Review on Cardiovascular System Disorder and Management Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa

Cardiovascular System Disorders Heart failure Hypertension Hyperlipidemias Arrhythmias Angina pectoris arrhythmia is a disorder of the heart rate or heart rhythm, such as beating too fast (tachycardia), too slow (bradycardia), or irregularly

Drugs Used to Treat Heart Failure Heart Failure (HF) A complex, progressive disorder, heart is unable to pump sufficient blood to meet the needs of the body HF is due to an impaired ability of the heart to adequately fill with and/or eject blood Drugs Used to Treat Heart Failure Renin-angiotensin System Blockers: ACE inhibitors: Captopril, Enalapril, Ramipril Angiotensin receptor blocker: Losartan, Valsartan β-Blockers: Atenolol, Metaprolol Diuretics: Furosemide Direct Vasodilators: Hydralazine Inotropic Agents: Digitoxin, Digoxin Aldesterone Antagonists: Spironolactone

Renin-Angiotensin System HF leads to activation of the renin-angiotensin system Production of angiotensin II, a potent vasoconstrictor and the subsequent stimulation of aldosterone release are the cause of HF High levels of angiotensin II and aldosterone have direct detrimental effects on the cardiac muscle ACE Inhibitors An agents of choice in HF Block the enzyme that cleaves angiotensin I to form angiotensin II By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone (ACE)

ACE Inhibitors: Action on the Heart Decrease vascular resistance, and blood pressure, resulting in an increased cardiac output The use of ACE inhibitors in the treatment of HF has significantly decreased both morbidity and mortality

ACE Inhibitors: Pharmacokinetics Adequately but incompletely absorbed following oral administration The presence of food may decrease absorption, so they should be taken on an empty stomach Except for captopril, ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes Eliminated through urine ACE Inhibitors: Adverse Effects Postural hypotension, renal insufficiency, hyperkalemia, and a persistent dry cough ACE inhibitors should not be used in pregnant women, because they are fetotoxic

Angiotensin Receptor Blockers (ARB) ARBs are nonpeptide, orally active compounds that are extremely potent competitive antagonists of the angiotensin type 1 receptor Have the advantage of more complete blockade of angiotensin action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II

ARBs: Pharmacokinetics Orally active and require only once-a-day dosing Losartan, the first approved member of the class, differs from the others in that it undergoes extensive first-pass hepatic metabolism, including conversion to its active metabolite. The other drugs have inactive metabolites Elimination occurs in the urine and feces ARBs: Adverse Effects Adverse effect profile similar to that of ACE inhibitors ARBs are contraindicated in pregnancy

Direct Vasodilators Dilation of venous blood vessels leads to a decrease in cardiac preload by increasing the venous capacitance; arterial dilators reduce systemic arteriolar resistance and decrease afterload These drugs are used if the patient is intolerant of ACE inhibitors or β-blockers

Inotropic Drugs Digitalis Positive inotropic agents enhance cardiac muscle contractility and, thus, increase cardiac output Inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of cardiac muscle Digitalis The cardiac glycosides are often called digitalis They can increase the contractility of the heart muscle and, therefore, are widely used in treating HF Influence the sodium and calcium ion flows in the cardiac muscle, thereby increasing contraction of the atrial and ventricular myocardium

Digitalis: Adverse Effects Digitalis: Pharmacokinetics All digitalis possess the same pharmacologic actions, but they vary in potency and pharmacokinetics Very potent, with a long half-life of around 36 hrs Eliminated intact by the kidney Digitalis: Adverse Effects Digoxin levels must be closely monitored in the presence of renal insufficiency, and dosage adjustment may be necessary Common side effects are arrhythmia, anorexia, nausea, and vomiting Headache, fatigue, confusion, and blurred vision

Aldosterone Antagonists Patients with advanced heart disease have elevated levels of aldosterone due to angiotensin II stimulation and reduced hepatic clearance of the hormone Spironolactone is a direct antagonist of aldosterone, thereby preventing salt retention, myocardial hypertrophy, and hypokalemia Adverse effects: gastric disturbances, such as gastritis and peptic ulcer CNS effects, such as confusion endocrine abnormalities, such as gynecomastia Cardiac hypertrophy is a thickening of the heart muscle

Summary: Drugs Used to Treat HF

Hypertension Defined as either a sustained systolic blood pressure of greater than 140 mm Hg or a sustained diastolic blood pressure of greater than 90 mm Hg Results from increased peripheral vascular smooth muscle tone, which leads to increased arteriolar resistance and reduced capacitance of the venous system Chronic hypertension can lead to strokes, congestive heart failure, myocardial infarction, and renal damage

Etiology of Hypertension A family history of hypertension increases the likelihood that an individual will develop hypertensive disease Occurs more often among middle-aged males than among middle-aged females, and its prevalence increases with age and obesity Environmental factors, such as a stressful lifestyle, high dietary intake of sodium, and smoking are also responsible for the occurrence of hypertension

Hypertension: Treatment Strategy The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality The relationship between blood pressure and the risk of a cardiovascular event is continuous, and thus lowering of even moderately elevated blood pressure significantly reduces cardiovascular disease Mild hypertension can often be controlled with a single drug; however, most patients require more than one drug to achieve blood pressure control

Drugs Used to Treat Hypertension Diuretics β-Blockers ACE Inhibitors Angiotension β-Receptor Blockers Renin Inhibitors Calcium Channel Blockers

Hypertension: Diuretic Drugs Used as first-line drug therapy for hypertension unless there are compelling reasons to choose another agent Diuretic therapy is safe, inexpensive, and effective in preventing stroke, myocardial infarction, and congestive heart failure, all of which can cause mortality Classification of diuretic class of drugs: Thiazide diuretics Loop diuretics Potassium-sparing diuretics

Thiazide Diuretics: Action Thiazide diuretics, such as hydrochlorothiazide , lower blood pressure initially by increasing sodium and water excretion This causes a decrease in extracellular volume, resulting in a decrease in cardiac output and renal blood flow Thiazide Diuretics: Therapeutic Uses Decrease blood pressure Useful in combination therapy with a variety of other antihypertensive agents, including β-blockers, ACE inhibitors, and angiotensin-receptor blockers Not effective in patients with inadequate kidney function

Thiazide Diuretics: Pharmacokinetics Orally active All thiazides are ligands for the organic acid secretory system of the nephron, and as such, they may compete with uric acid for elimination Thiazide Diuretics: Adverse Effects Induce hypokalemia, and hyperglycemia

Potassium-sparing Diuretics Loop Diuretics The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics Loop diuretics cause decreased renal vascular resistance and increased renal blood flow Potassium-sparing Diuretics Amiloride as well as spironolactone reduce potassium loss in the urine Spironolactone has the additional benefit of diminishing the cardiac remodeling that occurs in heart failure

β-Adrenoceptors Blocking Agents Currently recommended as first-line drug therapy for hypertension when concomitant disease is present, e.g., with heart failure Reduce blood pressure by decreasing cardiac output Therapeutic Uses More effective for treating hypertension in white than in black patients and in young compared to elderly patients Useful in treating conditions that may coexist with hypertension, such as previous myocardial infarction, chronic heart failure, and migraine headache

β-Adrenoceptors Blocking Agents: Pharmacokinetics Orally active Propranolol undergoes extensive and highly variable first-pass metabolism May take several weeks to develop their full effects Adverse Effects Cause bradycardia and CNS side effects Disturb lipid metabolism, decreasing high-density lipoprotein cholesterol and increasing plasma triacylglycerol Abrupt withdrawal induce myocardial infarction, or even sudden death in patients with ischemic heart disease

ACE Inhibitors: Actions Block the ACE that cleaves angiotensin I to form the angiotensin II Decrease angiotensin II By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention ACE Inhibitors: Adverse Effects Common side effects include dry cough, rash, fever Fetotoxic and should not be used by pregnant women

Ranin Inhibitors A selective renin inhibitor, aliskiren has been used for the treatment of hypertension It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides May combine with other antihypertensives, such as diuretics, ACE inhibitors, or calcium-channel blockers

Calcium-Channel Blockers Recommended when the preferred first-line agents are ineffective Effective in treating hypertension in patients with diabetes Classes of calcium channel blockers: Diphenylalkylamines Benzothiazepines Dihydropyridines Therapeutic Use Useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease

Calcium-Channel Blockers: Pharmacokinetics Short half-lives (3 to 8 hours) following an oral dose Treatment is required three times a day to maintain good control of hypertension Sustained-release preparations are available Adverse Effects Constipation occurs in 10 percent of patients treated with verapamil Dizziness, headache, and fatigue with dihydropyridines Verapamil should be avoided in patients with congestive heart failure

Summary: Drugs Used to Treat Hypertension

Hyperlipidemias Coronary heart disease (CHD) is a major cause of deaths CHD is correlated with elevated levels of LDL cholesterol and triacylglycerols and with low levels of HDL cholesterol Other risk factors for CHD include cigarette smoking, hypertension, obesity, and diabetes Cholesterol levels may be elevated as a result of an individual's lifestyle Hyperlipidemias can also result from a single inherited gene defect in lipoprotein metabolism or from a combination of genetic and lifestyle factors

Hyperlipidemias: Treatment Goals Appropriate lifestyle changes in combination with drug therapy can lead to a decline in the progression of CHD The occurrence of CHD is positively associated with high total cholesterol, with elevated LDL cholesterol in the blood High levels of HDL cholesterol have been associated with a decreased risk for heart disease, whereas, reduction of the LDL level is the primary goal of cholesterol-lowering therapy Hyperlipidemias: Treatment Options Treatment options for Hypercholesterolemia hypertriacylglycerolemia

Hypercholesterolemia: Treatment Options In patients with moderate hyperlipidemia, lifestyle changes, such as diet, exercise, and weight reduction, can lead to modest decreases in LDL levels and increases in HDL levels Patients with LDL levels higher than 160 mg/dL and with one other risk factor, such as hypertension, diabetes, smoking, or a family history of early CHD, are candidates for drug therapy Patients with two or more additional risk factors should be treated aggressively, with the aim of reducing their LDL level to less than 100 mg/dL

Hypertriacylglycerolemia: Treatment Options Elevated triacylglycerol (triglyceride) levels are independently associated with increased risk of CHD Diet and exercise are the primary modes of treating hypertriacylglycerolemia If indicated, niacin and fibric acid derivatives are the most efficacious in lowering triacylglycerol levels

Treatments of Hyperlipidemia Strategies: decrease production of the lipoprotein carriers increase the degradation of lipoprotein decrease cholesterol absorption increase cholesterol removal from the body Drugs: HMG CoA reductase inhibitors Niacin The fibrates Bile acid binding resins Cholesterol absorption inhibitors

HMG CoA Reductase Inhibitors: MOA 3-Hydroxy-3-methylglutaryl (HMG) coenzyme A (COA) reductase inhibitors (commonly known as statins) lower elevated LDL cholesterol levels Inhibition of HMG CoA reductase: Analogs of HMG, the precursor of cholesterol Because of their affinity for the enzyme, they inhibit HMG CoA reductase, the rate-limiting step in cholesterol synthesis Increase in LDL receptors: Depletion of intracellular cholesterol causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs End result is a reduction in cholesterol, both by lowered cholesterol synthesis and by increased catabolism of LDL

HMG CoA Reductase Inhibitors: MOA

HMG CoA Reductase Inhibitors: Pharmacokinetics Pravastatin and fluvastatin are absorbed after oral administration; oral doses of lovastatin and simvastatin are from 30 to 50 percent absorbed Pravastatin and fluvastatin are active as such, whereas lovastatin and simvastatin hydrolyzed to their acid forms Primary action of these drugs is on the liver Excretion takes place principally through the bile and feces, but some urinary elimination also occurs Half-lives range from 1.5 to 2 hours HMG CoA Reductase Inhibitors: Adverse Effects Biochemical abnormalities in liver function Contraindicated during pregnancy and in nursing mothers

Niacin Mechanism of Actions Reduce LDL levels by 10 to 20 percent and is the most effective agent for increasing HDL levels Used in combination with statins Mechanism of Actions Inhibits lipolysis in adipose tissue Liver utilizes fatty acids as a major precursor for triacylglycerol synthesis Niacin causes a decrease in liver triacylglycerol synthesis, which is required for VLDL, and eventually LDL production

Niacin: Therapeutic Uses Lowers plasma both cholesterol and triacylglycerol Used to treat other severe hypercholesterolemias, often in combination with other antihyperlipidemic agents Most potent antihyperlipidemic agent for raising plasma HDL levels Niacin: Pharmacokinetics Administered orally Converted in the body to nicotinamide Niacin, and its metabolites are excreted in the urine Niacin: Adverse Effects Side effects include intense cutaneous flush, nausea, abdominal pain, hepatotoxicity

Summary: Drugs Used to Treat Hyperlipidemias

Study Questions A 58-year-old man is admitted to the hospital with acute heart failure and pulmonary edema. Which one of the following drugs would be most useful in treating the pulmonary edema? A. Digoxin. B. Dobutamine. C. Furosemide. D. Minoxidil. E. Spironolactone Correct answer = C. Furosemide has the ability to dilate vessels in the context of acute HF. It also mobilizes the edematous fluid and promotes its excretion. Dobutamine increases contractility but does not appreciably improve pulmonary edema. Digoxin acts too slowly and has no vasodilating effects. Minoxidil decreases arterial pressure and causes reflex tachycardia. Spironolactone does not alleviate acute pulmonary edema.

A 46-year-old man is admitted to the emergency department A 46-year-old man is admitted to the emergency department. He has taken more than 90 digoxin tablets (0.25 mg each), ingesting them about 3 hours before admission. His pulse is 50 to 60 beats per minute, and the electrocardiogram shows third-degree heart block. Which one of the following is the most important therapy to initiate in this patient? A. Digoxin immune Fab. B. Potassium salts. C. Lidocaine. D. Phenytoin. E. DC cardioversion Correct answer = A. In the severely poisoned patient, reduction of digoxin plasma concentrations is paramount and can be accomplished with administration of antidigoxin antibodies. Potassium concentrations, if low, can be increased, but not much greater than 4 mM. Antiarrhythmics are useful if there is need, but not in this case. DC cardioversion is used only if ventricular fibrillation occurs.

A 45-year-old man has recently been diagnosed with hypertension and started on monotherapy designed to reduce peripheral resistance and prevent NaCl and water retention. He has developed a persistent cough. Which of the following drugs would have the same benefits but would not cause cough? A. Losartan. B. Nifedipine. C. Prazosin. D. Propranolol. Correct answer = C. The cough is an adverse effect of an ACE inhibitor. Losartan is an ARB that will have the same beneficial effects as an ACE inhibitor but will not produce a cough. The other drugs also do not cause this side effect.

A 48-year-old hypertensive patient has been successfully treated with a thiazide diuretic for the last 5 years. Over the last 3 months, his diastolic pressure has steadily increased, and he has been started on an additional antihypertensive medication. He complains of several instances of being unable to achieve an erection and that he is no longer able to complete three sets of tennis. The second antihypertensive medication is most likely which one of the following? A. Captopril. B. Losartan. C. Minoxidil. D. Metoprolol. E. Nifedipine. Correct answer = C. The side effect profile of β-blockers, such as metoprolol, are characterized by interference with sexual performance and decreased exercise tolerance. None of the other drugs is likely to produce this combination of side effects