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

2. 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

3. 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

4. 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)

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Summary: Drugs Used to Treat HF

14. 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

15. 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

16. 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

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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Summary: Drugs Used to Treat Hypertension

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. HMG CoA Reductase Inhibitors: MOA

36. 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

37. 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

38. 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

39. Summary: Drugs Used to Treat Hyperlipidemias

40. 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.

41. 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.

42. 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.

43. 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