Summary of Drugs for Cardiovascular System Part II (1445)

Cardiovascular system Part II ‫كليــة الصيدلة‬ Short Review on Drugs for Dyslipidemia (Lipid-lowering drugs)  Dyslipidemia Definition:  Dyslipidemia is defined as elevated total cholesterol (TC), low-density lipoprotein chol...

Cardiovascular system Part II ‫كليــة الصيدلة‬ Short Review on Drugs for Dyslipidemia (Lipid-lowering drugs)  Dyslipidemia Definition:  Dyslipidemia is defined as elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), or triglycerides (TG)  With low HDL-C (high-density lipoprotein cholesterol); or a combination of these abnormalities.  Disorders of lipid metabolism occur as primary conditions that may be familial or polygenic in origin, or secondary to an underlying disease state or drug treatment Risks of dyslipidemias:  The risk of atherosclerosis is directly related to increasing levels of serum cholesterol  Abnormalities of plasma lipids can result in a predisposition to ischaemic heart disease (IHD), cerebrovascular and peripheral vascular diseases.  Pathophysiology of dyslipidemia Cholesterol, triglycerides, and phospholipids are transported in the bloodstream as complexes of lipid and proteins known as lipoproteins. Abbreviations: FFA, free fatty acids; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein Serum Levels of Lipids  Non-pharmacological treatment of dyslipidemia In a compliant and motivated patient total cholesterol may be reduced by about 10% within a few months of adherence to dietary modification such as: 1. Reduced intake of saturated fats (red meat, dairy products, egg yolk) 2. In the obese patient, reduce total calorie intake 3. Increase the intake of unsaturated fats (Olive oil, salmon, cashews, almonds) 4. Increase the level of physical activity  Lipid-lowering drugs Drugs Mechanism of action Examples Adverse effects Statins Inhibit the enzyme HMG CoA reductase, Atorvastatin, Muscle pain (Myositis), responsible for cholesterol synthesis Simvastatin, Liver damage Rosuvastatin Ezetimibe Decreases cholesterol absorption in the Ezetimibe Headache small intestine Nicotinic acid Decreases hepatic VLDL secretion Niacin Myositis, Flushing (Niacin)-Vit B3 Fibrates Agonist of PPAR-alpha therefore increases Gemfibrozil, Myositis, pruritus, lipoprotein lipase expression Fenofibrate cholestasis Cholestyramine Binds bile acid and decreases its Cholestyramine GI side-effects reabsorption in the small intestine. As a result, more cholesterol is used to synthesize bile acids. Lipid-lowering drugs Sites of action of HMG-CoA reductase inhibitors, PCSK9 MAB, niacin, ezetimibe, and resins used in treating hyperlipidemias. VLDL: very-low-density lipoproteins R: LDL receptor L: lysosome HMG-CoA: 3-hydroxy-3-methylglutaryl- coenzyme A PCSK9 mAbs: Proprotein convertase subtilisin/kexin 9 monoclonal antibodies B-100: apolipoprotein B-100 (apoB-100) Pulmonary arterial hypertension (PAH): features and management ‫كليــة الصيدلة‬ Pulmonary arterial hypertension (PAH): is defined as a sustained elevation in mean pulmonary arterial pressure of greater than 25 mmHg at rest or 30 mmHg after exercise. Classification: Group 1: Cause unknown (idiopathic) pulmonary arterial hypertension Group 2: Pulmonary hypertension caused by left-sided heart disease such as mitral valve or aortic valve disease Group 3: Pulmonary hypertension secondary to lung disease/hypoxia: - COPD - High altitude - Sleep apnea - Interstitial lung disease (ILD) Group 4: Pulmonary hypertension due to thromboembolic disease Group 5: Miscellaneous conditions. e.g. secondary sarcoidosis Features: Exertional dyspnea is the most frequent symptom Chest pain and syncope may also occur Loud P2 (Pulmonic closure sound P2) Left parasternal heave (due to right ventricular hypertrophy) Management: should first involve treating any underlying conditions, for example with anticoagulants or oxygen. Following this: Acute vasodilator testing: aims to decide which patients show a significant fall in pulmonary arterial pressure following the administration of vasodilators such as IV Epoprostenol or inhaled nitric oxide. Pathophysiology of PAH: 3 pathways are involved in the pathogenesis of PAH: 1- Nitric oxide pathway 2- Prostacyclin pathway 3- Endothelin pathway  If there is a positive response to acute vasodilator testing: Oral calcium channel blockers. If there is a negative response to acute vasodilator testing:  Endothelin receptor antagonists: Bosentan and ambrisentan (They significantly reduce pulmonary artery pressure, but adverse effects include peripheral oedema and liver function monitoring is recommended). Prostacyclin analogues: iloprost, treprostinil Phosphodiesterase- 5 (PDE-5) inhibitors: sildenafil Drugs Affecting Blood Coagulation Platelet Aggregation and Blood Coagulation Antiplatelet Drugs Anticoagulants  Anticoagulants: injectable Standard heparin Low molecular weight heparin (LMWH) Administration Intravenous Subcutaneous Duration of Short Long action Side-effects Bleeding Bleeding Heparin-induced thrombocytopaenia (HIT) Lower risk of HIT and Osteoporosis osteoporosis with LMWH Heparin overdose may be Monitoring Activated partial Anti-Factor Xa (although reversed by protamine thromboplastin time routine monitoring is not (APTT) required) sulphate, although this only partially reverses the effect of Notes Useful in situations where Now standard in the LMWH. there is a high risk of management of venous bleeding as thromboembolism anticoagulation can be treatment and prophylaxis terminated rapidly and acute coronary syndromes  Anticoagulants: Oral Warfarin Warfarin is an oral anticoagulant which inhibits the reduction of vitamin K to its active hydroquinone form, which in turn acts as a cofactor in the carboxylation of clotting factor II, VII, IX and X (mnemonic = 1972) and protein C. Indications Venous thromboembolism Atrial fibrillation, Mechanical heart valves Narrow therapeutic index Patients on warfarin are monitored using the INR (international normalised ration), the ratio of the prothrombin time for the patient over the normal prothrombin time. Warfarin has a long half-life and achieving a stable INR may take several days.  Anticoagulants: Oral Warfarin Factors that may potentiate warfarin  Liver disease  P450 enzyme inhibitors, e.g.: amiodarone, ciprofloxacin  Cranberry juice  Drugs which displace warfarin from plasma albumin, e.g. NSAIDs  Drugs which inhibit platelet function: NSAIDs  Anticoagulants: Oral Warfarin Side-effects Hemorrhage Teratogenic, although can be used in breast-feeding mothers Skin necrosis: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis purple toes DOACs Direct oral anticoagulants have a fixed dosing regimen and do not require frequent monitoring, offering greater convenience to patients compared to Vitamin K antagonists (e.g. warfarin). Not approved in mechanical heart valves