Anticoagulants, Antiplatelets, Hyperlipidemia Drugs

• This is a summary of anticoagulants, antiplatelet medications, and hyperlipidemia drugs

Thromboembolic Disorders

• These include acute myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), and acute ischemic stroke.

Resting Platelets

• Platelets that are not activated and do not aggregate, acting only when needed.

Prostacyclin

• Healthy endothelial cells release prostacyclin.
• Prostacyclin binds to receptors on platelets, which increases cAMP.
• Increased cAMP is associated with decreased calcium, leading to a lack of platelet activation and aggregation.

Thrombin, Thromboxane, and Collagen

• In the absence of injury, thrombin and thromboxane concentrations are low.
• Collagen is not exposed.
• Platelet activation and aggregation are not initiated.

Platelet Aggregation Inhibitors

• These medications inhibit COX-1, block GP IIb/IIIa receptors, or block ADP receptors.
• They are used for the prevention or treatment of cardio-occlusive diseases, maintenance of vascular grafts and arterial patency, and as adjuncts to thrombin inhibitors or thrombolytics in MI.

Aspirin

• Aspirin inhibits COX-1, preventing the formation of thromboxane A2, thus suppressing platelet aggregation for the life of the platelet.
• Uses include transient cerebral ischemia and MI, at dosages of 50mg-325mg daily.
• Enteric-coated and chewable forms exist.
• It is metabolized to salicylic acid in the liver.
• Immediate-release aspirin should be taken 60 minutes before or 8 hours after NSAIDs.
• Adverse effects include prolonged bleeding time, angioedema, bronchospasm, GI disturbances, Reye's syndrome (in children), and Stevens-Johnson Syndrome (SJS).

P2Y12 Receptor Antagonists

• Clopidogrel, prasugrel, and ticagrelor are P2Y12 receptor antagonists which block ADP from binding to its receptor.
• P2Y12 is typically used in dual antiplatelet therapy with aspirin.
• They generally require oral loading doses.

Clopidogrel

• Clopidogrel is used for the prevention of atherosclerotic events in previous MI, stroke, and peripheral artery disease (PAD).
• Also used for prophylaxis of thrombotic events in acute coronary syndrome and post percutaneous coronary intervention (PCI).
• It is a prodrug activated by CYP2C19.
• Avoid concomitant use of CYP2C19 inhibitors, such as omeprazole, to avoid drug interactions and consider alternatives in poor metabolizers.

Prasugrel

• Prasugrel is indicated to decrease thrombotic cardiovascular events in patients with acute coronary syndrome undergoing PCI.
• More potent compared to other drugs in this class.
• Should not be used in patients with a history of TIA or stroke, or in those >75 years old.

Ticagrelor

• Ticagrelor is used to prevent thromboembolism in patients with unstable angina or acute MI.
• Its effectiveness is decreased with aspirin doses > 100 mg daily.
• It is metabolized by CYP3A4.

Adverse Effects of P2Y12 Receptor Antagonists

• Prolonged bleeding and thrombocytopenic purpura (clopidogrel and prasugrel) can occur.

GPIIb/IIIa Inhibitors

• Abciximab, eptifibatide, and tirofiban are GPIIb/IIIa inhibitors, which bind to the GPIIb/IIIa receptor on platelets preventing fibrinogen from binding.
• These are used with heparin and aspirin as an adjunct to PCI.
• Administered as an IV bolus followed by IV infusion.
• Increased bleeding risk is observed with concurrent use of ginkgo biloba, SSRIs, SNRIs, and antiplatelets.

Dipyridamole

• Given with aspirin, dipyridamole inhibits phosphodiesterase to increase cAMP.
• Used for stroke prevention.
• Should not be used in unstable angina.

Cilostazol

• Cilostazol inhibits phosphodiesterase type III to increase intracellular levels of cAMP.
• Used to reduce the symptoms of intermittent claudication.
• Contraindicated in heart failure (HF).

Heparin and Low Molecular Weight Heparins (LMWH)

• They limit the expansion of thrombi by preventing fibrin formation.
• Heparin binds to antithrombin III and inhibits thrombin (IIa) and Xa.
• LMWH binds to antithrombin III and primarily inhibits Xa.
• Used in the treatment of acute thromboembolism and prophylaxis of venous thrombosis (undergoing surgery, acute MI, hospitalized patients).
• Heparin is the DOC in pregnant women needing anticoagulation.
• LMWH is useful in the outpatient setting.
• Heparin is administered IV or deep SC, with an IV bolus for immediate anticoagulation.
• LMWH is administered SC.
• Protamine sulfate is the antidote for heparin.
• Heparin can cause bleeding, antigenic responses (chills, fever, hives, anaphylactic shock), Heparin-Induced Thrombocytopenia (HIT) and osteoporosis.
• Contraindicated in hypersensitivity, bleeding disorders, alcoholism, and recent surgery of the brain/eye/spinal cord.

Argatroban

• Argatroban is a direct thrombin inhibitor, used for prophylaxis or treatment of venous thromboembolism in patients with HIT and prophylaxis of thrombi during PCI in patients at risk for HIT.

Fondaparinux

• Fondaparinux binds to antithrombin III to inhibit factor Xa.
• It is used for the treatment of DVT and PE and prevention of venous thromboembolism in orthopedic and abdominal surgery.
• Administered SC.
• Contraindicated in severe renal impairment.
• No reversal agent.

Warfarin

• Warfarin inhibits vitamin K epoxide reductase, interfering with the ability of vitamin K to act as a cofactor in the synthesis of factors II, VII, IX, and X.
• Peak effect occurs after 72-96 hours.
• Effects can be overcome with administration of vitamin K.
• Used for prevention and treatment of DVT and stroke.
• INR should be monitored - increased INR indicates increased bleeding risk, while decreased INR indicates increased clotting risk.
• INR can be increased by inhibitors (acute alcohol intoxication, amiodorone, fluconazole, metronidazole, sulfa) and decreased by inducers (chronic alcohol intoxication, barbiturates, carbamazepine, rifampin).
• Rare adverse effects include skin lesions and necrosis, purple toe syndrome.
• Contraindicated in pregnancy due to teratogenic effects.

Dabigatran Etexilate

• Prodrug that is an oral direct thrombin inhibitor.
• Used for prevention of stroke in non-valvular atrial fibrillation and treatment of DVT and PE in patients who have already received parenteral anticoagulants.
• Can cause bleeding, with idaruzcizumab as a reversal, and GI adverse effects.
• Abrupt discontinuation should be avoided due to increased risk of stroke.

Direct Factor Xa Inhibitors

• Apixaban, betrixaban, edoxaban, and rivaroxiban are drugs which inhibit Xa to reduce the conversion of prothrombin into thrombin.
• Apixaban, edoxaban and rivaroxiban are used for prevention of stroke in nonvalvular A-fib and treatment of DVT and PE.
• Betrixaban is used for prophylaxis of DVT and PE in at-risk hospitalized patients.
• Can cause bleeding, requiring renal adjustment and abrupt discontinuation should be avoided.

Thrombolytics

• These increase the conversion of plasminogen to plasmin to digest fibrin clot.
• Alteplase and tenecteplase are commonly used thrombolytics.
• Alteplase is used for treatment of acute MI, massive PE, and acute ischemic stroke.
• Tenecteplase is used for acute MI.
• For MI, thrombolytics are given via intercoronary delivery.
• Contraindicated in pregnancy, healing wounds, history of CVA, brain tumor, head trauma, intracranial hemorrhage, and metastatic cancer.
• Alteplase has a short half-life, requiring infusion after initial bolus, and may cause angioedema.

Hyperlipidemia

• Coronary artery disease is associated with high LDL and total cholesterol, and low HDL.
• Hypercholesterolemia can be caused by lifestyle or genetic defects in lipoprotein metabolism.
• Therapy includes lifestyle modifications and pharmacotherapy.

HMG-CoA Reductase Inhibitors (Statins)

• They inhibit HMG-CoA reductase, decreasing intracellular synthesis of cholesterol, which leads to cell upregulation of surface LDL receptors to internalize LDL-C.
• Examples are rosuvastatin, atorvastatin, simvastatin, pitavastatin, and lovastatin.
• First-line treatment for patients in the 4 statin benefit groups: clinical ASCVD, LDL-C ≥ 190mg/dL, diabetes type 1 or 2, age 40-75 years, or 10-year ASCVD risk ≥ 7.5% and age 40-75 years.
• High-intensity statins lower LDL on average by 50%, moderate-intensity by 30-49%.

Fibrates

• These increase lipoprotein lipase and decrease triglycerides.
• Adverse effects include mild GI discomfort, gallstones, myositis (gemfibrozil when used with statins), and increased INR when used with warfarin.

Bile Acid Sequestrants

• Cholestyramine, colestipol, and colesevelam are examples.
• They form a complex with bile acids and bile salts in intestines which is excreted in feces, leading to hepatocytes making more bile acids and bile salts using LDL-sourced cholesterol.
• Used in type IIA and IIB hypercholesterolemia, in combination with diet or niacin.
• Cholestyramine also helps with pruritis associated with biliary stasis, and colesevelam helps with glucose lowering in DM.
• Not absorbed or metabolically altered.
• Can cause GI disturbances and impaired absorption of fat-soluble vitamins and drugs (administer other drugs 1-2 hours before or 4-6 hours after BAS).

Add-On Drugs

• These include cholesterol absorption inhibitors, PCSK9 inhibitors, and omega-3 fatty acids.
• Ezetimibe is a cholesterol absorption inhibitor that provides modest LDL lowering.
• Used with maximum doses of statins or in patients who cannot tolerate statins.
• Alirocumab and evolocumab are PCSK9 inhibitors, administered SubQ every 2-4 weeks, and used with statins (50-70% LDL decrease).
• Allergic reactions are common with PCSK9 inhibitors.
• Omega-3 fatty acids lower triglycerides by 25-30% by inhibiting VLDL and TG synthesis in the liver.
• Used as an adjuvant to other therapies in patients with TG >500 mg/dL.
• Sources include marine sources, OTC fish oil capsules, and icosapent (Rx).