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Pharmacology – I [PHL 313]

Pharmacology – I [PHL 313]. Drugs acting on the Cardiovascular System. Dr. Mohammad Nazam Ansari. Topics. The drugs having their primary action on heart or blood vessels, or those used primarily for cardiovascular disorders: Cardiotonic Drugs Antihypertensive Drugs Antidysrrythmic Drugs

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Pharmacology – I [PHL 313]

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  1. Pharmacology – I [PHL 313] Drugs acting on the Cardiovascular System Dr. Mohammad Nazam Ansari

  2. Topics • The drugs having their primary action on heart or blood vessels, or those used primarily for cardiovascular disorders: • Cardiotonic Drugs • Antihypertensive Drugs • Antidysrrythmic Drugs • Diuretics

  3. Physiology of the Cardiovascular System

  4. Cardiovascular System • A closed system of the heart and blood vessels • The heart pumps blood • Blood vessels allow blood to circulate to all body parts • Pulmonary circuit: flow of blood through the lungs. • Pulmonary arteries: carry O2-poor blood from right ventricle to the lungs. • Pulmonary veins: carry O2-rich blood from lungs to the left atrium. • Systemic circuit: flow of blood through the rest of the body. • Aorta: carries O2-rich blood from left ventricle to all body tissues. • Vena cava: returns O2-poor blood to the right atrium. • The function of the CVS is to deliver oxygen and nutrients and to remove carbon dioxide and other waste products

  5. The Heart: Size & Location • The heart is a hollow, cone-shaped, muscular pump • Nine (9) inches long x three (3) inches wide. • Located in the centre of Thorax between the lungs, posteriorly by the backbone, and anteriorly by the sternum & resting upon the diaphragm. • Base--attached to several large blood vessels and lies beneath the second rib. • Pointed apex at the fifth intercostal space directed toward left

  6. Heart & Blood Circulation

  7. The Heart: Valves • Allow blood to flow only in one direction • Four valves • Two Atrioventricular valves – between atria and ventricles • Tricuspid valve (Right) • Bicuspid or Mitral valve (left) • Two Semilunar valves (3 cusps)- between ventricle and artery • Pulmonary semilunar valve • Aortic semilunar valve

  8. Superior View of Heart Valves

  9. Heart Sounds • Closure of heart valves causes vibrations in adjacent heart walls and blood; these vibrations constitute the heart sounds • “Lub”: Produced by the closing of AV valves at the start of ventricular systole • “Dub”: Produced by the closing of the semilunar valves at the end of ventricular systole

  10. Heart Covering: Pericardium • Pericardium (3 layers) • fibrous pericardium(outer layer)made of dense CT, holds heart in place, prevents overfilling • serous pericardium (2 layers) • parietal layer sticks to fibrous pericardium • visceral layer (= epicardium) is the outermost layer of the heart wall • Between parietal and visceral layers is the pericardial cavity, which contains serous fluid (which reduces friction)

  11. Layers of the Heart Wall • Epicardium:visceral layer of serous pericardium • Myocardium: consists mainly of cardiac muscle • Endocardium: sheet of endotheliumresting on a thin layer of CT; lines heart chambers and makes up heart valves epicardium Heart wall myocardium endocardium

  12. The systemic circuit is longer than the pulmonary circuit, therefore, the left ventricle must be able to generate greater force and pressure with each pump, than the right ventricle. • Note the difference in their wall thicknesses. • Atria are relatively thin walled; they pump blood in the direction of gravity and only have to move blood into the ventricles.

  13. The Heart • Two-sided pump that circulates 5-6 liters of blood every minute • Conduction by special cells that carry electrical impulses: • SA node, • AV node, • bundle of HIS, • right and left bundle branches and • Purkinje fibers

  14. Pharmacology – I [PHL 313] Cardiotonic Drugs Dr. Mohammad Nazam Ansari

  15. Congestive Heart Failure (CHF) • A Clinical syndrome that occurs when the heart is unable to supply blood & O2 to meet the metabolic needs of the body • Characterized by inadequate contractility, so that the ventricles have difficulty in expelling sufficient blood => rise in venous blood pressures • Raised venous pressures impair fluid drainage from the tissues and produce a variety of serious clinical effects: • Right sided heart failure causes lower limb oedema. Blood pooling in the lower extremities • Left sided heart failure produces pulmonary oedema and respiratory distress

  16. Factors contributing to CHF • Ischemic Heart Disease: most prevalent • CAD (Coronary Artery Disease): less blood flow to heart, increased damage • Myocardial Infarction: damaged tissue • Hypertension: “overworked” heart • Diabetes • Lung Disease • Viral Infections • Leaky heart valves

  17. Factors contributing to CHF • Cardiomyopathies: heart muscle disease • dilated - enlarged chambers (ventricle/atria) • hypertrophic - thickened ventricle walls • Abnormal heart valves: inefficient pumping • causes are genetic, infection or disease • Congenital heart defects: present at birth • Severe Anemia • Hyperthyroidism • Cardiac Arrhythmia

  18. Symptoms Associated with CHF • High diastolic BP & occasional decrease in systolic BP • Pale, cold sweaty skin • Cardiomegaly • Acute Pulmonary Edema • Shortness of breath • Persistent coughing/wheezing • Edema (or excess fluid buildup in body tissues) • venous pooling • swelling in extremities • Necrosis • Tiredness/Fatigue • Lack of appetite/nausea • decreased blood supply to digestive tract • confusion/impaired thinking • increased heart rate

  19. Therapeutic Overview Problems • Reduced force of contraction • Decreased cardiac output • Increased TPR • Inadequate organ perfusion • Development of edema • Decreased exercise tolerance • Ischemic heart disease • Sudden death TPR: Total peripheral resistance

  20. Cardiotonic Drugs • Drugs that increase force of contraction of heart • The cardiotonics are drugs used to increase the efficiency & improve the contraction of the heart muscle, which leads to improved blood flow to all body tissues

  21. Therapies Non-drug • Reduce cardiac work • Rest • Weight loss • low Na+ diet Drug • Acute heart failure • PDE inhibitors • Diuretics • vasodilators • Chronic heart failure • Digoxin • Beta-agonists • Diuretics • ACE inhibitors • ATII antagonists • Aldosterone antagonists

  22. Treatment options • Cardiac Glycosides • Digitoxin, Gitoxin, Digoxin, Strophantin K • Phosphodiesterase III – Inhibitors • Milrinone (Primacor), Amrinone(Inocor) • β1-adrenoceptors agonists • Dobutamine, dopamine, Epinephrine • Diuretics • Carbonic anhydrase inhibitors: Acetazolamide • Loop diuretics: Furosemide • Thiazides: Hydrochlorothiazide • Potassium Sparing Diuretics:Amiloride, Spironolactone

  23. Treatment options • • ACE inhibitors: • Captopril (Capoten), Enalapril (Vasotec), Enalaprilat (Vasotec IV), Fosinopril, Monopril, Ramipiril (Altace) • AT II antagonists • Losartan (Cozaar), Valsartan (Diovan) • β-adrenergic receptor antagonists • Propranolol, carvedilol • Aldosterone antagonists • Spironolactone, Eplerenone • • Vasodilators • Nitrates, Hydralazine (Apresoline), Nitroglycerin, • Sodium Nitroprusside (Nipride)

  24. Cardiac Glycosides • • Cardiac glycosides slow the heart rate and increase the force of contraction (=positive inotrope) • • Digitalis is the drug of choice for heart failure associated with atrial fibrillation • Increases cardiac output, Increase urine output, Decreased renin release • SOURCE GLYCOSIDES • 1. D. purpurea - Digitoxin, Gitoxin, Gitalin • 2. D. lanata - Digitoxin, Gitoxin, Digoxin

  25. Mechanism of Action The cardiac glycosides inhibit the Na+/K+-ATPase pump, which causes an increase in intracellular Na+ => slowing of the Na+/Ca++-exchanger => increase in intracellular Ca++.

  26. The Sodium-Potassium Pump (Na+K+ATPase) Three sodium ions from inside the cell first bind to the transport protein. Then a phosphate group is transferred from ATP to the transport protein causing it to change shape and release the sodium ions outside the cell. Two potassium ions from outside the cell then bind to the transport protein and as the phosphate is removed, the protein assumes its original shape and releases the potassium ions inside the cell.

  27. Structure of Actin and Myosin Troponin is composed of three subunits: Tn-A : binds to actin Tn-T :binds to tropomyosin, Tn-C :binds to calcium ions.

  28. Pharmacological Action • Cardiac Effects: Digitalis direct effects on myocardial contractility & electrophysiological properties. • Positive inotropic effect: enhancement of systolic tension; increase the force of contraction of the normal and failing myocardium. • Negative chronotropic effect: cardiac glycosides slow down the heart rhythm. • Positive tonotropic effect: enhancement of diastolic tension; reduce the size of the heart. • Positive bathmotropic effect: increase the excitability of the myocardium, which can cause arrhythmias (extrasystole, ventricular fibrillation). • Other Effects: • Indirect vasodilation (little effect on the BP) • Increase diuresis, secondary to improved circulation. • Induce contractions of intestinal muscles

  29. Pharmacokinetic of Digoxin • Amongst various cardiac glycosides used, digoxin & digitoxin are very common. • Available IV & Orally • Oral ABS: Depend on formulation (Soft Gelatin Caps > Elixir > Tablets ) • Absorption is confined to small intestine. • Digitoxin is the most lipid soluble, digoxin is relatively polar. • Digoxin absorption is variable (60-80%), digitoxin is absorbed almost (100%). • Digitoxinmetabolized in liver, partly to digoxin & undergoes some enterohepatic circulation. • Digoxinexcreted by kidney

  30. ADRs of Digoxin • Central nervous system reaction: • Headache; weakness; drowsiness; visual disturbance, • Cardiovascular and gastrointestinal reactions: • Arrhythmias; gastrointestinal upset; anorexia, Nausea, Vomiting, • Rare ADR • Eosinofilia, skin rashes, gynecomastia

  31. Preparation Digoxin 0.25 mg tab, 0.05 mg/ml pediatric elixir, 0.5 mg/2ml inj. Digitoxin 0.1 mg tab Uses • Chronic heart failure • Atrial fibrillation

  32. PDE III Inhibitor: MOA Inhibition of phosphodiesteraseIII ↑ intracellular cAMP activation of protein kinase A Ca2+ entry through L type Ca channels Inhibition of Ca2+ sequestration by SR ↑ contractility ↑ cardiac outputand ↓ peripheral vascular resistance

  33. PDE III Inhibitor • Drug – Amrinone(Inocor) , Milrinone(Primacor) • Have a positive inotropiceffect. • Cause vasodilatation, decrease BP & decrease preload & afterload • ROA: IV • Effective in patients taking Beta-blockers • Indications: Used only for short term in acute heart failure and Unresponsive CHF to other treatment • ADRs: Arrhythmia, hypotension, thrombocytopenia, GI Complaint (pain, nausea, vomiting), Liver dysfunction, allergy. • Long-term use increases the risk of mortality. • Sudden death secondary to ventricular arrhythmia

  34. β1 – Agonist MOA: Adrenergic stimulation of β1-adrenergic receptors produces positive inotropic effect. Drugs: Dobutamine, Dopamine, Epinephrine ROA: IV Most widely used, but limited to emergency case due to cardiogenic, traumatic & hypovolemicshock. SE: Restlessness, tremor, headache, cerebral hemorrhage, cardiac arrhythmias, used with caution in patients taking β-blockers, can develop dobutamine tolerance Long-term use increases risk of cardiac arrhythmias, hypertension and the risk of mortality

  35. Diuretics: MOA & ADRs Failing heart pumping function • Diuretics decreases preload through several mechanisms: • Diuresis (excretion of water and electrolytes) • Vasodilation (loop diuretic: furosemide) • ADRs : • Skin rashes • Hepatic dysfunction Sodium and water retention Increased intravascular volume Increased preload

  36. Renin-Angiotensin System antagonists

  37. The Renin-Angiotensin-Aldosterone (RAA) System Adrenal cortex secretes aldosterone Kidneys secreterenin Liver secretes angiotensinogen Angiotensinconvertingenzyme (ACE) Blood Renin Angiotensinogen Angiotensin I Angiotensin II Aldosterone Na+ retention H2O retention K+ excretion Mg+ excretion Growthfactor stimulation Vascular smooth muscle constriction Sympathetic activation

  38. Angiotensin Converting Enzyme Inhibitors • Examples: Quinipril, captopril, enalapril, benaepril • MOA: Block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. There will be reduction in blood pressure by vasodilatation. This results in decreased PVR. • Decreased preload & afterload • Adverse Effects: Dry cough, hyperkalemia, Angioedema, Hypotension, Renal insufficiency, Rashes • Contraindications: Pregnancy – renal failure in infants, renal impairment.

  39. Angiotensin II receptor blockers • Examples: Losartan (Cozaar), Valsartan (Diovan), Irbesartan, Candesartan, Telmisartan, Olmesartan • They block angiotensin II effect at the angiotensin type 1 receptors. Thus, there is vasodilatation and blood pressure lowering. • Has comparable effect to ACE I • Can be used in certain conditions when ACE I are contraindicated (angioneurotic edema, cough) • Therapeutic uses: • Hypertension, Heart failure, • Diabetic nephropathy, Myocardial infarction, • Stroke prevention, Migraine headache • Adverse effects: Angioedema, Fetal harm, Renal failure

  40. β-adrenergic receptor antagonists • β- blockers were once contraindicated in CHF, as they have the potential to worsen the condition, studies in the late 1990s showed their efficacy at reducing morbidity and mortality in CHF. • Carvediloland sustained-release metaprololare specifically indicated as adjuncts to standard ACEIs and diuretic therapy in CHF. • reduce sudden death caused by other drugs • Propranolol: prototype • Carvedilol: combination effects

  41. Mechanism of Action • β-blockers, in addition to their sympatholyticβ1 activity in the heart, influence the renin/angiotensin system at the kidneys. β blockers cause a decrease in renin secretion, which in turn reduce the heart oxygen demand by lowering extracellular volume and increasing the oxygen carrying capacity of blood. • Prevents development of arrhythmias

  42. Therapeutic Use • Administered orally • Effective in patients with chronic systolic heart failure • Prevents remodeling and cardiac damage Side Effects • Cardiac decompensation • Bradycardia • Hypoglycemia • Cold extremities • Fluid retention • Fatigue

  43. Aldosterone Antagonists • Elevated Angiotensin II levels increase production of aldosterone in the adrenal cortex (~20X increase) • Aldosterone activates mineralocorticoid receptors in epithelial cells in kidney • aldosterone promotes • Na+ retention, water retention, Mg2+ and K+ loss • increased SNS activity • decreased PSNS activity • myocardial/vascular fibrosis

  44. Therapeutic Use • Goal: inhibit aldosterone negative effects in CHF • Aldosterone receptor antagonists • Spironolactone • Eplerenone • Reduce mortality in patients with moderate to severe CHF • Only use in patients with normal renal function and K+ levels • Use with K+ sparing diuretic

  45. Side Effects • Hyperkalemia • Agranulocytosis • Anaphylaxis • Hepato-toxicity • Renal failure • Spironolactone: gynecomastia, sexual dysfunction • Eplerenone: arrhythmia, myocardial infarct/ischemia

  46. Vasodilators • Examples: Hydralazine (Apresoline), Nitroprusside(Nipride), Nitroglycerine. • MOA: Vasodilators cause a direct relaxation of vascular smooth muscle to decrease PVR and lower BP. There are two types: atreriolar dilators and venous dilators. • They are usually given with a beta blocker. • Reduction of afterload by arteriolar vasodilatation (hydralazin)  reduce LVEDP, O2 consumption, improve myocardial perfusion,  stroke volume and CO • Reduction of preload By venous dilation (Nitrate)  ↓ the venous return ↓ the load on both ventricles. • Usually the maximum benefit is achieved by using agents with both action.

  47. Mechanism of Action Nitrovasodilators NO release Activate guanylylcyclase and ↑cGMP ↓Intracellular calcium Smooth muscle relaxation Vasodilatation Preload and afterload reduction Improved cardiac function

  48. Thank you

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