1 drugs acting on cardiovascular system

1. Drugs acting on Cardiovascular system

2. The drugs acting on cardiovascular system are divided into four groups: Cardiotonic drugs Anti-hypertensive drugs Anti-arrhythmic drugs Anti- anginal drugs

3. Cardiotonic drugs Drugs which increase the force of contraction of the heart, are called cardiotonic drugs. Classification: Cardiac glycosides 3. A nticholinergic drugs Digoxin -Atropine Digitoxin -Scopolamine Sympathetic drug 4. Xanthine s - Adrenaline - Theophylline -Dopamine - Theobromine - I soprenaline

4. Cardiac glycosides Cardiac glycosides are those glycosides which have specific action to the failing heart. Increase the force of contraction of failing heart and lower the heart rate and thereby maintain an effective circulation. Classification of cardiac glycosides: Natural A). Plant source From leaves of foxgloves: Digitalis purpurea : Digoxin , Digitoxin Digitalis lanata : D igoxin , Lanatoside -C

5. From the seeds of foxgloves: Strophanthus kombe : Cymarin , Cymarol Strophanthus gratus : Ouabain squill B) Animal source: Toad venom: Bufotoxin Synthetic: - Digitoxigenin - Digoxigenin - G itoxigenin

6. Digitalis Digitalis is a powerful inhibitor of Na + /K + ATPase . As a result they increase the efficiency of failing heart increasing Na + concentration within cell membrane;which enhances Ca ++ availability to the contractile apparatus and increase the contractility.

7. Mechanism of action: It alters ion transport system by inhibiting membrane bound enzyme Na + /K + ATPase , which is associated with Na + pump. So It decreases active transport of Na + out of the cell increasing intracellular Na + concentration; this in turn decreases Ca ++ transport out of cell. Release of stored Ca ++ from the sarcoplasmic reticulum increases. Permeability of Ca ++ increases. The net effect is increased intracellular Ca ++ ions which increases the force of contraction of the cardiac muscles.

8. Pharmacological actions: Cardiac effects: On normal heart Direct positive inotropic action Decrease heart rate so decrease cardiac output Increase systolic and mean systemic arterial pressure due to direct arteriolar contraction Decrease central venous pressure On failing heart Direct action: Positive inotropic action Indirect action: decrease sinus rate, so decrease heart rate

9. Extra-cardiac effects: Kidneys: Diuresis(due to increase renal perfusion) oedema (due to aldosterone antagonism) Eye: Xanthopsia (appearance of yellow-green tings cause visual disturbance CNS: paraesthesia , toxic psychosis Blood vessels: vasoconstriction, venodilation GIT: anorexia, nausea, vomiting Gynaecomastia (due to prolonged use)

10. Indications of Digitalis: Congestive heart failure due to ischemia, hypertensive or valvular heart disease. Atrial fibrillation Atrial flutter Paroxysmal supraventricular tachycardia Left ventricular failure

11. Contraindications Digitalis toxicity CVS Recent myocardial infarction Heart block Arrhythmia renal impairment Hepatic failure Electrolyte imbalance specially hypokalaemia and hypocalcaemia

12. Digitalisation : Subjection of a patient to the action of digitalis is called digitalisation . Cautions: Therapeutic index of digitalis is low ( therapeutic dose is very near to toxic dose) The dose of digitalis should be individualized. Danger signs of digitalis toxicity after initial dose are: nausea, vomiting, sinus bradycardia (HR<60beats per min)

13. Digitalisation is done by three ways: Emergency digitalisation Rapid digitalisation Slow digitalisation Total digitalisation dose (TDD): It is the initial loading dose of digoxin . -Oral route: 0.75-1.25mg - i /v route: 0.5-1mg

14. Maintenance dose: Oral route: 0.125-0.5mg i /v route: 0.25mg

15. Anti-hypertensive drugs Hypertension: Persistent rise of blood pressure above the upper limit of normal level according to the age and sex of the individual is called HYPERTENSION (HTN) Normal limits of blood pressure: Systolic: 100-140 mm Hg(120±20) Diastolic : 60-90 mm Hg (75±15)

16. Causes of hypertension: Primary hypertension (90-95%): also called as essential hypertension Unknown etiology or idiopathic Secondary hypertension(5-10%): Renal disease Endocrine diseases (Conn’s disease, acromegaly , Phaeochromocytoma ) Cushing's disease Vascular causes (renal artery stenosis , coarctation of aorta) Drugs (sympathomimetics, NSAIDs, contraceptive pills, steroids

17. Risk factors: Age Hereditary Anxiety Obesity and lack of exercise Alcohol consumption Salt intake Special patient groups Race Elderly Diabetes Renal disease Stroke Pregnancy Hormone replacement therapy Oral contraceptives

18. Management of hypertension Non-pharmacologic approaches: Weight reduction in obese patients: reduces about 2.5/1.5 mm Hg per kg wt. lost Restriction to salt intake: not more than 6 g NaCl Dietary considerations: legumes, fresh fruits and vegetables, whole grains Regular exercise Restricted alcohol intake Smoking cessation to reduce cardiovascular risk

19. Pharmacologic approach: Classification: Diuretics: Carbonic anhydrase inhibitors : acetazolamide Loop diuretics: Furosemide , ethacrynic acid , mercurials Thiazide diuretics: Hydrochlorthiazide Potassium sparing : amiloride , triamterene , spironolactone Osmotic diuretics : mannitol Sympatholytics : Centrally acting: Methyl- dopa , Clonidine Beta-blockers: Atenolol , Propranolol , Metoprolol Alpha-blockers: Prazosin , Phentolamine Adrenergic neuron blockers: Guanethidine , Reserpine

20. C. Direct vasodilators: Arteriolar dilators Diazoxide Hydralazine Minoxidil Prazosin Vasodilators (non-selective) Nitroprusside Prazosin

21. D. Calcium Channel blockers: Nifedipine Verapamil Diltiazem E. Angitensin converting enzyme (ACE) inhibitors: Captopril Enalapril Lisinopril Ramipril

22. α -Methyl dopa It is useful in treatment of mild to moderately severe hypertension. It reduces the BP chiefly by reducing peripheral vascular resistance. It inhibits noradrenaline synthesis: DOPA Dopamine DOPA decarboxylase α -methyl dopa methyldopamine α methyl- noradrenaline Remains inside the vesicles and released in the same way as noradrenaline .

23. Mechanism of Action α -Methyl dopa forms false neurotransmitter α -Methyl noradrenaline which combines with α - adrenoceptors present in the surface of the lower brain stem, inhibiting the neurons of nucleus of tractus solitarius of vagus which in turn decrease central and peripheral sympathetic activities resulting in decreased BP. It also inhibits the decarboxylation of DOPA and 5-HT, thus decreased sympathetic tone. It also directly reduces renin activity which is responsible for conversion of angiotensin -I to angiotensin -II thereby reducing BP.

24. Pharmacokinetics: Well absorbed from the GIT Half-life: 1.5 hrs Antihypertensive effects; 4-6 hrs Effective twice daily Dose: 1-2 g in divided doses Indications: Moderate to severe hypertension Hypertensive crisis Pheochromocytoma Malignant carcinoid

25. Adverse effects: Mental symptoms (sedation, lassitude, vertigo) Electrolyte imbalance Thrombocytopenia Headache Psychic depression Lactation Dryness of mouth Oedema Postural hypotension Allergic reaction

26. Unique side effects: Flushing of skin Failure of ejaculation Depression Hemolytic anemia Granulocytopenia Hepatic disturbance

27. Clonidine It is centrally acting sympatholytic agent ( α 2 adrenoceptor agonist) and acts by decreasing central sympathetic activity. Mechanism of action: It combines with α 2 –receptors of lower brainstem which in turn inhibits release of noradrenaline from the neurons. It decreases sympathetic activity which results in decreased cardiac output due to decrease heart rate and relaxation of capacitance vessels. Thus BP is decreased.

28. Pharmacological actions of Clonidine : CNS: suppress sympathetic outflow CVS: decrease heart rate; decrease CO Blood vessels: reduction in resistance and relaxation of capacitance vessels Indications: Hypertension Prophylaxis of migraine Diagnosis of pheochromocytoma

29. Adverse effects: Sedation Dry mouth Drowsiness Rebound hypertension

30. Pharmacokinetics of Clonidine : Bioavailability: 75% Half-life : 8-12 hours Excretion: half of the drug excreted unchanged Dose: 0.2 and 1.2 mg/day Sudden withdrawal effects: It can result in life threatening crisis. Patient exhibit nervousness, tachycardia, headache and sweating if one or two dose is omitted. Note: sudden withdrawal of the drug must be avoided. If required should be done gradually.

31. Calcium channel blockers Calcium is the chief ion required for Cardiac contraction Smooth muscle contraction Propagation of cardiac impulse Classification of Ca ++ channel blockers Dihydropyridine family: Nifedipine Nicardipine Nisoldipine Amlodipine isradipine

32. 2. Miscellaneous: Verapamil Deltiazem Bepridil General pharmacokinetics for Ca ++ channel blockers Orally administered Highly protein bound Hepatic first pass metabolism Renal excretion

33. Mechanism of action: Calcium channel blockers bind with voltage dependent Ca ++ channel (L-type) in depolarised membrane. The resultant effect is relaxation of the smooth muscles and negative ionotropic and chronotropic action in the heart.

34. Pharmacological action of Calcium channel blockers CVS: Dilates main coronary vessels: improves myocardial perfusion Negative chronotropic effect: cardiac slowing and AV block Negative ionotropic effect: decrease force of contraction Vasodilation : decrease total peripheral resistance Smooth muscles Smooth muscles: Vascular smooth muscle: generalized relaxation Coronary vasodilation : antianginal action Visceral smooth muscle: relaxation of biliary tract; uterus and bladder.

35. Indications: Angina pectoris (variant) Hypertension Cardiac arrhythmias Prevention of ischemic neurological damage due to subarachnoid damage Raynaud’s disease Migraine Premature labour

36. Contraindication: Heart failure Bradycardia Second or third degree AV block Sick sinus syndrome Wolf Parkinson-White syndrome

37. Adverse effects: Due to vasodilation : Postural hypotension, reflex tachycardia Bradycardia, palpitation Headache, flushing, dizziness, ankle edema Gastrointestinal Constipation Nausea, vomiting Gum hypertrophy

38. ACE-Inhibitors Angiotensin converting enzyme (ACE) inhibitors are : Captopril Enalapril Lisinopril Ramipril ACE inhibitors act by inhibiting the conversion of angiotensin I to angiotensin II; which is a powerful vasoconstrictor. It acts preferably on angiotensin sensitive vascular bed of kidney, brain and brain.

39. Mechanism of Action It inhibits the conversion of angiotensin I to angiotensin II, thus vasoconstrcitive action of angiotensin II is inhibited. Also ACE causes inactivation of bradykinin (vasodilator peptides) but in presence of ACE inhibitors bradykinin is active and causes vasodilation which in turn decrease TPR and finally BP.

40. Pharmacological actions Vasodilation (reduction of TPR) Reduce preload and afterload Reduction in the secretion of aldosterone so decreased salt and water retention. Increase in renal blood flow.

41. Indications Hypertension Renovascular hypertension due to excess renin Malignant hypertension Hypertensive crisis of scleroderma End stage renal disease Refractory heart failure Ischemic heart disease

42. Adverse effects First dose hypotension Dry cough Angioneurotic oedema Hyperkalaemia Loss of appetite Stomatitis Abdominal pain Neutropenia Proteinuria Blood disorders

43. Contraindications Systolic blood pressure < mm Hg Bilateral renal artery stenosis Second and third trimester of pregnancy Renal failure

44. Angiotension receptor blockers These are the agents that act on the angiotensin type I (AT 1 ) receptor. Drugs: Losartan Valsartan Candesartan Eprosartan Irbesartan Telmisartan

45. Unique features of ARBs from ACE-inhibitors: These agents are unique from ACE –inhibitors in that they don’t have effect on bradykinin . They cause more complete inhibition of angiotensin action because besides ACE other enzymes are present which can angiotensin II.

46. Losartan : Mechanism of action: It causes antagonism in the angiotensin receptor thus causing a complete blockade of angiotensin II activity . Pharmacokinetics: Orally administered Extensively metabolized; metabolites retain activity Plasma half-life: 2 hrs Dose: 50 mg/d; can range from 25-100 mg/d

47. Indications: Hypertension Adverse effects: similar to ACE-inhibitors except that no angioedema and cough is present; both of which are mediated via bradykinin . Contraindications : pregnancy

48. Saralasin is an analog and competitive inhibitor of angiotensin II at its receptors. It also blocks the pressor and aldosterone releasing effect of infused angiotensin II and reduce blood pressure in high renin activity state such as renal artery stenosis . It has been withdrawn from market due to its unpredictable pharmacological outcomes.

49. Vasodilators Drugs: Oral vasodilators: Hydralazine Minoxidil Parenteral vasodilators: Nitroprusside Diazoxide Fenoldopam Mechanism of action : This class of compounds cause the dilation of arteries or both arteries and veins; thus reducing overall peripheral resistance and in turn decreases the blood pressure.

50. Hydralazine : It is a hydrazine derivative and is known to dilate arterioles only but not veins. It causes tachyphylaxis to hypertensive effects developed rapidly. It can be used in combination. Pharmacokinetics: Orally administered Extensive 1 st pass metabolism Low bioavailability Half-life 2-4hrs Dose: 40-200mg/day.

51. Adverse effects: Headache Nausea Anorexia Palpitations Seating Flushing Systemic lupus erythrematosus (SLE)

52. Minoxidil Orally active; half life-4hrs; 5-10mg/d in two doses Vasodilation results due to opening of K + ions which brings the membrane to hyperpolarized state, producing relaxation. It also dilates arterioles but not veins. Headache, sweating and hypertrichosis , tachycardia and angina and edema are side effects

53. Fenoldopam : It is indicated for severe hypertension and postoperative hypertension. Acts as Dopamine (D 1 receptors) agonist resulting dilation of peripheral ateries . Given parenterally ( i.v . infusion); extensively metabolized and very short half-life of 5 mins . Very small dose of 0.025-0.05µg/kg/min.

54. Individualised care approach Calcium channel blockers : Suited for : Elderly Isolated systolic hypertension Asthma/COPD patients Raynauds disease/ migraine Pregnant hypertensive Avoid in : CHF Conduction defects Patients receiving beta blockers IHD/ post MI Left ventricular hypertrophy Males with enlarged prostate GERD

55. ACE Inhibitors Suited for : High renin cases or those on low salt Physically active Diabetics/ with nephropathy Co existing angina / post MI cases Coexisting Left ventricular failure / left ventricular hypertrophy Gout/ PVD?Dyslipidemic patients Avoided in : Bilateral renal artery stenosis Pregnancy Hyperkalemia Pre existing dry cough

56. Beta adrenergic blockers Suited for : Angina or post MI cases Coexisting anxiety or techycardia Non obese high renin hypertensive Pregnancy Avoided in : CHF Bradycardia , conduction defects Asthma / PVD Diabetic or borderline glucose tolerance Abnormal lipid profile 6) Patient to remain physically active

57. Diuretics : Suited for : Elderly patients Low renin hypertensive Isolated systolic hyeprtension Obese with volume overload Renal disease with salt retention Low cost therapy Avoided in : Young active hypertensive Diabetes Gout Abnormal lipid profile Pregnancy induce hypertension

58. Combination therapy Drugs increasing renin activity ( diuretics . Vasodilators , CCBs, ACE inhibtors ) with drugs having low renin activity ( beta blockers , clonidine , methyl dopa ) Drugs causing fluid retention ( adrenergic blockers except beta blockers ) with diuretics Drugs causing tachycardia ( hydralazine , DHPs) with non selective beta blockers ACE inhibitors / AT1 blockers with diuretics CCB with diuretics Beta blocker + prazosin

59. Combinations to be avoided : Adrenergic blocker with clonidine Hydralazine with prazosin Verapamil / diltiazem with beta blocker Methyl dopa + clonidine

60. Hypertension in pregnancy Suitable drugs Methyl dopa Hydralazine Dihydropyridine CCBs Cardioselective adrenergic blockers ( atenolol , pindolol , acebutolol ) Prazosin Clonidine Drugs to be avoided Diuretics ACE inhibitors Reserpine Non selective beta blockers Sod nitroprusside

61. ABCD method of drug sequencing Younger and non black Step 1 : A Older and black Step 1: C or D Step 2: A+ c or D Step 3 : A+C+ D Step 4 : Add alpha blocker or spironolactone or Beta blocker

62. Diabetes First line therapy : Type 1 : monotherapy :ACE inhibitors / AT1 blockers Combination : + beta blockers / CCBs / thiazides / alpha blockers Type 2 : ACE inhibitors / AT1 blockers / CCBs

63. Renal disease ACE inhibitors Thiazide diuretics not used in severe renal impairment, instead loop diuretics are used

64. Anti- anginal drugs Angina pectoris It is a clinical syndrome characterized by pre-cardiac pain or discomfort due to myocardial ischemia, which is precipitated by exercise and relief by rest or sublingual nitro- glycerine . It occurs when coronary blood flow is insufficient to meet the metabolic requirement of the heart muscle. Myocardial oxygen demand mainly depends on Preload, After load and Heart rate

65. atherosclerotic angina, classic angina ( angina of effort ) vasospastic or variant angina ( Prinzmetal's angina ) Unstable angina

66. Determinants of Myocardial Oxygen Consumption . Wall stress Intraventricular pressure Ventricular radius (volume) Wall thickness Heart rate Contractility

67. R egulation of smooth muscle contraction and relaxation 1 ) Increasing cGMP: dephosphorylation of myosin light chains , nitric oxide 2 ) Decreasing intracellular Ca 2 + : 3 ) Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: increase the permeability of K + channels, 4 ) Increasing cAMP in vascular smooth muscle cells: cAMP increases the rate of inactivation of myosin light chain kinase

68. Drugs: Organic nitrites and nitrates: Nitrites: sodium nitrite, amy -nitrite, octyl -nitrite Nitrates: glyceryl trinitrate , isosorbide dinitrate and isosorbide mononitrate Calcium channel blockers: Nifedipine Verapamil deltiazem

69. Beta- adrenoceptor blockers Atenolol Propranolol Oxaprenolol Xanthines : Theophylline Aminophylline Miscellaneous Dipyradimol

70. Drugs or Drug Groups under Investigation for Use in Angina. Metabolic modulators : eg , ranolazine Direct bradycardic agents, eg, ivabradine Potassium channel activators , eg, nicorandil Rho-kinase inhibitors, eg, fasudil Sulfonylureas : eg , glibenclamide Thiazolidinediones / glitazones Nitric oxide donors : eg, L-arginine Capsaicin Amiloride

71. Organic nitrates Pharmacokinetics of organic nitrates: Glyceryl trinitrate is a short-acting Undergoes 1 st pass metabolism if given orally Given sublingually usually 500mg tab/day Onset of action within 15-30 mins Duration:20-30mins Used mainly in acute attack.

72. Isosorbide di -and mono-nitrates are long acting Orally given Systemic availability more than GTN Used in prophylaxis.

73. Mechanism of action : Organic nitrates act by relaxing smooth muscles of blood vessels. It occurs in following steps: Denitration of org. nitrates ( org nitrates into inorganic) Inorganic nitrates converted to NO (like EDRF) Activation of guanylyl cyclase i.e. raised cGMP Reduces intracellular Calcium concentration Relaxation of vascular smooth muscles

74. Pharmaclogical actions: CVS: Reduces preload (due to venodilation ) Reduces afterload (due to generalized vasodilation ) Dilates coronary arteries and increase blood flow to ischemic areas Others: Relaxation of bronchial smooth muscle Relaxation of GIT smooth muscle i.e. decreased motility Relaxation of smooth muscle of biliary tract, urethra and uterus.

75. Indications: Angina pectoris Congestive heart failure Myocardial infarction Adverse effects: Flushing of face Throbbing headache Postural hypotension Syncope Nitrate tolerance

76. Contraindication: Organic nitrate intolerence Angina due to severe anemia High intra-cranial pressure Glaucoma Migraine

77. Nitrate tolerance: During long term use , the nitrate effects is gradually lowered and finally resulting in partial or complete loss of its benefit. Mechanism is reduced production of cGMP in vascular smooth muscles. Nitrate free period of 1-2 hours every 24 hrs helps prevent development of tachyphylaxis .

78. Anti-arrhythmic drugs Cardiac arrhythmias: The disorder in rate and rhythm of cardiac contraction due to myocardial damage is known as cardiac arrhythmias. Cardiac arrhythmias consist of cardiac depolarizations that deviate form the normal in one or more aspects; Abnormality at site of origin of impulse Its rate and regularity Its conduction

79. Vaughan Williams classification Class-I: Na + channel blocker Group A: Quinidine Procainamide Disopyramide Pharmacological actions: Membrane stabilizing action Prolongs refractory period Prolongs action potential

80. Group B: Lidocaine Mexiletine Tocainide Phenytoin Membrane stabilizing action Shortens refractory period Shortens action potential

81. Group C: Flecainide Encanide Membrane stabilizing action No effect on action potential

82. Class-II drugs: β -blockers (counteracts catecholamines ) Propranolol Atenolol Metoprolol Sotalol Abolish SA firing Decrease contractility Increase AV refractoriness

83. Class-III drugs: Repolarization prolonging Amidarone Bretylium Prolongs refractory period Prolongs action potential Prevents re-entry rhythm

84. Class-IV drugs: Calcium channel blockers Verapamil Deltiazem Inhibits slow Calcium channels Depress contractility of AV node.

85. Quinidine It is a class-I anti-arrhythmic drug. It is an optical isomer of quinine (anti-malarial drug). Pharmacokinetics: Orally active; i.v . in emergency; i.m . painful 80% bound to plasma proteins Half-life: 4-6 hrs Metabolized by liver (75%) Excretion: unchanged fraction by kidney

86. Pharmacological actions of quinidine : Cardiac tissue: Reduce automaticity Reduce excitability Reduce conductivity Prolong refractory period Reflex tachycardia Other action: Anti-malarial Anti-pyretic Decrease B.P ( vasodilation )

87. Adverse effects: Heart block Sinus arrest Myocardial depression Q-T prolongation Ventricular fibrillation Nausea Vomiting Diarrhoea Rash Oedema

88. Indications: As anti-arrhythmic used in, Atrial fibrillation and flutter Ventricular fibrillation and flutter Paroxysmal supra-ventricular tachycardia Premature supra-ventricular tachycardia Atrial, nodal and ventricular premature beats Also as anti-malarial Anti-pyretic During digitalis therapy

89. Cinchonism : Headache, vertigo Blurred vision Tinnitus Contraindications: Quinidine intolerance Digitalis intoxication Heart failure Hypotension hypokalemia

90. Propranolol as anti-arrhythmic drug: It blocks β -receptors in heart, thereby exerts Negative inotropic effect Negative chronotropic effect Depress atrioventricular conduction Depresses automaticity It has: Anti-arrhythmic effect Anti-hypertensive effect Anti- anginal -effect in CVS.

91. Lidgnocaine It is a local-anesthetic agent. Can terminate arrhythmia if quinidine fails Parenteral administration: i.v ./ i.m Indications: As local anesthetic As anti-arrhythmic

92. Mechanism of anti-arrhythmic effect of lignocaine : It has membrane stabilizing effect by blocking both activated and inactivated sodium channels; which in turn supresses SA node and also ectopic beats. Shortens refractory period and action potential; make uniform rhythm

93. Adverse effects: Bradycardia Hypotension Dizziness Blurred vision Sleepiness Confusion Convulsion