DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM

A brief on drugs acting on the respiratory system

1. DRUGS ACTING ON THE CARDIOVASCULAR SYSTEM

2. INTRODUCTION CARDIOVASCULAR SYSTEM The cardiovascular system involves the heart and vessels (arteries, capillaries and veins) which work intricately to provide adequate blood flow to all parts of the body. The blood vessels are critical because they control the amount of blood flow to specific parts of the body. The arteries carry blood from the heart and can divide into large arteries and smaller arterioles which account for most of the resistance in pulmonary circulation because they are more rigid than larger arteries. The capillaries branch off of arterioles and are a single-layer cell which allows for exchange of nutrients in tissue and organs. The veins have valves which prevent backflow of blood. Pulmonary circulation allows for oxygenation of the blood and systemic circulation provides for oxygenated blood and nutrients to reach the rest of the body.

3. DEFINITION OF HYPERTENSION AND ITS CRITERIA Hypertension is defined as either a sustained systolic blood pressure of greater than >140mmHg or a sustained diastolic blood pressure of greater than >90mmHg. Hypertension results from increased peripheral vascular arteriolar smooth muscle tone which leads to increased arteriolar resistance and reduced capacitance of venous system. Classification and stages of hypertension, as defined in recent American College of Cardiology (ACC) guidelines are: Normal: SBP less than 120 and DBP less than 80 mm Hg; Elevated: SBP 120 to 129 and DBP less than 80 mm Hg; Stage 1 hypertension: SBP 130 to 139 or DBP 80 to 89 mm Hg; Stage 2 hypertension: SBP greater than or equal to 140 mm Hg or DBP greater than or equal to 90 mm Hg. SBP= Systolic Blood Pressure DBP= Diastolic Blood Pressure

4. Additional types of Hypertension: White coat hypertension :  an hospital BP of 130/80 mm Hg or more but less than 160/100 mm Hg, which comes down to 130/80 mm Hg or less after at least 3 months of anti-hypertensive therapy ( Ambulatory or home blood pressure measurement is usually necessary for this diagnosis ). Masked hypertension : an elevated office systolic BP of 120 to 129 mm Hg and diastolic BP of less than 80 mm Hg but raised BP on ambulatory or home measurements (130/80 mm Hg or more

5. ANGINA Angina pectoris is a clinical syndrome of precordial discomfort or pressure due to transient myocardial ischemia without infarction. Types: Stable angina : Pain lasts a few minutes and occurs in a pattern, such as during exercise or stress. Rest or medicine relieves the pain. 2. Unstable angina : Pain can be stronger or last longer than stable angina and does not follow a pattern. Unstable angina is a medical emergency.  3. Prinzmetal , variant, vasospastic or rest-angina Prinzmetal angina is an uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm

6. ISCHAEMIC HEART DISEASE Ischemic heart disease, also called coronary heart disease (CHD) or coronary artery disease, is the term given to heart problems caused by narrowed heart (coronary) arteries that supply blood to the heart muscle. Although the narrowing can be caused by a blood clot or by constriction of the blood vessel, most often it is caused by buildup of plaque, called atherosclerosis. When the blood flow to the heart muscle is completely blocked, the heart muscle cells die, which is termed a heart attack or myocardial infarction (MI).

7. ANTIHYPERTENSIVE DRUGS

8. Diuretics are drugs which cause a net loss of Na+ and water in urine. This lowers the amount of fluid flowing through the veins and arteries. As a result, blood pressure goes down. Types of diuretics include: Thiazide diuretics : Examples include; Hydrochlorothiazide, chlorthalidone, Indapamide. Mechanism of Action of Thiazide Diuretics : They act on distal convoluted tubule of nephron to decrease the reabsorption of Na+ by inhibition of Na+/cl- cotransporters. Thiazide diuretics also increase potassium and water excretion. They decrease calcium excretion. They are the first line of drug for uncomplicated hypertension. Pharmacokinetics of Thiazide Diuretics Absorption : Thiazide diuretics are administered orally because they are absorbed well except chlorothiazide (IV). Distribution : Thiazides bind to the plasma protein & are transported through out the body. Their action starts within 1 to 2 hours of administration & their peak diuretic effect reaches within 8 to 48 hours. Metabolism: Thiazide type of drugs undergoes little or no biotransformation in the body. Excretion: They are excreted unchanged by the kidney. Side effects : hypokalemia, Metabolic alkalosis, hypovolemia, hyponatremia, hyperuricemia. DIURETICS

9. b. Loop diuretics : Examples include; Furosemide, Torsemide, Bumetanide. Mechanism of Action of Loop Diuretics : Loop diuretics inhibit the cotransport of Na+/K+/2Cl- in the luminal membrane of the ascending loop of Henle. Therefore, reabsorption of these ions into the renal medulla is decreased. Pharmacokinetics of Loop Diuretics Absorption : Loop diuretics are most commonly administered orally. They are also given intravenously for rapid effects such in such disorders as acute pulmonary edema. Distribution : Peak effect < 1 hr (30 min i.v. ) Bind strongly to albumin (it reaches its site of action via PCT excretion) Metabolism : Loop diuretics are not extensively metabolized in the liver. They undergo minimal hepatic metabolism, and most of the drug is excreted unchanged in the urine. Excretion : unchanged in kidney or by conjugation in the liver and secretion in bile. Side effects: Hypokalemia, hyponatremia, metabolic alkalosis, acute hypovolemia, hyperuricemia.

10. c. Potassium K+ sparing diuretics : Examples include; Spironolactone, eplerenone, amiloride, triamterene. Mechanism of Action : K+ sparing diuretics blocks the binding of aldosterone to it’s receptor. This prevents translocation of the receptor complex into the nucleus of the target cell, ultimately resulting in a lack of intracellular proteins that stimulates the Na+/K+ exchange sites of the collecting tubule. Thus aldosterone antagonist prevents Na+ reabsorption and, therefore, K+ and H+ secretion. Pharmacokinetics of Potassium K+ sparing Diuretics : Absorption : Potassium-sparing diuretics are generally well-absorbed after oral administration. The absorption can be influenced by food, and they are usually taken with meals. Distribution : These drugs are distributed throughout the body, and they can affect sodium and potassium transport in the renal tubules. Metabolism : Potassium-sparing diuretics may undergo some metabolism, but the primary focus is on their effects on renal ion transport rather than extensive metabolic changes. Elimination : The primary route of elimination is through the kidneys. These diuretics work by inhibiting sodium reabsorption in the distal tubules and collecting ducts while sparing potassium. Side effects: hyperkalemia, Gynecomastia.

11. BETA BLOCKERS: Mechanism of Action : Blocks sympathetic function on the heart by blocking beta 1 receptors on the heart. This prevents sympathetic catecholamines from binding to beta 1 receptor. This causes decrease in heart rate, cardiac output and blood pressure. Pharmacokinetics of Beta Blockers Absorption : Most of the drugs are absorbed well orally, peak concentrations occur 1-3 hours after ingestion. Distribution : Bioavailability of most p-blockers is limited. Rapidly distributed. Metabolism : Some like Propranolol and Pindolol are lipophilic and readily cross the blood-brain barrier. Most of them have half-lives in the range of 3-10 hours. Excretion : The most lipophilic beta-blockers are almost completely metabolized in the liver, whereas those of lower lipophilicity are mainly excreted via the kidneys. Side effects : Bradycardia, fatigue, hypotension, decreased libido, impotence, bronchoconstriction. Contraindication : Obstructive lung disease, peripheral vascular disease.

12. ANGIOTENSIN CONVERTING ENZYME INHIBITORS Examples include; Captopril, Enalapril, Ramipril, Lisinopril, Fosinopril . They block angiotensin converting enzyme from converting Angiotensin I to Angiotensin II. Pharmacokinetics of ACE Inhibitors Absorption : Oral bioavailability: variable (enalapril 95%, benazepril 40%) Distribution : Distribution in peripheral tissues (most compounds do not cross the blood-brain barrier) Metabolism : All compounds that are prodrugs are transformed by the liver into active metabolites. Half-lives are variable (captopril. 2 hours: benazepril. 20 hours) Excretion : Excreted by the kidney. Side effects : Dry cough, rash, nausea, vomiting, diarrhea, angiodema , headache. Contraindications : Pregnancy, asthma, chronic cough, allergy, kidney disease(renal stenosis).

13. ANGIOTENSIN RECEPTOR BLOCKERS : Mechanism of Action: blocks the binding of Angiotensin II to its receptor. Pharmacokinetics of Angiotensin Receptor Blockers Absorption : ARBs are well absorbed after oral administration except Enalaprilat(IV). Distribution : They have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60–80% for irbesartan); food does not influence the bioavailability, except for valsartan. Metabolism : All of the ARBs, except for telmisartan and olmesartan , are metabolized in some way by the cytochrome P450 enzyme, in the liver. Excretion : Excreted by the kidney. Side effects: Headache, nausea, diarroea , dizziness, back pain. Contraindication : Pregnancy, renal stenosis

14. RENIN INHIBITORS   Mechanism of Action of Renin : Renin is the enzyme responsible for conversion of Angiotensinogen to Angiotensin. Its secretion is stimulated by the response of baroreceptors in the kidney to reduced arterial pressure (and to sympathetic stimulation of β1-adrenoceptors) and by greater sodium loss. This pathway will produce Angiotensin II which increases blood pressure through various ways.   Renin Inhibitor : Acts by directly inhibiting renin and, thus, acts earlier in the renin- angiotensin–aldosterone system than ACE inhibitors or ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. An approved Renin inhibitor is Aliskiren . Aliskiren is metabolized by CYP3A4 which can result in drug-drug interaction Contraindications : Aliskiren should not be routinely combined with an ACE inhibitor or ARB. Aliskiren is contraindicated during pregnancy (it is teratogenic )   Adverse effects; Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough and angioedema .

15. ALPHA BLOCKERS Mechanism of Action : α blockers such as Prazosin, terazosin and doxazosin produce their antihypertensive effects by selectively blocking α1 receptors in arterioles and venules. Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. They are more effective when used in combination with beta blockers and a diuretic, than when used alone. α1 selective blockers are not the first line antihypertensive. Α 1 receptors causes vasoconstriction which increases both systemic and arterial blood pressure Antagonists will cause vasodilation by preventing binding of catecholamines . Metabolism : They are extensively metabolized in the liver. Terazosin undergoes very little first-pass metabolism and Doxazosin has an intermediate bioavailabity . Adverse effects : Retention of salt and water when used without a diuretic, dizziness, palpitations, headache

16. CALCIUM CHANNEL BLOCKERS Mechanism of Action : The L-type voltage gated calcium channel is the dominant form in cardiac and smooth muscle. The subunits are α1, α2, β, γ and δ. The binding of calcium antagonists are allosterically specific. Binding of the CCB’s to these calcium channels reduces the frequency of opening in response to depolarization. Since they are competitive blockers, the block can be reversed by increasing transmembrane flux of calcium. CCB can be duhydropyridines and nondihydropyridines . This channels are found in the heart, smooth muscles and pancreas Metabolism : Orally active with high first pass effect by the liver Adverse effect : Cardiac depression especially when used with beta blockers Apart from hypertension its also used clinically in: Supraventricular tachycardia (SVT) Hypertrophic cardiomyopathy Migraine Raynaud's phenomenon

17. ANTI -ANGINA DRUGS

18. Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms. It is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium, leading to ischemia. The imbalance between oxygen delivery and utilization may result during exertion, from a spasm of the vascular smooth muscle, or from obstruction of blood vessels caused by atherosclerotic lesions Angina pectoris has three overlapping patterns: 1) effort-induced, stable, classical, or typical angina; 2) unstable angina; and 3) Prinzmetal , variant, vasospastic, or rest angina ANGINA PECTORIS

19. Classical/stable angina: due to fixed obstruction, blood supply cannot increase, the heart becomes vulnerable to ischemia whenever there is increased demand, such as in physical activity. It can be relieved by rest. Unstable angina: Any episode of rest angina longer than 20 minutes, any new onset of angina, any increasing (crescendo) angina, and even sudden development of shortness of breath, is suggestive of unstable angina. Prinzmetal , variant, vasospastic or rest-angina Prinzmetal angina is an uncommon pattern of episodic angina that occurs at rest and is due to coronary artery spasm

20. CLASSES OF DRUGS USED Drugs used includes: Organic Nitrates Beta-Adrenergic Blockers Calcium Channel Blockers Others include; Sodium channel blockers

21. These agents cause a rapid decrease in myocardial oxygen demand leading to rapid resolution of symptoms. Nitrates are effective for all types of angina. MECHANISM OF ACTION : Nitrates inhibit coronary vasoconstriction or spasm, increasing perfusion of the myocardium and, thus, relieving vasospastic angina. In addition, nitrates relax the veins ( venodilation ), decreasing preload and myocardial oxygen consumption. Because of this action, nitrates are effective in treating effort-induced angina (classic angina). ORGANIC NITRATES

22. The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates ( eg , nitroglycerin and isosorbide dinitrate) is low. For this reason, the sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate both are absorbed efficiently by this route and reach therapeutic blood levels within a few minutes. PHARMACOKINETICS

23. The most common side effect of nitrates is headache due to veno -dilation, patients whom intermittently used nitrate preparation should be asked about headaches after nitrate use; lack of headache often indicates degradation of agent with a loss of therapeutic effect. Others includes postural hypotension and syncope, tachycardia ADVERSE EFFECT

24. BETA-ADRENERGIC BLOCKERS β-Blockers decrease O2 demands of the myocardium by lowering the heart rate and contractility (decrease CO) particularly the increased demand associated with exercise. They also reduce pulmonary vascular resistance (PVR) by direct vasodilation of both arterial & venous vessels reducing both pre- and after load. These effects are caused by blocking β1 receptors, selective β1 antagonists (atenolol, metoprolol and acebutolol) lose their selectivity at high doses and at least partially block β2 receptors (a concern for bronchospastic disease). β1 antagonists reduce the frequency and severity of anginal episodes particularly when used in combination with nitrates.

25. Non selective beta blockers are contraindicated in Asthma, severe bradycardia Selective beta blockers is used in patients with diabetes, peripheral vascular disease and chronic obstructive pulmonary disease but they are monitored closely Should not be withdrawn suddenly as it can cause rebound angina, hypertension and myocardial infarction

26. CALCIUM CHANNEL BLOCKERS Calcium is essential for muscular contraction. Calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. In turn, this promotes the activity of several adenosine triphosphate– consuming enzymes, thereby depleting energy stores and worsening the ischemia. The calcium-channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds. All calcium-channel blockers are, therefore, arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular resistance.

27. They can be divided into Dihydropyridine and N ondihydropyridine Dihydropyridine s include; Amlodipine and Nifedipine, and they are arteriolar vasodilators. Amlodipine is useful in the treatment of variant angina caused by spontaneous coronary spasm. Nondihydropyrindines such as Verapamil and Diltiazem slows AV conduction and decreases heart rate, contractility, blood pressure and oxygen demand. Contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities It is administered orally and undergoes hepatic metabolism to products that are eliminated in both urine and feces. ADR of nifedipine includes flushing, headache, hypotension and peripheral edema.

28. ISCHAEMIC HEART DISEASE

29. Ischemia is defined as inadequate blood supply (circulation) to a local area due to blockage of the blood vessels supplying the area. Ischemi a means that an organ (e.g., the heart) is not getting enough blood and oxygen. Ischemic heart disease, also called coronary heart disease (CHD) or coronary artery disease, is the term given to heart problems caused by narrowed heart (coronary) arteries that supply blood to the heart muscle. The n arrowing can be caused by a blood clot or by constriction of the blood vessel, most often it is caused by buildup of plaque, called atherosclerosis. When the blood flow to the heart muscle is completely blocked, the heart muscle cells die, which is termed a heart attack or myocardial infarction (MI).

30. CALCIUM CHANNEL BLOCKERS Verapamil, diltiazem Amlodipine, felodipine, isradipine , nicardipine, nifedipine, nisoldipine Mechanism of Action: They act by inhibiting calcium influx into arterial smooth muscle cells. Verapamil is a cardio depressant. Relaxation of vascular smooth muscles Verapamil inhibits insulin release Verapamil has been shown to reverse resistance to cancer chemotherapy.

31. Role of renin, angiotensin and aldosterone: Renin is secreted as a result of reduced renal arterial pressure, sympathetic neural stimulation and reduced sodium delivery or increased sodium concentration at the distal renal tubule. Angiotensinogen is the substrate for renin and produces angiotensin I This is converted by ACE to angiotensin II This is converted in the adrenal gland to angiotensin III which both stimulate aldosterone release.

32. RENIN ANGIOTENSIN SYSTEM Three classes of drugs act on this system: ACE inhibitors: - Captopril: inhibits peptidyl dipeptidase; Inhibits the renin-angiotensin system and stimulates the kallikrein-kinin system Enalapril is converted to its active metabolite analaprilat by hepatic hydrolysis Benazepril, fosinopril , moexipril , perindopril These drugs are particularly useful in patients with compromise of renal function They are part of the mainstay of the treatment of cardiac failure They may reduce the incidence of diabetes in patients with high cardiovascular risk

33. Captopril, Enalapril, Benazepril, foisnopril , moexipril , perindopril, quinapril, ramipril: They inhibit peptidyl dipeptidase that hydrolyses angiotensin I to II They also inactivate bradykinin The ACE inhibitors diminish proteinuria, useful in heart failure, useful in MI, ADR: severe hypotension, acute renal failure, hyperkalaemia , dry cough and angioedema Contraindicated in pregnancy NSAIDS may impair the effects of ACE inhibitors

34. PERIPHERAL ARTERY DISEASE Peripheral artery disease, or PAD, is an accumulation of plaque (fats and cholesterol) in the arteries in your legs or arms. There are drugs used in treatment of Peripheral artery disease: 1. Clopidogel 2. Aspirin

35. CLOPIDOGEL Absorption : Clopidogrel is orally administered and absorbed in the gastrointestinal tract. It’s a prodrug and needs hepatic activation for its antiplatelet effects. In the liver, specifically through the cytochrome P450 system, especially the CYP2C19 isoenzyme, clopidogrel undergoes a two-step process to become an active metabolite. Distribution : Once activated, the active metabolite circulates in the bloodstream and binds to platelets throughout the body. Metabolism : The active metabolite is further metabolized, and both the parent compound and its metabolites are eliminated mainly through the liver and excreted in the urine and feces. Elimination : The elimination half-life of clopidogrel is relatively short, but its irreversible inhibition of platelet function persists for the lifespan of the platelet, which is around 7-10 days. Common side effects of clopidogrel may include gastrointestinal issues like abdominal pain or diarrhea.

36. ASPIRIN Aspirin’s mechanism of action as an antiplatelet agent involves its ability to inhibit the formation of thromboxane A2, a molecule that plays a crucial role in platelet activation and blood clot formation. PHARMACOKINETICS : Absorption : Rapidly absorbed in the stomach and small intestine. Metabolism : Metabolized in the liver to salicylate, its active form . Distribution: Widely distributed in body tissues, including the central nervous system. Elimination: Excreted primarily through the kidneys. Half-life: Relatively short half-life, but its irreversible inhibition of platelets persists for the lifespan of platelets (about 7-10 days). Common side effects of aspirin may include gastrointestinal issues like stomach upset or heartburn. Less frequently, individuals may experience nausea, vomiting, or allergic reactions.

37. QUESTIONS 1. Which antihypertensive medication can cause the rare side effects of angioedema? A. Amlodipine B.Fosinopril C.Praxosin D.Propanol 2. Which is contraindicated in a patient with hyperkalemia? A. Acetazolamide B. Chlorothiazide C. Ethacrynic acid D. Eplerenone

38. 3. Which of the following correctly outlines a major difference in electrolyte disturbance associated with Thiazide and Loop diuretics? A. Thiazide diuretics decrease potassium and loop diuretics increase potassium B. Thiazide diuretics increase potassium and loop diuretics decrease potassium C. Thiazide diuretics decrease calcium and loop diuretics increase calcium D. Thiazide diuretics increase calcium and loop diuretics decrease calcium 4. A 45year old man was started on therapy for hypertension and developed a persistent dry cough, which is most likely responsible for the side effects? A. Lisinopril B.Losartan C.Nifedipine D.Atenolol

39. 5. A 56-year-old patient complains of chest pain following any sustained exercise. He is diagnosed with atherosclerotic angina. He is prescribed sublingual nitroglycerin for treatment of acute chest pain. Which of the following adverse effects is likely to be experienced by this patient? Hypertension. Throbbing headache. Bradycardia. Sexual dysfunction. E. Anemia ESSAY Write and essay on the drugs used for treating hypertension stating their pharmacodynamics and side effects. Write a short note on the Pharmacological therapy of Peripheral Artery Disease. a. Definition. b. Name of drug. c. Pharmacokinetics. d. mechanism of action.

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