Pharmacology of the CVS

Pharmacology of the CVS - Heart failure - Cardiac arrhythmias - Ischemic heart disease (IHD) - Hypertension - Hyperlipidemias - Atherosclerosis & thrombosis - Anemias

Drugs used in heart failure Introduction: CO: The amount of blood ejected from the heart/min. This depends on: 1. Pressure in venous system (preload) 2. Arterial blood, that is the resistance against which the heart pumps (afterload) 3. Heart rate

In normal individuals: ↑ HR → ↑ CO In Ht. failure: ↑ HR → ↓ CO 4. Contractile efficiency of Ht. muscle In Ht. failure ↓ contractility → ↓ CO → ↓ O2 to tissues → fatigue Also ↓ CO → ↑ renin-angiotensin-aldosterone system → salt & water retention → edema in legs & lungs → dyspnea

Causes of heart failure: - Hypertension - Cardiac myopathies - Coronary artery thrombosis Drugs in heart failure: - Drugs ↑ contractility of the heart (+ve inotropic effect)… Digitalis - Drugs ↑ salt & water excretion… (diuretics) - Drugs ↓ renin-Angio.-ald. system {ACE inhibitors; Ald. antagonists; Angio. receptor blockers (ARB’s)}

Angiotensinogen Angiotensin I Angiotensin II Aldosterone Renin Angiotensin I Converting Enzyme (CE) Angiotensin II Aldosterone

Cardiac glycosides Digitalis: 2 in common use; Digoxin & digitoxin; both are effective orally & I.V Digoxin: - Short acting(2 days) - Excreted by the kidneys Digitoxin: - Long acting (7 days) - Excreted by the liver

Digitalis effects: More on failing heart - ↑ Ht. contractility (+ve inotropic effect) - ↓ Ht. rate (-ve chronotropic effect) - ↓ conduction in A-V node & bundle of His Digitalis clinical uses: 1. Heart failure…digitalization

Digitalization could be achieved orally or I.V Oral dose: 0.5 mg stat, then 0.25 mg x 3 till control of disease (2-3 days), then 0.125-0.5 mg maintenance dose Less doses are required in old patients or patients with renal disease (digoxin) 2. Cardiac arrhythmias Supraventricular tachycardia; atrial flutter; atrial fibrillation

Digitalis side effects: Cardiac glycosides have narrow therapeutic window (low TI), drug monitoring is important - Nausea & vomiting, blurred vision - Confusion, bradycardia (if pulse rate < 60 stop drug) - Heart block ** Important interaction: ↓ K+ ( hypokalemia) → ↑ digitalis toxicity Diuretics → ↓ K+ blood level → ↑ toxicity of digitalis

Cardiac arrhythmias ** Bradyarrhythmias Pacemaker; atropine I.V ** Tachyarrhythmias - Extrasystoles Common in normal healthy individuals Mainly due to excessive smoking, tea or coffee drinking. Rarely require treatment

- Supraventricular tachycardia Rapid Ht. rate ≈ 150-170 beats/min - Atrial flutter Ht. rate > 300 beats/min but regular - Atrial fibrillation Ht. rate > 300 beats/min but irregular - Ventricular fibrillation & tachycardia - Digitalis-induced arrhythmias

Drugs in supraventricular tachycardia (SVT): - Verapamil (drug of choice) Ca++ channel blocker, inhibits flow of Ca++ into cells → ↓ contractility of myocardium & ↓ Ht. rate It dilates coronary & peripheral B.V’s Given orally & I.V Don’t combine with β-blockers → severe drop in B.P & cardiac arrest

Other drugs effective in (SVT): - β- blockers - Digitalis - Adenosine, given I.V Drugs in atrial flutter & fibrillation Digitalis (drug of choice)

Drugs in ventricular tachycardia & fibrillation: - Lidocaine (lignocaine; xylocaine) (drug of choice); given I.V - Mexiletine, effective orally & I.V Drugs effective in both atrial & ventricular tachyarrhythmias: - Disopyramide, given orally & I.V - Amiodarone, given orally & I.V

- Flecainamide, given orally & I.V Drugs in digitalis-induced cardiac arrhythmias: - Lidocaine (drug of choice) - Phenytoin An anticonvulsant Also effective in digitalis-induced arrhythmias

Drugs in angina pectoris Atherosclerosis → narrowing of coronary arteries →↓ O2 to myocardium → ischemia; necrosis → chest pain Objectives of Rx: - ↑ O2 supply or - ↓ O2 demand by myocardium or both

1. Nitrates: Dilate all smooth muscles of vessels especially coronary arteries - Nitroglycerin (Glyceryl trinitrate) Causes generalized vasodilatation & ↓ B.P Highly lipid soluble drug Nitroglycerin clinical uses: Rx & prophylaxis of angina & M.I

Nitroglycerin dosage forms: - Oral tab. & caps - Buccal or transmucosal tab.; sublingual tab. - Spray (metered aerosol) sprayed under tongue - I.V preparation - Transdermal skin patches & discs Nitroglycerin disadvantage: development of rapid tolerance especially with the skin patches

- Isosorbide dinitrate Similar to nitroglycerin Available in immediate and sustained oral tab. and in chewable oral tab. Dosage forms - Isosorbide mononitrate Similar in its pharmacological properties to the dinitrate but has more prolonged action

2. β-blockers: ↓ O2 demand, when given regularly they prevent pain rather than treating an attack They block overactivity of sympathetic system (↑ Ht. rate & contractility) due to exercise 3. Calcium channel blockers (CCB’s): Verapamil; nifedipine; diltiazem Given orally

CCB’s pharmacological effects: - Dilate coronaries → ↑ O2 supply - ↓ Ht. contractility →↓ O2 demand - Dilate peripheral B.V’s →↓ B.P → ↓ resistance to blood flow 4. Antiplatelet drugs: Aspirin Clopedogril Dipyridamole

Antihypertensive drugs Remember: 1. The equation of B.P B.P = CO x Peripheral resistance ( diameter of B.V) Ht. rate Blood volume & contractility

2. NA (NE) synthetic pathway

Angiotensinogen Angiotensin I Angiotensin II Aldosterone 3. Renin-angiotensin-aldosterone system Angiotensinogen Renin Angiotensin I Converting Enzyme (CE) Angiotensin II Aldosterone

1. Drugs ↓ blood volume Diuretics 2. Drugs ↓ CO β-blockers; CCB’s 3. Dugs ↓ peripheral resistance a. Prazocin α1-rceptor blocker → dilates arteries & veins, Given orally major side effect: Dizziness

b. Ca++ channel blockers (CCB’s) Verapamil, nifedipine, diltiazem, amlodepine.. Lead to peripheral vasodilatation → ↓ in peripheral resistance → ↓ B.P Side effect: Constipation c. Directly acting vasodilators - Hydralazine Given orally & I.M Side effect: Systemic lupus-like syndrome

- Minoxidil Given orally Side effect: Hirsutism - Diazoxide Given I.V & used in hypertensive emergency - Sodium nitroprusside Given I.V & used in hypertensive emergency (drug of choice)

4. Centrally acting sympatholytics - Clonidine α2-agonist Given orally - α-methyl dopa ↓ NA release centrally

5. Drugs blocking postsynaptic adrenergic neurons - Reserpine Depletes NA (NE) stores in CNS & periphery Given orally Side effect: Depression - Guanethidine ↓ NA release in CNS & given orally

6. Drugs interfering with renin-angiotensin-aldosterone system a. ACE inhibitors Angiotensin converting enzyme inhibitors Captopril, enalapril, quinapril, lisinopril… ↓ angiotensin II synthesis & hence aldosterone Effective orally

ACE inhibitors differ in potency, onset of action and duration of action ACE inhibitors clinical uses: - Hypertension - Heart failure - Hyperaldosteronism ACE inhibitors side effects: Dry cough (also considered major & absolute contraindication), allergy, and hyperkalemia

b. Angiotensin II receptor blockers (ARB’s) Losartan; valsartan; candesartan… Effective orally inhibiting angiotensin II- induced vasoconstriction Actions and uses are similar to ACE inhibitors Have similar side effects to ACE inhibitors but they don’t produce cough (known as non cough ACE inhibitors)

c. Aldosterone antagonists Spironolactone Known as K+-sparing diuretics Compete with aldosterone receptor Given orally Side effects: Hyperkalemia

Drugs in hyperlipidemias High cholesterol → atherosclerosis → coronary artery disease → MI Lipids are carried in blood by specific lipoproteins: - Chylomicrones & VLDL… carry triglycerides - LDL carries dangerous cholesterol - HDL removes cholesterol from blood

High LDL & low HDL → bad Normal or low LDL & high HDL → good Management of hyperlipidemias: a. Eliminate risk factors High B.P; D.M; smoking; high cholesterol… b. Diet, exercise, weight reduction Avoid saturated fat (animal fat)

c. ↑ excretion of cholesterol Cholestyramine; colestipol Known as bile acid sequestering agents or resins Bind bile acids which contain cholesterol & ↑ their excretion → ↓ cholesterol blood level Given orally

d. ↓ absorption of cholesterol Ezetimibe ± statins; neomycin; d-thyroxine e. Interfere with metabolism of cholesterol Clofibrate, bezafibrate, gemfibrozil f. Inhibition of de novo synthesis of cholesterol Statins (lovastatin; simvastatin; pravastatin) All antihyperlipidemic drugs are given orally Major side effect Rhabdomyolysis

g. Nicotinic acid ( Niacin ) ↓ TG’s ↑ HDL ↓ LDL in large doses MOA - Inhibition of the release of VLDL from the liver → ↓ IDL → ↓ LDL - Also reduces release of free fatty acids from adipose tissue into the general circulation → ↓ substrate for TG synthesis → ↓ TG’s - It increases HDL levels possibly by inhibiting its Catabolism Major side effect Skin flushing