CV Pharmacology - Cholesterol & Angina 2024 PDF

BMS2047 - PHARMACOLOGY: INTRODUCTION TO DRUG ACTION CV PHARMACOLOGY DR PENNY LYMPANY [email protected] 28AY04 OUTLINE Hypercholesterolaemia Statins Angina/coronary artery disease Thrombosis HYPERCHOLESTEROLAEMIA CHOLESTEROL Cholesterol key facts Chole (bile), stereos (solid), -ol (alcohol) Ster...

BMS2047 - PHARMACOLOGY: INTRODUCTION TO DRUG ACTION CV PHARMACOLOGY DR PENNY LYMPANY [email protected] 28AY04 OUTLINE Hypercholesterolaemia Statins Angina/coronary artery disease Thrombosis HYPERCHOLESTEROLAEMIA CHOLESTEROL Cholesterol key facts Chole (bile), stereos (solid), -ol (alcohol) Steroid component of animal membranes and precursor of steroid hormones (cortisol, aldosterone etc), sex hormones (testosterone, oestrogen), Vit D, bile salt Synthesised from Acetyl-CoA in the ER Regulation of synthesis in liver by changes in 3-Hydroxy-methylgluatryl coenzyme A (3-HMG CoA) reductase Transported in complex with proteins (lipoproteins) – HDL, IDL, LDL, VLDL, chylomicrons Cholesterol and other lipids in excess of those needed by liver are exported as VLDL, then converted to LDL Liver takes up LDL by receptor mediated endocytosis. Cholesterol CHOLESTEROL & LDL High cholesterol → atherosclerosis Contributes to many CV diseases Origin – early in life Progression → symptomatic manifestation Takes decades Lifestyle risk factors Obesity, smoking, alcohol consumption, hypertension, type II diabetes Raised LDL or lowered HDL Genetic risk factors HMG CoA reductase polymorphism (activates LDL receptors) LDL-R gene polymorphism – familial hypercholesterolemia ATHEROSCLEROSIS https://www.nature.com/articles/nature01323 STATINS – LIPID LOWERING DRUGS Statins INTESTINE LIVER HMG CoA Melvalonic acid Chylomicron LDL-R Healthy numbers Total cholesterol ≤ 5mMol/L Non HDL ≤ 4mMol/L LDL ≤ 3mMol/L TC/HDL ratio ≤ 6 www.heartuk.org.uk HMG CoA reductase Lipids Cholesterol LDL-R VLDL Lipoprotein lipase BLOOD VESSEL ANGINA/CORONARY ARTERY DISEASE ANGINA IN CORONARY HEART DISEASE Angina “chest pain” is a symptom of coronary heart disease Coronary artery disease Narrowing/blocking of coronary arteries Often due to atherosclerotic plaques ANGINA Increased O2 demands Increased cardiac O2 demands Exercise Ischaemia Mild ischaemia Release of mediators K+, H+, adenosine Vasodilatation & pain ANGINA – CONT. Stable angina Chest pain on exertion (predictable) Increased demand on the heart Fixed narrowing(s) of coronary vessels Or aortic stenosis Unstable angina Chest pain occurs with less & less exertion – pain at rest Pathology similar to MI Platelet & fibrin thrombus with ruptured atheroma Not complete occlusion Drugs.com TREATMENT FOR ANGINA Nitrates - relax smooth muscle Metabolised - release nitric oxide (NO) NO binds sGC produces cGMP which activates PKG PKG – inhibits myosin light chain kinase (MLCK) contraction +++ Vasodilatation Β-blockers Negative inotropic effect - ↓ force of heartbeat Decrease heart rate Atenolol (β1 selective) Decrease work done & O2 demand Angina Glyceryl trinitrate, nitroprusside Decrease work done & O2 demand, increases blood flow in coronary arteries Ca2+ channel blockers Inhibits Ca2+ influx → ↓SMC contraction Vasodilatation sGC - soluble guanylyl cyclase Nifedipine (vascular), verapamil (heart) Decrease pre & post-load, work done & O2 demand THROMBOSIS COAGULATION CASCADE PAF, platelet-activating factor; TXA2, thromboxane A2. Rang & Dale’s Pharmacology 8th Ed THROMBIN VITAMIN K Fat soluble vitamin Essential for formation of clotting factors Factor II Factor VII Factor IX Factor X Essential for production of protein C & S (anti-coagulants) Occurs in plants (green leafy veg) and can be synthesised by gut flora Potential for deficiency – coeliac disease, steatorrhea THROMBOSIS Thrombotic & thromboembolic disease has severe consequences Myocardial infarction Stroke Deep vein thrombosis Pulmonary embolism Drugs Antiplatelet & fibrinolytic drugs Platelet-rich arterial thrombi Anticoagulants Venous thrombi ANTICOAGULANTS – SITES OF ACTION Rang & Dale’s Pharmacology HEPARINS Heparin endogenous anticoagulant Not a single substance – family of glycosaminoglycans Found in mast cell granules Extracted from animals Needs to be assayed for potency which is stated in units of activity rather than mass Used in patients where LMWH unsuitable – patients with renal failure Heparin fragments/low-molecular-weight heparins (LMWH) More commonly used than extractions from animals LMWHs – preferred, longer-acting, more predictable pharmacokinetic profile Enoxaparin, dalteparin, fondaparinux MECHANISM OF ACTION HEPARIN AND LMWHS Rang & Dale’s Pharmacology 8th Ed NOVEL ANTICOAGULANTS Direct thrombin inhibitors & related drugs Hirudins – direct thrombin inhibitors, do not rely on ATIII activation Given i.v. Used for thromboembolic disease (patients with type 2 HIT) – Lepirudin Prior and during and after percutaneous coronary artery surgery – Bivalirudin (combined with aspirin and clopidogrel Bind to the fibrin-binding and catalytic sites on thrombin (often irreversibly) Orally active drugs Dabigatran – synthetic serine protease inhibitor (knee and hip replacement) – rapid acting Rivaroxaban – direct inhibitor of Factor Xa - DVT WARFARIN Vitamin K antagonist Requires frequent blood tests to titre dose Lifestyle changes ?interactions Rang & Dale’s Pharmacology 8th Ed WARFARIN Onset of action – several days Distribution – strongly bound to plasma proteins Can cross the placenta Avoid first few months of pregnancy – teratogenic Avoid latter stages of pregnancy - intracranial haemorrhage during delivery Therapeutic balance required Monitored by measuring prothrombin time (PT) Expressed as international normalised ratio (INR) Looking to achieve INR of 2-4 FACTORS THAT POTENTIATE WARFARIN Disease Liver disease – impairs synthesis of clotting factors High metabolic rate – fever- increase degradation of clotting factors Drugs Inhibition of hepatic drug metabolism Ciprofloxacin, metronidazole, some NSAIDs and many antifungal azoles Inhibition of platelet function NSAIDs (inc. aspirin) – inhibition of thromboxane synthesis Some antibiotics – moxalactam, carbenicillin Displacement of warfarin from plasma albumin Some NSAIDs and chloral hydrate Inhibition of vitamin K reduction Cephalosporins Decrease vitamin K availability Broad spectrum antibiotics & sulphonamides FACTORS WHICH ATTENUATE WARFARIN Physiological/disease state Pregnancy Hypothyroidism Drugs Vitamin K supplementation Induction of P450 enzymes Metabolised by CYP2C9 – rifampicin, carbamazepine Reduce warfarin absorption Bind to warfarin in the gut - colestyramine Antiplatelet drugs ▪ Aspirin ▪ Low-dose chronic use, inhibits platelet thromboxane synthesis ▪ Irreversibly inhibits COX-1 ▪ Efficacious in ▪ Thrombotic stroke evolution ▪ Acute myocardial infarction ▪ Initial dose of 300mg followed by daily 75mg doses ANTIPLATELET DRUGS Dipyridamole Inhibits platelet aggregation – inhibits TXA2 synthesis Effects are additive to aspirin’s Side effects – dizziness, headache, GI disturbances Unlike aspirin does not increase bleeding ADP receptor (purine P2YX1/12) antagonists Combine with aspirin – unstable coronary artery disease Can be used as a single agent in patients intolerant to aspirin Clopidogrel, prasugrel, ticagrelor Glycoprotein IIB/IIIA receptor antagonists Inhibit all platelet activation pathways Abciximab – high risk patients undergoing coronary angioplasty Tirofiban, eptifibatide – give i.v. reduce early events in acute coronary syndrome ANTI-PLATELET DRUGS - TARGETS Rang & Dale’s Pharmacology 8th Ed LEARNING OUTCOMES Describe and explain the mechanism of action for selected drugs in the treatment of: Hypercholesterolaemia Angina/coronary artery disease Anti-coagulants ? 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