Mixed Pharm Exam 3

Hyperlipidemia

• Coronary heart disease is associated with high LDL and total cholesterol, and low HDL levels
• Other risk factors include smoking, hypertension, obesity, diabetes mellitus, chronic kidney disease, and advanced age
• Hypercholesterolemia can be caused by lifestyle and genetic defects in lipoprotein metabolism
• Therapy includes lifestyle modifications and pharmacotherapy

Hyperlipidemia Guidelines

• Emphasize a heart-healthy lifestyle for everyone
• Reduce low-density lipoprotein cholesterol with high-intensity statin therapy or maximally tolerated statin therapy in patients with clinical atherosclerotic cardiovascular disease
• In very high-risk atherosclerotic cardiovascular disease, use a low-density lipoprotein cholesterol threshold of 70 mg/dL to consider adding non-statins to statin therapy
• Begin high-intensity statin therapy in patients with severe primary hypercholesterolemia (low-density lipoprotein cholesterol level ≥190 mg/dL) without calculating 10-year atherosclerotic cardiovascular disease risk
• Start moderate-intensity statin therapy without calculating 10-year atherosclerotic cardiovascular disease risk in patients 40 to 75 years of age with diabetes mellitus and low-density lipoprotein cholesterol ≥70 mg/dL
• Have a clinician-patient risk discussion before starting statin therapy in adults 40 to 75 years of age evaluated for primary atherosclerotic cardiovascular disease prevention
• Start a moderate-intensity statin if a discussion of treatment options favors statin therapy in adults 40 to 75 years of age without diabetes mellitus and with low-density lipoprotein cholesterol levels ≥70 mg/dL, at a 10-year atherosclerotic cardiovascular disease risk of ≥7.5%
• Risk-enhancing factors favor initiation of statin therapy for patient age 40 to 75 without diabetes with a 10-year risk of 7.5% to 19.9%
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium for adults 40 to 75 years of age without diabetes mellitus and with low-density lipoprotein cholesterol levels ≥70 mg/dL-189 mg/dL, at a 10-year atherosclerotic cardiovascular disease risk of ≥7.5% to 19.9%
• Assess adherence and percentage response to low-density lipoprotein cholesterol-lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.

HMG-CoA Reductase Inhibitors

• Inhibits HMG-CoA Reductase
• Decreases intracellular cholesterol synthesis
• Cell upregulates surface LDL receptors to internalize LDL-C
• Decreases plasma cholesterol levels
• First line treatment for patients in 4 statin benefit groups
• ASCVD Risk Score Calculator: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/
• Effective in all types of hypercholesterolemia
• Homozygous familial hypercholesterolemia: Less benefit
• L or S, rosuvastatin or simvastatin, are prodrugs hydrolyzed to active drug
• Metabolized by cytochrome P450 enzymes except pravastatin
• Increases the effect of warfarin
• Adverse drug effects include elevated liver enzymes and myopathy and rhabdomyolysis
• Contraindicated in pregnancy and active liver disease

High-Intensity Statin Therapy

• Daily dose lowers LDL on average by ≥50% eg. Atorvastatin 40-80 mg, Rosuvastatin 20-40 mg

Moderate-Intensity Statin Therapy

• Daily dose lowers LDL on average by approximately 30-49%
• Atorvastatin 10-20 mg, Rosuvastatin 5-10 mg, Simvastatin 20-40 mg, Pravastatin 40-80 mg, Lovastatin 40 mg, Fluvastatin XL 80 mg, Fluvastatin 40 mg BID, Pitavastatin 2-4 mg

Low-Intensity Statin Therapy

• Daily dose lowers LDL on average by <30% eg. Simvastatin 10 mg, Pravastatin 10-20 mg, Lovastatin 20 mg, Fluvastatin 20-40 mg

Niacin

• Effective at increasing HDL and reducing triglycerides (20-35%)
• Inhibits lipolysis in adipose tissue
• Reduces production of FFA in adipose, circulating FFA, formation of TG in the liver, and hepatic VLDL production
• Used for familial hyperlipidemia and severe hypercholesterolemia
• Adverse effects include Flushing, Nausea, abdominal pain, Hyperuricemia, gout, Impaired glucose tolerance, and Hepatotoxicity

Fibrates

• Decreases TG most compared to other agents
• Increases HDL
• Very modest decrease of LDL
• Activates PPAR resulting in an Increased expression of lipoprotein lipase and Decreased TG
• Used to treat Hypertriglyceridemia
• Adverse effects include Mild Gl discomfort and Gallstones
• Increases the risk of Myopathy and rhabdomyolysis must be evaluated with muscle weakness or tenderness
• Increased INR when used with warfarin

Bile Acid Sequestrants

• Forms a complex with bile acids and bile salts in intestines which is then excreted in feces.
• Hepatocytes make more bile acids and bile salts using LDL sourced cholesterol
• Used in patients that have Type IIA and IIB Hypercholesterolemia, in combination with diet or with niacin
• Colesevelam lowers glucose in diabetic patients
• Cholestyramine is used to treat pruritis associated with biliary stasis
• Not absorbed or metabolically altered
• Adverse effects include GI disturbances and Impaired absorption of fat-soluble vitamins (KADE)
• Impaired drug absorption so should be given 1-2 hours before, or 4-6 hours after BAS

Adjuvants

• Cholesterol Absorption Inhibitor: Ezetimibe inhibits absorption of dietary and biliary cholesterol, results in modest LDL lowering (18 – 23%) and is used in conjunction with max doses of statins or in patients who can't tolerate statins
• PCSK9 Inhibitors: Alirocumab, Evolocumab decrease breakdown of LDL receptors, increasing uptake of LDL into hepatocytes from subcutaneous administration every 2 to 4 weeks with statins (50-70% LDL decrease) or in intolerant patients, allergic reactions most common
• Omega-3 Fatty Acids: Lower TG 25-30% by inhibiting VLDL and TG synthesis in the liver. Use: Adjuvant to other therapies in pts with TG > 500mg/dL from sources such as Marine, OTC Fish Oil capsules, and Icosapent (Rx)

Platelets, Clotting and Medications

• Thrombosis or Hemophilia are types of Hemostasis Disorders
• Arterial thrombus are platelet rich while venous thrombus are rich in fibrin
• Resting platelets are not activated and do not aggregate
• Healthy endothelial cells release Prostacyclin which Binds to platelet receptors, increasing cAMP, and Lack of platelet activation and aggregation
• Aspirin is an Inhibitor of COX-1 that Prevents formation of Thromboxane A2 with Irreversible inhibition
• Suppression of platelet aggregation for the life of a platelet
• Use Aspirin to treat Transient cerebral ischemia and MI in a 50mg-325mg Daily dose
• Caution in Enteric coated patients and avoid Gl upset and Chewable patients
• Aspirin metabolized to salicylic acid in the liver and IR aspirin must be consumed 60 min before or 8 hours after NSAIDS
• Prolonged bleeding time, Angioedema, Bronchospasm, GI Disturbances, Reye syndrome in liver failure, and SJS are Adverse drug effects of aspirin
• P2Y12 Receptor Antagonists, Clopidogrel, Prasugrel, Ticagrelor, works to block ADP from binding to its receptor
• Clopidogrel is a prodrug
• Used in a dual antiplatelet therapy with ASA to Prevent atherosclerotic event in previous MI, Stroke, and PAD and Prophylaxis of thrombotic events in Acute Coronary Syndromes involving PCI
• Prasugrel: Decrease thrombotic CV events in patients with ACS undergoing PCI
• Ticagrelor: Prevent thromboembolism in patients with unstable angina or Acute MI
• Clopidogrel is a prodrug activated by CYP2C19, avoid inhibitors such as Omeprazole and use alternative in poor metabolizers
• Prasugrel: Not in patients with history of TIA or Stroke or > 75 yo
• Ticagrelor: decreased effectiveness with ASA > 100mg daily, metabolized by CYP3A4
• IV only administration of Abciximab, Eptifibatide, and Tirofiban should be Given with heparin and aspirin as an adjunct to PCI to Bind to the GP IIb/IIIa receptor on platelets preventing fibrinogen from binding
• Increased bleeding seen with ginkgo biloba, SSRIs, and SNRIs, antiplatelets with side effect, Bleeding
• Dipyridamole Inhibits phosphodiesterase to increase intracellular levels of cAMP
• Typically given with ASA for Stroke prevention in patients with previous Ischemic Stroke or TIA and should Not use in patients with unstable angina
• Cl in HF with Cilostazol medication to reduce the symptoms of intermittent claudication

Anticoagulation

• Binds to antithrombin III and inhibits thrombin (IIa) and Xa for heparin while LMWH binds to antithrombin III and inhibit Xa
• Administer Hemoglobin in venous (IV)
• Administer LMWH for pregnant women and may be useful in outpatients with LMWH
• Heparin: IV or Deep SC. IV bolus for immediate anticoagulation then lower doses or continuous infusion
• Anticoagulation within minutes of IV admin
• Unpredictable response: Monitor aPTT or Xa
• LMWH: SC. Anticoagulation about 4 hours after SC admin
• Predictable response: Monitoring not required*
• Contraindications hypersensitivity, bleeding disorders, alcoholism, recent surgery of the brain/eye/spinal cord with side effects, Bleeding
• Treatment Protamine sulfate
• Argatroban is a Direct thrombin inhibitor that treats venous thromboembolism of patients with HIT
• Fondaparinux: Binds to Antithrombin III to inhibit factor Xa
• Used for Treatment of DVT & PE and Prevention of venous thromboembolism in orthopedic and abdominal surgery
• Warfarin inhibits inhibits vitamin K epoxide reductase to act as a co-factor in the synthesis of factors II, VII, IX, X
• Overcome with administration of vitamin K and may cause bleeding
• Dabigatran etexilate is given in a prodrug used as Oral Direct Thrombin Inhibitor
• Uses Prevention of stroke in nonvalvular A-fib and Treatment of DVT & PE for patients who need anticoagulants
• Caution in bleeding for Idaruzcizumab to reserve
• Avoid abrupt changes
• Direct Xa Inhibitors: Apixaban, Betrixaban, Edoxaban, Rivaroxiban inhibit Xa to reduce the conversion of prothrombin into thrombin
• Direct Xa: Prevention of stroke in non-valvular A-fib, treatment of DVT & PE prophylaxis of DVT & PE in at-risk hospitalized patients
• Thrombolytics: Alteplase & Tenecteplase which increase conversion of plasminogen to plasmin to digest fibrin clot