PHTH1011 004 Cardiovascular Drugs - McKenzie.pdf

CARDIOVASCULAR DRUGS Presenter: Kimberley McKenzie ([email protected]) Cardiovascular Drugs Propranolol – antagonist (beta receptors) → decrease in HR & FOC Nitroglycerin- precursor of nitric oxide (NO) → dilates BV Digitalis (Digoxin)- increase FOC → increased stroke volume Aspiri...

CARDIOVASCULAR DRUGS Presenter: Kimberley McKenzie ([email protected]) Cardiovascular Drugs Propranolol – antagonist (beta receptors) → decrease in HR & FOC Nitroglycerin- precursor of nitric oxide (NO) → dilates BV Digitalis (Digoxin)- increase FOC → increased stroke volume Aspirin- antiplatelet → reduce clot formation Heparin – anticoagulant → reduce clot formation Warfarin – anticoagulant → reduce clot formation Clotting factors + VII, II→ firbrin Beta Blockers PROPRANOLOL Inhibits contraction of the HEART β1 PROPRANOLOL + ATP AC cAMP ↑Ca2+ influx in cell ↑heart rate & force of contraction Propranolol Non selective β-antagonist Used for angina, hypertension, arrhythmias, glaucoma Adverse effects: bronchi-constriction, cardiac failure, fatigue and depression Route of administration: oral Half life= 4 hours, high first pass metabolism Vasodilator NITROGLYCERIN Dilates blood vessels (arteriolar & venous dilation) Nitroglycerin Smooth muscle relaxation Blood vessels dilation ↓ blood pressure ↓ work of the heart Nitric oxide Inhibition of smooth muscle contraction Increased blood flow ↓anginal symptoms ↑ blood supply to myocardium Nitroglycerin Prodrug: converted by mitochondrial aldehyde dehydrogenase (MtALDH) to give nitric oxide (NO) ROA: intravenous, sublingual Absorbed rapidly, often used in emergency situations Peak conc. Time: approx. 4.4 mins. Plasma protein binding: appro. 60% Half-life: 2.8± 0.9 mins. (IV), 6 mins. (sublingual) Adverse effects: hypotension, vertigo, flushed skin, diaphoresis, fever, syncope, dyspnea, bradycardia Clinical uses: hypertensive emergency, angina (chest pain), acute heart failure with MI Cardiac Glycosides/ Digitalis DIGOXIN Increase force at which the heart muscles contract Digitalis Extracted from the foxglove plant (Digitalis spp.) Main drug in this class is digoxin (others: digitoxin, quabain) Digoxin acts mainly on the heart and is used in the treatment of congestive cardiac failure (CCF). CCF: failure of the heart to provide sufficient cardiac output to meet the physiological needs of the body Digitalis CCF: pumping action of ventricles is impaired resulting in back pressure of blood, with congestion of the lungs and liver, and swelling of legs In CCF- digoxin: ↑ force of contraction of the heart Digitalis MOA Binds to Na+/K+ ATPase pump and inhibits it ↑intracellular Na+ concentrations →increased intracellular Ca2+ concentrations Increased intracellular calcium concentration → increased release from the sarcoplasmic reticulum, which ↑ the FOC Digitalis Digoxin given orally or IV Half life=36- 40 hrs Interactions: quinidine, amiodarone, verapamil, NSAIDs, calcium channel blockers Adverse effects: arrhythmia (tachycardia, atrioventricular block) hypokalemia*, abdominal discomfort, nausea and vomiting Excreted via kidneys Antiplatelets ASPIRIN Prevents clotting of blood Synthesis of Prostanoids corticosteroids Phospholipid (from cell membranes) Arachidonic acid Phospholipase A2 Aspirin Prostaglandin H2 Prostaglandin Prostacyclin F2 (PGI2) Platelet inhibitor Cyclooxygenase (COX) Prostaglandin E2 Thromboxane A2 Platelet activator ASPIRIN MOA Irreversible inhibition of cyclooxygenase (COX) enzyme – specific interest – COX 1 ❖ in platelets prevents formation of thromboxane A2 (TX A2) – synthesized in platelets ❖platelet activation & aggregation prevented ❖Platelets do not synthesize new proteins ❖Therefore activity on platelet is permanent requiring new platelet formation – 7-10 day ASPIRIN Oral: 160- 320 mg /d Onset: 30-60 mins Chewable aspirin for quicker onset effect on PGI2 is spared at lower doses. Duration: 7-9 days ADR: GIT irritation Uses: prophylaxis intervention for ischemic stroke, MI ASPIRIN USED AT LOW DOSE WHY? Inhibition of PGI2 formation in endothelium at higher concentrations (prevent platelet aggregation) Anticoagulants HEPARIN & Low Molecular Weight HEPARIN (LMWH) Prevent clotting of blood HEPARINS MOA Inactivate clotting factors: IIa (thrombin), IXa, Xa, XIa and XIIa Inhibit coagulation cascade (end product fibrin) Prevent fibrin formation →clotting of blood Heparins Given: IV, subcutaneous Monitored using the activated partial thromboplastin time (aPTT) Low therapeutic index (TI) Safe in pregnancy ADRs: osteoporosis >6 months, hyperkalemia, hypersentivity rxns, heparin induced thrombocytopenia Antidote: protamine sulphate (acid/base rxn) Metabolism: heparinase enzymes Uses: deep vein thrombosis, atrial fibrillation, valvular disease Heparin-induced Thrombocytopenia (HIT) Sequela Incidence Thrombosis 30-50% Amputations 20% Death 30% Anticoagulants WARFARIN Inhibits blood clot formation WARFARIN vitamin K antagonist Structurally related to vitamin K Prevent the synthesis of clotting factors II, VII, IX & X (2,7,9,10) Inhibit coagulation cascade Prevent fibrin formation Prevent blood clot formation WARFARIN Given orally Slow onset = 48 hrs Peak anticoagulant effect 72-96 hours duration 4-5 days PPB= 99% t½ 25 - 60hrs Crosses placenta- teratogenic Metabolised by CYP450 2C9 WARFARIN ADRs: diarrhoea, bleeding (reversed with vitamin K), warfarin induced skin necrosis Low TI Monitored using: prothrombin time (PT), international normalized ratio (INR) Drug/drug interactions: inhibition/ induction of CYP enzymes, decreased absorption of vitamin K, displacement of drug from plasma proteins Uses: atrial fibrillation, deep vein thrombosis, valvular disease WARFARIN INDUCED SKIN NECROSIS A rare , serious ADR Seen 3-6 days after initiation  Ratio in males: females = 1:4  Most likely in postmenopausal women obese women  Treated with heparin