Lipid-Lowering Agents, Anti-Coagulants, and Anemia Drugs PDF

LIPID-LOWERING AGENTS  Lipoprotein Structure 2  Composition of Lipoproteins 3  Elevated cholesterol can be due to: 1. Lifestyle: lack of exercise and consumption of a diet containing excess saturated fatty acids 2. A single inherited gene defect in lipoprotein metabolism...

LIPID-LOWERING AGENTS  Lipoprotein Structure 2  Composition of Lipoproteins 3  Elevated cholesterol can be due to: 1. Lifestyle: lack of exercise and consumption of a diet containing excess saturated fatty acids 2. A single inherited gene defect in lipoprotein metabolism 3. A combination of genetic and lifestyle factors. 4  TREATMENT GOALS The primary goal: Reduction of the LDL level Recommendations for the reduction of LDL cholesterol to specific target levels are influenced by – Coexistence of CHD – number of other cardiac risk factors The higher the overall risk of heart disease, the more aggressive the recommended LDL-lowering therapy. 5  ATHEROSCLEROSIS A. Significance: Major cause of death in the U.S. (heart attacks and strokes) B. Risk Factors: Hypertension, age, obesity, diabetes, high fat diet, smoking, stress, low HDL, lack of exercise, family history and high plasma lipoproteins (VLDL, IDL and LDL). 6  ATHEROSCLEROSIS C. Pathogenesis: - Elevated plasma lipoproteins such as VLDL, IDL and LDL are a major risk factor in atherosclerosis - Endothelium of blood vessel is injured and blood components (LDL and platelets) infiltrate injured area. - Growth factors cause proliferation of cells and plaque starts to form at site of injury. 7  ATHEROSCLEROSIS C. Pathogenesis: (Continue) - Cells internalize LDL (oxidized) and form foam cells (saturated with fat). - Cells die and plaque is formed. - Narrowed vessel gets clogged by blood clot and stroke or heart attack is the consequence. 8  ATHEROSCLEROSIS D. Rationale of treatment: Studies have clearly demonstrated that appropriate diet and drugs reduces atherosclerosis-induced mortality 20 to 40%. 9 HMG-CoA Reductase Inhibitors (Statins) Atorvastatin, Fluvastatin Therapeutic Actions The early rate-limiting step in the synthesis of cellular cholesterol involves the enzyme HMG-CoA reductase. If this enzyme is blocked, serum cholesterol and LDL Statins levels decrease In contrast, HDL levels increase slightly with this alteration in fat metabolism.  Indications of Statins Treatment of high cholesterol and high LDL levels Prevention of a first myocardial infarction (MI) in patients with multiple risk factors Main Adverse Effects of statins Headache Hepatotoxicity Myopathy (muscle tenderness) and rhabdomyolysis Fibrates (Fibric acid derivatives) Drugs: Fenofibrate They lower serum triacylglycerol and increase HDL levels  Pharmacological effects of Fibrates Increase expression of lipoprotein lipase, which enhances clearance of triglyceride rich lipoproteins. Increase the level of HDL Moderately reduce LDL Indications To decrease triglycerides levels To increase HDL levels To reduce LDL Main adverse effects: Myopathy (Myositis): - Inflammation of skeletal muscles) causing muscle weakness and tenderness - Rhabdomyolysis can occur - Risk is greatly increased in combination with statins (contraindicated) Nausea Skin Rash 15  Niacin (nicotinic acid) Pharmacological actions:  It reduces VLDL and TG production  Effective in reducing LDL  The most effective in increasing HDL 16 Adverse effects of Niacin Cutaneous dilator – flushing, itching Liver dysfunction Hyperglycemia 17 DRUGS AFFECTING BLOOD COAGULATION  Anti-Clotting Thrombolytics Anti-Platelet Aggregation Anti-Blood Coagulation (Antiplatelets) (Anticoagulants) 19  Platelet activation inhibitors Blockade of ADP Blockade of GP COX-1 inhibition receptors IIb/IIIa Aspirin Clopidogrel Abciximab Ticagrelor 20 COX-1 inhibition 21  Aspirin (Acetylsalicylic acid) Mechanism of action: irreversibly inhibit COX-1 enzyme in the platelets, thus prevents TXA2 synthesis, thereby preventing platelets aggregation. Platelets do not have nuclei, thus cannot produce new COX-1 Inhibition of platelet aggregation lasts for the life of the platelets (7-10 days) 22  Therapeutic use of Aspirin (Acetylsalicylic acid) Prophylactic treatment of:  Transient cerebral ischemia  Prevention of MI 23  Adverse effects of Aspirin (Acetylsalicylic acid) It increases bleeding time: increase risk of hemorrhagic stroke and GI bleeding (especially at high doses) Allergy 24 Blockade of ADP receptors 25  Blockade of ADP receptors Clopidogrel Ticagrelor Mechanism of action: Block the P2Y ADP receptors on platelets, which is necessary for platelet activation 26 Therapeutic uses: Clopidogrel: Prevention of thrombosis associated with: Atherosclerotic events with recent MI or stroke Acute coronary syndrome (unstable angina) Percutaneous coronary intervention (PCI), with/without coronary stenting PCI 27  Side effects These agents can prolong the bleeding time  No antidote available  More pronounced with Prasugrel & Ticagrelor 28 Blockade of GP IIb/IIIa 29  Abciximab Mechanism of action: they block GP IIb/IIIa receptors on the platelets, thus prevent the binding of fibrinogen and von Willebrand factor. 30  Therapeutic uses of GP IIb/IIIa receptor blockers Given IV with Heparin & Aspirin as adjunct to PCI to prevent cardiac ischemic complications. Abciximab is approved for unstable angina not responding to conventional therapy when PCI is planned within 24 hr Adverse effects: Bleeding especially if used with anticoagulants 31 Blood coagulation 32  Blood coagulation Intrinsic pathway Extrensic pathway Vascular injury Expose collagen Vascular injury to blood XII XIIa Expose tissue factor XI XIa (Thromboplastin) IX IXa VIIa VII X Xa X Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin  Anticoagulants They work by two mechanisms: I. inhibit the action of the coagulation factors (e.g. Heparin) or II. inhibit the synthesis of these factors (e.g. Warfarin). 34  Heparin Large sulfated polysaccharide polymer obtained commercially from porcine intestinal mucosa Molecular weight: 15,000-20,000 Highly acidic, can be neutralized by Protamin (basic molecule) that function as an antidote. 35  Heparin Half life: 1.5 hr Administration: SC or IV bolus (loading dose) followed by slow IV infusion. It causes hematoma when given IM 36  Low-Molecular Weight Heparins (LMWHs) Drugs: Enoxaparin Molecular weight: 2000-6000 Longer duration of action, 3-12 hr (given less frequently, once or twice daily) Administration: SC 37  Mechanism of action of Heparin & LMWHs Heparin inactivate factors IIa and Xa + ATIII LMWH inactivate factor Xa only 38  Therapeutic uses of Heparin & LMWHs Provides an immediate anticoagulant activity Given in the following cases: - Acute venous thrombosis (DVT & PE) - Prophylaxis of post-operative thrombosis - Acute MI 39  Therapeutic uses of Heparin & LMWHs Safe in pregnancy (do not cross the placenta) The anticoagulant activity of Heparin is monitored by “activated partial thromboplastin time” test (aPTT). 40  Adverse effects of Heparin & LMWHs Bleeding: - May result in hemorrhagic stroke  Discontinue Heparin and give slow IV infusion Protamine sulfate. 41  Adverse effects of Heparin & LMWHs Hypersensitivity reactions: because it comes from Porcine Heparin-induced thrombocytopenia (HIT): - Serious condition - Immune-mediated - Risk of venous & arterial embolism 42  FondaparinuX Small synthetic drug Structure-activity relation ship similar to LMWHs Selectively binds ATIII and increase neutralization of factor Xa by ATIII Indication: treatment and prevention of DVT & PE 43  Direct thrombin (IIa) inhibitors Drugs: - Dabigatran etexilate Mechanism of a action: Directly inhibit thrombin (IIa) thereby inhibit fibrin generation 44  Inhibitors of factor Xa Drugs: - Rivaroxaban Mechanism of a action: Directly inhibit factor Xa thereby inhibit thrombin generation Administered orally Therapeutic uses: Prevention of DVT, PE and stroke Side effects: Bleeding (antidote: coagulation factor Xa [recombinant] 45  Coumarin anticoagulants (Warfarin) This family of drugs is used as rudenticide Warfarin is the only one used clinically Warfarin has narrow therapeutic window Requires continuous monitoring by INR test 46  Mechanism of action of Warfarin Inhibit Vitamin K reactivation Inhibit clotting factor synthesis by the liver 47  Therapeutic uses of Warfarin Prophylaxis and treatment of DVT & PE Prevention of thromboembolism during surgery Thromboembolic disorders:  Atrial fibrillation  Patients with prosthetic valves  Following MI 48  Side effects of Warfarin Bleeding: requires monitoring by INR test, also called prothrombin time (PT) test Antidote: Vitamin K Teratogenic 49  Thrombolytic Drugs Streptokinase Alteplase 50  Thrombolytic Drugs Mechanism of action: They facilitate the conversion of Plasminogen to Plasmin (a protease that hydrolyzes fibrin meshwork) thus dissolve clots and tissue reperfusion occurs. All are given IV Thrombolytics 51  Clinical uses of thrombolytic drugs Treatment of acute thrombosis: Acute MI Acute ischemic stroke (hemorrhagic stroke must be excluded before) DVT & PE  Effective within the first 2 - 6 hr only  Their tendency to cause bleeding limited their use 52 Drugs Used to Treat Bleeding 53  Causes of inadequate blood clotting Vit K deficiency Genetic mutation of clotting factors - Factor VIII: hemophilia A - Factor IX hemophilia B Drug induced Thrombocytopenia 54  Vit K deficiency Most common causes: Elderly with impaired absorption of fat Newborns Dietary deficiency Antimicrobial therapy 55  Treatment of Vit K deficiency Oral or parenteral administration of Phytonadione (vit. K) It is recommended that all newborns should receive an injection of Phytonadione at birth 56  Clotting factors Clotting factors are obtained by recombinant DNA technology 57  Antiplasmin Agents Drugs: Tranexamic acid MOA: Inhibit plasminogen activation, thus inhibit fibrinolysis Clinical indication: Prevention and management of acute bleeding episodes in patients with hemophilia or other bleeding disorders Risk: MI, stroke, renal damage Antiplasmin Agents 58