, labetalol, and nebivolol have both beta-blocking and vasodilating effects, making them particularly useful.

ACE inhibitors are first-line drugs for all grades of hypertension. They are especially preferred in patients with diabetes because they protect the kidney. They are used in heart failure, post-MI, and diabetic nephropathy. The main side effect remains dry cough, and angioedema is the serious rare reaction. ARBs are the alternative for patients who cannot tolerate ACE inhibitors.

Calcium channel blockers are divided into non-dihydropyridines (verapamil and diltiazem, which act mainly on the heart) and dihydropyridines (nifedipine, amlodipine, felodipine, which act mainly on blood vessels). For hypertension treatment, dihydropyridines are preferred because they cause arterial vasodilation with less effect on heart rate and conduction. They are safe in asthma and peripheral vascular disease because they have no beta-blocking effect.

Verapamil and nifedipine represent the contrast within calcium channel blockers. Verapamil acts strongly on the heart - it slows AV conduction, reduces heart rate, and decreases contractility (negative inotrope, chronotrope, and dromotrope). It also has some alpha-blocking activity. Nifedipine acts almost exclusively on vascular smooth muscle, causing powerful arterial vasodilation with minimal direct cardiac effect. Because nifedipine drops blood pressure rapidly, it causes reflex tachycardia. Verapamil must never be combined with beta-blockers as both slow the heart and combining them risks dangerous bradycardia and heart block. Verapamil is used for arrhythmias and angina, while nifedipine is used for hypertension and variant angina.

Centrally acting drugs include methyldopa (alpha-methyldopa), which is a prodrug that is converted to alpha-methyl noradrenaline in the brain. This acts as an alpha-2 agonist in the brainstem, reducing sympathetic outflow and lowering blood pressure. It is the drug of choice for hypertension in pregnancy because it has a long safety record and does not harm the fetus.

Aliskiren is a direct renin inhibitor. It inhibits the enzyme renin, which is the first step in the RAAS pathway - the conversion of angiotensinogen to angiotensin I. By acting at this earliest point in the cascade, it suppresses the entire RAAS pathway. It is the only drug in its class currently available.

Alpha-blockers like prazosin, terazosin, and doxazosin block alpha-1 receptors in blood vessels, causing vasodilation. Prazosin causes first-dose postural hypotension, so it is started at a very low dose (0.5mg) at bedtime. Non-selective alpha blockers are not used in chronic hypertension.

Sodium nitroprusside is a powerful vasodilator used exclusively in hypertensive emergencies. It releases nitric oxide spontaneously, which increases cGMP and relaxes both arterial and venous smooth muscle equally and powerfully. It works within seconds and stops within minutes when the infusion stops, making blood pressure perfectly controllable. It is given only as an IV infusion with continuous monitoring. Prolonged use carries a risk of cyanide toxicity.

Hydralazine and minoxidil are direct vasodilators that are not used as primary antihypertensives because they cause reflex tachycardia and fluid retention. They are used in resistant hypertension when other drugs have failed.

Antihypertensives to be avoided in pregnancy include ACE inhibitors, ARBs, and most diuretics. The drugs considered safer in pregnancy include methyldopa and hydralazine.


SECTION 15 - ANTIARRHYTHMIC DRUGS
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Arrhythmias are disturbances in the heart rate, rhythm, impulse generation, or conduction of electrical impulses. They arise from either abnormal automaticity, delayed after-depolarizations, or re-entry phenomena where an impulse circulates repeatedly in the heart causing repeated activation.

Understanding the phases of the cardiac action potential is important for understanding antiarrhythmics. Phase 0 is rapid depolarization caused by fast inflow of sodium ions. Phase 1 is partial repolarization as the sodium current deactivates and potassium flows out. Phase 2 is the plateau phase caused by slow inward calcium current - this is unique to cardiac muscle and explains why the heart has such a long refractory period compared to skeletal muscle. Phase 3 is full repolarization as calcium current inactivates and potassium flows out. Phase 4 is the pacemaker potential in automatic cells - slow sodium inflow and slowing of potassium outflow cause the cell to gradually depolarize until it fires again.

The Vaughan-Williams classification divides antiarrhythmic drugs into four classes based on their primary mechanism.

Class I drugs are sodium channel blockers. They reduce the rate of depolarization (slow phase 0) and make cells less excitable. Class I is divided into three subclasses. Class IA includes quinidine, procainamide, and disopyramide. These drugs block sodium channels and also block potassium channels, which prolongs the action potential duration (APD) and lengthens the refractory period. This can cause QT prolongation on the ECG, increasing the risk of dangerous arrhythmias like torsades de pointes. Quinidine is derived from cinchona bark and was the first antiarrhythmic drug. Its adverse effects include arrhythmias and heart block, hypotension from alpha-blocking activity, GI disturbances, thrombocytopenia, and at high doses a syndrome called cinchonism. Class IB includes lignocaine, mexiletine, and phenytoin. These block sodium channels but shorten the action potential duration because they also enhance potassium outflow. They preferentially affect diseased, ischemic, or rapidly firing tissue while sparing normal tissue. Lignocaine has high first-pass metabolism so it must be given parenterally. It is used for ventricular arrhythmias especially after myocardial infarction. Class IC includes flecainide, encainide, and propafenone. These are the most potent sodium channel blockers and have minimal effect on repolarization. However, they carry a risk of sudden cardiac death and ventricular fibrillation, so they are rarely used and reserved for severe resistant ventricular arrhythmias.

Class II drugs are beta-adrenergic blockers. They suppress adrenergically-mediated ectopic activity, depress automaticity and conduction velocity. Propranolol is used for supraventricular arrhythmias especially those triggered by exercise, emotion, or hyperthyroidism. Esmolol is a short-acting IV drug used for arrhythmias during surgery or after MI.

Class III drugs are potassium channel blockers. By blocking potassium channels, they increase the action potential duration and prolong the refractory period. Amiodarone is the most important drug in this class. It is a multi-action drug that blocks potassium channels, sodium channels, calcium channels, and also has beta-blocking activity. Its adverse effects are extensive - cardiac effects include heart block, bradycardia, and QT prolongation. Pulmonary toxicity causing pneumonitis and pulmonary fibrosis is the most dangerous and potentially fatal side effect. Thyroid problems occur because amiodarone contains iodine - it can cause both hypothyroidism and hyperthyroidism. Skin shows bluish-grey discoloration from iodine deposits. Hepatotoxicity and GI disturbances also occur. Despite all these side effects, amiodarone is widely used because it is one of the most effective antiarrhythmics for both supraventricular and ventricular tachycardias. Sotalol has both beta-blocking and K+ channel blocking effects. Dofetilide and ibutilide are selective K+ channel blockers used in atrial fibrillation.

Class IV drugs are calcium channel blockers, specifically verapamil and diltiazem. They inhibit inward calcium movement, reducing contractility, automaticity, and AV node conduction. Verapamil is used to terminate PSVT and to control ventricular rate in atrial flutter and fibrillation. An important interaction is that verapamil displaces digoxin from binding sites and reduces its renal clearance, raising digoxin levels and potentially causing digoxin toxicity.

Outside the four classes, adenosine is the drug of choice for PSVT. It acts on A1 adenosine receptors on the AV node, opening acetylcholine-sensitive potassium channels, which hyperpolarizes the cell and blocks conduction through the AV node. Since most PSVT involves a re-entry circuit through the AV node, this terminates the arrhythmia. Adenosine's half-life is approximately 10 seconds, making it extremely safe - any adverse effects resolve almost instantly. Digoxin is used for atrial fibrillation and flutter for rate control. Atropine is used for sinus bradycardia and AV block. Magnesium sulfate is used for digoxin-induced arrhythmias and torsades de pointes.


SECTION 16 - COAGULATION MODIFIER DRUGS
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Coagulation modifier drugs include anticoagulants, antiplatelet drugs, thrombolytics, and antifibrinolytics.

Anticoagulants prevent clot formation but have no direct effect on a clot that has already formed. They are used to prevent thrombus formation in conditions like deep vein thrombosis, pulmonary embolism, atrial fibrillation, mechanical heart valves, and to prevent stroke or MI.

Heparin is a large, negatively charged molecule that works by binding to antithrombin III, a natural anticoagulant protein already present in the blood. This binding causes a conformational change in antithrombin III that greatly accelerates its ability to inactivate thrombin and Factor Xa. Because antithrombin III already exists in the circulation, heparin's effect is immediate - it works within minutes of injection. Heparin is given parenterally, either by intravenous infusion or subcutaneous injection. It must never be mixed with any other medication. Its half-life is very short at 1 to 2 hours. The therapeutic effect is monitored by the activated partial thromboplastin time (aPTT), with a goal of 1.5 to 2.5 times the normal control value. The antidote for heparin overdose is protamine sulfate.

Low molecular weight heparins (LMWH) like enoxaparin (Lovenox) and dalteparin (Fragmin) are smaller, more uniform fragments of heparin. They preferentially inhibit Factor Xa rather than thrombin, and they bind fewer plasma proteins, giving a much more predictable anticoagulant response. This predictability means they do not require frequent laboratory monitoring with aPTT. They can be given subcutaneously once or twice daily and patients can administer them at home. Protamine sulfate can partially reverse LMWH in overdose.

Warfarin (Coumadin) is an oral anticoagulant that works by a completely different mechanism. Vitamin K is required for the carboxylation (activation) of clotting factors II, VII, IX, and X in the liver. Warfarin interferes with this process by blocking vitamin K-dependent production of these clotting proteins. It also reduces protein S and C levels. Because warfarin blocks synthesis of new clotting factors rather than inactivating existing ones, its effect is delayed - it takes 3 to 5 days for existing factors to be depleted through natural turnover. Factor VII has the shortest half-life (about 6 hours) so the PT/INR rises first, but full anticoagulation takes days. This is why when switching from heparin to warfarin, both drugs are given together for a few days - warfarin is typically started 2 to 3 days before heparin is discontinued. Warfarin is monitored by the International Normalized Ratio (INR), with a goal of 2 to 4 depending on the indication. The antidote is phytonadione (Vitamin K). Warfarin has many drug and food interactions. Foods high in vitamin K such as dark leafy green vegetables and tomatoes can reduce its effect.

The fundamental difference between heparin and warfarin is the route, mechanism, onset, monitoring, and antidote. Heparin is parenteral, acts immediately by activating antithrombin III, monitored by aPTT, and reversed by protamine sulfate. Warfarin is oral, acts with a delay by blocking synthesis of vitamin K-dependent factors, monitored by INR, and reversed by vitamin K. Heparin does not cross the placenta and is safe in pregnancy. Warfarin crosses the placenta, causes warfarin embryopathy in the first trimester, and is absolutely contraindicated in pregnancy.

Direct Oral Anticoagulants (DOACs) are newer drugs that directly inhibit specific clotting factors. Rivaroxaban, apixaban, and edoxaban inhibit Factor Xa directly. Dabigatran is a direct thrombin inhibitor. They do not require routine laboratory monitoring and are given orally with predictable effects.

Antiplatelet drugs prevent platelet aggregation. They are used for arterial thrombosis prevention, such as in myocardial infarction, stroke, and coronary stenting.

Aspirin irreversibly inhibits COX-1, the enzyme that produces thromboxane A2 in platelets. Thromboxane A2 normally promotes platelet aggregation and vasoconstriction. By permanently destroying COX-1, aspirin prevents thromboxane A2 production for the entire remaining life of the platelet (8 to 10 days). Since platelets have no nucleus and cannot synthesize new COX-1, a single low dose of aspirin provides sustained antiplatelet effect.

Clopidogrel, ticlopidine, prasugrel, and ticagrelor are P2Y12 receptor antagonists. They block the P2Y12 adenosine diphosphate (ADP) receptor on platelets. ADP is a powerful platelet activator released from activated platelets - by blocking its receptor, these drugs prevent platelet activation and aggregation. Clopidogrel and prasugrel are prodrugs requiring liver conversion to active metabolites. Ticagrelor is already active.

The difference between anticoagulants and antiplatelets is that anticoagulants work on the coagulation cascade to prevent fibrin formation, and are used for venous thrombi in conditions like DVT, PE, and AF. Antiplatelets work on platelets and are used for arterial thrombi in conditions like MI and atherosclerotic stroke.

Thrombolytic drugs break down clots that have already formed, unlike anticoagulants which only prevent new clot formation. They work by activating plasminogen and converting it to plasmin. Plasmin is a proteolytic enzyme that directly digests fibrin, the structural scaffold of a clot, dissolving it. Alteplase (tissue plasminogen activator, tPA) is clot-selective because it works best when bound to fibrin within a clot. Older drugs like streptokinase work systemically and are less specific. They are used in STEMI when PCI is not immediately available, in massive pulmonary embolism, and in acute ischemic stroke within 4.5 hours of symptom onset. The major and most feared risk is serious bleeding, especially intracranial hemorrhage.

Antifibrinolytic drugs like aminocaproic acid (Amicar) and tranexamic acid prevent fibrinolysis (dissolution of clots), thereby promoting clot stability. They are used to control excessive bleeding in conditions like surgical complications.


SECTION 17 - PHYSIOLOGY OF CARDIAC MUSCLE CONTRACTION
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Cardiac muscle contraction is triggered by the cardiac action potential. When the action potential arrives at the cardiomyocyte membrane, phase 0 depolarization causes L-type voltage-gated calcium channels (also called dihydropyridine receptors) to open. A relatively small amount of calcium flows into the cell from outside.

This initial calcium entry then triggers a much larger calcium release from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyR2). This process is called calcium-induced calcium release and it is unique to cardiac muscle. The massive rise in cytosolic calcium that results is what triggers contraction.

The elevated cytosolic calcium binds to troponin C, a component of the troponin complex on the actin thin filaments. This binding causes a conformational change in troponin I and troponin T, which shifts tropomyosin away from the myosin-binding sites on actin. With these sites now exposed, the myosin heads can attach to actin and form cross-bridges, and the power stroke of cross-bridge cycling pulls the actin filaments inward, shortening the sarcomere and producing contraction.

For relaxation to occur, calcium must be rapidly removed from the cytosol. It is pumped back into the sarcoplasmic reticulum by SERCA (SR Ca-ATPase) and is also extruded from the cell via the sodium-calcium exchanger and the sarcolemmal calcium pump. As cytosolic calcium falls, it dissociates from troponin C, tropomyosin moves back to block the myosin-binding sites, cross-bridges detach, and the muscle relaxes.

The amount of calcium in the SR, and therefore the force of contraction, depends on the balance of calcium entering the cell during each action potential and calcium leaving the cell during relaxation. Drugs that increase intracellular calcium (like digoxin, which reduces calcium extrusion via the Na-Ca exchanger) increase the force of contraction. Drugs that block L-type calcium channels (calcium channel blockers) reduce calcium entry and decrease contractility.


SECTION 18 - PREDICTED EXAM QUESTIONS AND ANSWERS
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The question "what is the after effect of digoxin?" is answered by saying that digoxin increases the force of contraction (positive inotropic effect) and decreases heart rate (negative chronotropic effect).

The question "what is the first-line treatment for heart failure?" is answered by ACE inhibitors given together with diuretics.

The question "what is the most common side effect of ACE inhibitors?" is answered by dry cough, caused by accumulation of bradykinin.

The question "if ACE inhibitors are contraindicated or not tolerated, what is the next alternative?" is answered by ARBs (losartan or valsartan), which provide the same benefits without causing dry cough.

The question "what is the difference between ARBs and ACE inhibitors?" is answered by explaining that ACE inhibitors block the enzyme ACE and raise bradykinin (causing cough), while ARBs block the AT1 receptor and do not affect bradykinin, so no cough.

The question "what is the difference between warfarin and heparin?" is answered by explaining the differences in route (oral vs parenteral), onset (delayed vs immediate), mechanism (blocks synthesis vs activates antithrombin III), monitoring (INR vs aPTT), and antidote (vitamin K vs protamine sulfate).

The question "what are the four classes of antiarrhythmic drugs?" is answered by sodium channel blockers (Class I), beta-blockers (Class II), potassium channel blockers (Class III), and calcium channel blockers (Class IV).

The question "what is the four classes of antihypertensives?" is answered by diuretics, beta-blockers, ACE inhibitors/ARBs, and calcium channel blockers.

The question "what is given to pregnant women for hypertension?" is answered by methyldopa (alpha-methyldopa).

The question "what is the direct renin inhibitor?" is answered by aliskiren.

The question "what is the most potent diuretic?" is answered by loop diuretics, with furosemide as the prototype.

The question "what are the potassium-sparing diuretics?" is answered by spironolactone, eplerenone, and amiloride.

The question "what is the first-line drug for acute angina?" is answered by sublingual nitroglycerin (GTN).

The question "what is the first-line drug for chronic stable angina?" is answered by beta-blockers.

The question "what is the drug of choice for variant angina?" is answered by calcium channel blockers (diltiazem or verapamil).

The question "why is sublingual route used for nitroglycerin?" is answered by explaining that oral GTN undergoes massive first-pass liver metabolism and essentially no drug survives to reach systemic circulation, while sublingual absorption bypasses the liver entirely, giving an onset within 1 to 3 minutes.

The question "what is the drug of choice for PSVT?" is answered by adenosine.

The question "what are the side effects of amiodarone?" is answered by pulmonary fibrosis, thyroid dysfunction (both hypo and hyper), bluish skin discoloration, hepatotoxicity, and cardiac effects like bradycardia and heart block.

The question "why can nitroglycerin not be combined with sildenafil?" is answered by explaining that both increase cGMP in vascular smooth muscle through different mechanisms - together they cause massive vasodilation and a potentially fatal drop in blood pressure.

The question "what is digoxin?" is answered by saying it is a cardiac glycoside derived from the Digitalis plant that increases force of contraction by inhibiting Na+-K+ ATPase, raising intracellular calcium.

The question "what is hypertension?" is answered by persistently elevated blood pressure at or above 140/90 mmHg. In 85-90% of cases no specific cause is found (essential hypertension).

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END OF NOTES
Compiled from: Drugs for Heart Failure, Anti-Hypertensive Drugs, Anti-Anginal & Anti-Arrhythmic Drugs, Coagulation Modifier Drugs PPTs by Professor G. Gurgenidze
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