CVS 1 (9) PDF - Cardiovascular Drugs

Uses: - IV infusion due to its very short half-life (2-3 min.). - During hemodialysis if heparin is contraindicated. - Treatment of pulmonary arterial hypertension (avoid abrupt withdrawal as it results in rebound pulmonary hypertension. Cilostazol an...

Uses: - IV infusion due to its very short half-life (2-3 min.). - During hemodialysis if heparin is contraindicated. - Treatment of pulmonary arterial hypertension (avoid abrupt withdrawal as it results in rebound pulmonary hypertension. Cilostazol and Pentoxifylline Mode of action: - Phosphodiesterase inhibitors→↑cAMP→ VD, inhibit platelets aggregation. - Pentoxifylline also increases deformability of RBCs. Uses: - Peripheral vascular disorders (e.g. intermittent claudication). 5- Thrombin receptor (protease-activated receptor-1, PAR-1) blockers: Vorapaxar − Mode of action: reversible selective antagonism of thrombin receptor (protease-activated receptor 1, PAR-1). − Long half-life, its effect remains 4 weeks after discontinuation with high risk of bleeding. − Primarily metabolized by the CYP3A enzymes, so has interaction with CYP3A4 inhibitors or inducers. − An adjunct with aspirin and/or clopidogrel for patients with a history of myocardial infarction or peripheral vascular disorders. Drugs used in treatment of ischemic heart diseases A. Drugs that ↓ O2 demand a. ↓ Heart rate and contractility: β-blockers, Ca++ channel blockers 161  b. ↓ preload: organic nitrates c. ↓ afterload: Ca++ channel blockers d. Shifting metabolism to substrates not requiring less O2: trimetazidine B. Drugs that ↑ myocardial O2 supply a. ↑coronary flow: Ca++channel blockers b. ↑ regional myocardial blood flow: antiplatelet and statins Nitro-vasodilators Include: organic nitrates and nicorandil Organic nitrates Pharmacokinetics and preparations: Nitroglycerin and isosorbide dinitrate have low oral bioavailability due to extensive hepatic first pass, while isosorbide mononitrate has 100% bioavailability with no first pass. They are de-nitrated in liver, then de-nitrated metabolites conjugate with glucuronide and excreted in kidney. Nitroglycerin can be administered by sublingual route (escape first pass effect, rapid onset), oral, buccal, transdermal patches and IV. Isosorbide dinitrate: used by sublingual and oral routes metabolized to isosorbide mononitrates which are active and have long duration. Isosorbide mononitrate: used sublingual and sustained release oral tablets or capsules. It has the longest duration. Pharmacodynamics: Mode of action: de-nitrated by glutathione-s-transferase in smooth muscle → releases NO combine and activate soluble guanylyl cyclase → ↑ cGMP 162  → reduced phosphorylation of myosin light chain → smooth muscle relaxation. Drugs affecting vascular smooth muscle contraction MLC: myosin light chain, MLCP: MLC phosphate, MLCK: MLC kinase, GC: guanylyl cyclase, GC*: activated GC, GTP: guanosine triphosphate cGMP: cyclic guanosine monophosphate, NO: nitric oxide Effects: o Cardiovascular: ▪ Dilate veins more than arteries due to less ability of arteries to release NO, venodilation results in ↑ venous capacitance →↓preload → ↓ventricular size and end-diastolic pressure→↓cardiac work. ▪ Arteriolar dilation of face, neck and meningeal vessels ▪ Dilate large epicardial coronaries→ improve O2 delivery. ▪ Weak negative inotropic due to NO ▪ Higher doses→ ↓peripheral resistance due to arterial dilation ▪ Orthostatic hypotension with reflex tachycardia ▪ Bradycardia and hypotension may occur due to coronary VD (Bezold Jarish reflex) with sublingual nitroglycerin. 163  o Platelets: inhibit platelet aggregation o Other smooth muscles: relax smooth muscle of bronchi and GIT Therapeutic uses: Stable and variant angina sublingual and buccal spray for acute attack, tablets and transdermal patch for long-term treatment Unstable angina and myocardial infarction: IV nitroglycerin Acute congestive heart failure: IV nitroglycerine relieve pulmonary congestion. Relieve biliary and esophageal spasm which cause atypical chest pain Adverse effects: Throbbing headache (common) due to meningeal VD, fades within few days. Face and neck flushing due to subcutaneous VD. Orthostatic hypotension: pallor, dizziness, weakness and reflex tachycardia (can be antagonized by β-blockers or verapamil) Tolerance: (can be avoided via drug holiday 8-12h every day) o Diminished release of NO due to reduced sulfhydryl donors as glutathione-s-transferase consumed in de-nitration. o Compensatory salt and water retention. o Loss of soluble guanylyl cyclase responsiveness to NO Dependence: not to stop chronic treatment suddenly to avoid coronary spasm Drug interactions: Sildenafil and nitrates → extreme hypotension and myocardial infarction Nitrates and Nifedipine→ severe hypotension Nicorandil Mode of action: VD (NO release) and activate K channels so produces hyperpolarization and relaxation of smooth muscle (No tolerance). 164  Used in resistant angina and IV during angioplasty for acute MI. Ca++ channel-blocking drugs Classification: Phenylalkylamine: verapamil Benzothiazepines: diltiazem Dihydropyridine: nifedipine, amlodipine, nimodipine, etc., Pharmacokinetics: Administered orally (verapamil and diltiazem also used by IV route), low oral bioavailability due to extensive hepatic first pass. High plasma protein binding (70%-98%) Amlodipine has slow onset due to slow absorption → prolonged effects so produce minimal fluctuation in serum levels. Pharmacodynamics: Mode of action: they block Ca++ entry through L-type Ca++ channels via acting on channels from inside the membrane in cardiac and smooth muscle, this can be reversed by sympathomimetics. Effects: o Smooth muscle: more with dihydropyridine group ▪ Vascular: relax arterial smooth muscle > veins ▪ Relax bronchiolar, GIT and uterine smooth muscle. ▪ Verapamil lacks this effect due to block of vascular K+ channels. ▪ Nifedipine is the prototype of dihydropyridine group, selectively dilate arterial smooth muscle→↓arterial blood pressure →reflex sympathetic stimulation→ tachycardia and increased contractility. ▪ Amlodipine: Coronary and arterial dilation with less reflex tachycardia due to long half-life preferred in angina 165 o All Ca++ channel blockers dilate coronaries. o Cardiac muscle: more with verapamil and diltiazem ▪ ↓ Heart rate by suppressing SA node. ▪ ↓ AV conduction ▪ ↓ Myocardial contractility ▪ Less with dihydropyridine as it blocks smooth muscle Ca++ channels at levels below the required to depress cardiac tissue. ▪ Diltiazem: Arterial dilation → ↓ BP, has direct -ve chronotropic effect, modest -ve inotropic effect. Therapeutic uses of Ca++ channel blockers: Angina o Variant angina: can relieve coronary spasm. o Exertional angina: due to coronary dilation and reduction of myocardial oxygen demand especially verapamil and diltiazem and long-acting dihydropyridine (short-acting dihydropyridine without β-blockers may worsen angina). o Unstable angina: adjunct to relief coronary spasm if not corrected with nitrates. Myocardial infarction: not first line but verapamil and diltiazem may be used if β-blockers are contraindicated. Hypertension Tachyarrhythmia: verapamil for supraventricular arrhythmia. Hypertrophic cardiomyopathy: verapamil improves outflow obstruction due to negative inotropic effect. Prophylaxis of migraine: verapamil. Nicardipine and nimodipine: relive cerebral vasospasm after subarachnoid hemorrhage 166  Adverse effects: Nifedipine: headache, flushing, dizziness, peripheral edema, worsen myocardial ischemia due to excessive hypotension, coronary steal, and excessive tachycardia which increase O2 demand. Verapamil: constipation, bradycardia, exacerbation of heart failure, liver enzymes elevation Contraindications: Nifedipine: gastroesophageal reflux disease Verapamil: heart block, heart failure Drug interactions: Nifedipine: with nitrates → severe hypotension Verapamil: o With β-blockers causes AV block and severe depression of myocardium o Increase concentration of digitalis due to reduced excretion o With quinidine causes excessive hypotension. β-blockers Examples: atenolol, metoprolol, etc., They are effective against exertional angina and myocardial infarction except variant angina (worsen the condition) Combination with nitrates is effective in exertional angina. Trimetazidine Mode of action: o In myocardial ischemia there is shift of metabolism to fatty acids which ↑ O2 requirements 167  o Trimetazidine ↓ fatty acid oxidation & ↑ glucose oxidation which require less O2, antioxidant, ↓intracellular acidosis, Ca++and Na+ accumulation. Ivabradine Pharmacokinetics: oral, 40% bioavailability due to first pass, metabolized by CYP3A4, excreted in urine, t½ 2h Mode of action: Block of pacemaker current in SA node→ bradycardia, ↓ cardiac work → prolong diastole so improve myocardial perfusion. Uses: chronic stable angina if β blockers are contraindicated Antianginal combination Nitrates and β-blockers: beta blockers block reflex tachycardia induced by nitrates, and nitrates decrease the increased end diastolic volume induced by beta blockers. Nitrates and verapamil: nitrates ↓ preload + ↑ heart rate while verapamil ↓ afterload +↓ heart rate, both are coronary dilators. Drugs used in treatment of heart failure - Renin-angiotensin aldosterone system inhibitors o Angiotensin converting enzyme inhibitors (ACEIs) o Angiotensin receptor blockers (ARBs) o Direct renin inhibitors: Aliskiren - Diuretics - β-blockers - Vasodilators - Positive inotropic drugs: digoxin, phosphodiesterase inhibitors, dobutamine 168