Anticoagulants Pharm

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Clot that adheres to a vessel wall

Thrombus

Intravascular clot that floats around in the blood

Embolus

most often appear in medium arteries that have plaque in them—this thrombus is platelet-rich clot

Arterial thrombosis

Triggered by stasis or inappropriate activation of the clotting cascade—this clot is rich in fibrin with fewer platelets

Venous thrombosis

-MOA: Inhibits thromboxane A2 synthesis by acetylation of a serine residue on the active site of COX1, irreversibly inactivating the enzyme -This shifts the balance of chemical mediation to favor anti-aggregation effects of prostacyclin—thus preventing platelet aggregation

Aspirin

Uses for Asprin

• Preventative therapy for TIA • Reduce recurrent MI • Decrease mortality in primary and secondary prevention of MI • Complete inactivation of platelets occurs with 75 mg of ASA daily • Antiplatelet dose ranges from 50- 325 mg daily

Pharmacokinetics of Aspirin

• When taken orally, it is absorbed by passive diffusion in the liver • Metabolized in the liver and some is excreted in the liver • 1⁄2 life is 15-20 minutes • 1⁄2 life is 3-12 hours

ADEs of Aspirin

• High doses are toxic and inhibit prostacyclin production • Bleeding time is prolonged • NSAIDs with ASA increases bleeding

Clopidogrel is the prototype drug, and includes Ticlopidine, Prasugrel, Ticagrelor, and Cangrelor

P2Y12 Receptor Antagonists

MOA: inhibit the binding of ADP to P2Y12 receptor on platelets—inhibiting activation of the GP IIa/IIIb receptors needed for platelets to bind to fibrinogen and to each other

P2Y12 Receptor Antagonists

• Prevent CV events in those with recent MI or stroke and in those with PAOD • Prevention of thrombosis of acute coronary syndromes • Prevent thrombosis from PCI with or without coronary stenting

Clopidogrel

• Similar to Clopidogrel, used to prevent TIA and strokes in patients with prior cerebral thrombotic event • Due to hematologic ADEs—reserved for those intolerant to other agents

Ticlopidine

Approved to decrease thrombotic CV events in those with acute coronary syndromes

Prasugrel

Approved for prevention of arterial thrombo- embolism in those with unstable angina and acute MI, including those undergoing PCI

Ticagrelor

Approved as an add- on during PCI to reduce thrombotic events in select patients

Cangrelor

• These agents require oral loading dose for quicker effect [except Cangrelor—fast onset with IV route] • Food interferes with Ticlopidine, but not with the others • Drugs extensively protein bound • Hepatic metabolism by CYP 450 into active metabolites • Elimination of drugs and metabolites is renal and fecal

Pharmacokinetics of P2y12 Receptor Antagonists

• Is a prodrug and a P2y12 Receptor Antagonist—metabolized by CYP 450 2C19 • Genetic polymorphisms of the CYP 450 2C19 leads to reduced effect in those who are “poor metabolizers” • Other drugs that inhibit CYP 450 2C19, such as Omeprazole and Esomeprazole, should not be used with this drug

Clopidogrel

Associated with hematologic reactions that limit its use— agranulocytosis, TTP, aplastic anemic

ADEs of Ticlopidine

• Fewer SE than Ticlopidine and low incidence of neutropenia • TTP has been reported

ADEs of Clopidogrel

• TTP has been reported • Contraindicated in those with a history of TIA or stroke • BB warning for bleeding

ADEs of Prasugrel

BB warning for bleeding

ADEs of Cangrelor

• BB warning for bleeding • BB warning for decreased effectiveness with concomitant use of ASA about 100 mg/day

ADE of Ticagrelor

Abciximab is the prototype and includes Eptifibatide and Tirofiban

Glycoprotein IIb/IIIa Inhibitors

• Antibody that inhibits GP IIb/IIIa receptor complex • By binding to GP IIb/IIIa it blocks binding of fibrinogen and von Willebrand factor—aggregation does not occur

Abciximab

• Act similarly to Abciximab • Cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine- glycine-aspartic acid sequence of fibrinogen

Eptifibatide

• Act similarly to Abciximab • Not a peptide, but blocks as the same site as Eptifibatide

Tirofiban

-Coronary vasodilator; increases cAMP by inhibiting phosphodiesterase—resulting in less thromboxane A2 synthesis -May potentiate effect of prostacyclin and decrease platelet adhesion to thrombogenic surfaces -Usually given with ASA for stroke prevention

Dipyridamole

-Usually given with ASA for stroke prevention -Variable bioavailability after oral route -Highly protein bound -Hepatic metabolism—mainly glucuronidation; excreted in feces

Pharmacokinetics of Dipyridamole

-ADEs—headache, dizziness, orthostatic low BP [if given IV] -Should not be given to those with unstable angina—because it is a dilator—it can worsen cardiac ischemia—create a coronary steel phenomena

ADEs of Dipyridamole

-Oral antiplatelet agent with vasodilatory effects -This drug inhibit phosphodiesterase type III, which prevents breakdown of cAMP causing vasodilation -Treats intermittent claudication

Cilostazol

Extensively metabolized by CYP 450 3A4 and 2C19—many drug interactions Eliminated via kidney

Pharmacokinetics of Cilostazol

-ADEs—headache, diarrhea, abnormal stools, dyspepsia, abdominal pain -Rare—thrombocytopenia or leukopenia -Phosphodiesterase type III inhibitors have been shown to increase mortality in those with advanced HF—drug is contraindicated in HF

ADEs of Cilostazol

Name the LMWHs

Enoxaparin is the prototype and Dalteparin

Is an injectable, rapid acting anticoagulant used acutely to interfere with formation of thrombi

Heparin

• Anticoagulant effect is from binding to antithrombin III with inactivation of the coagulation factors • Antithrombin III is an alpha-globulin that inhibits factor IIa and factor Xa • In the absence of this drug, antithrombin III interacts very slowly with thrombin and factor Xa • When these molecules bind to antithrombin III, a change occurs that inhibits thrombin 1000 fold • LMWHs complex with antithrombin III and inactivate factor Xa—but do not bind as actively to thrombin

MOA of Heparin

• Limit the expansion of thrombi to prevent fibrin formation • Used to treat acute DVT or PE • Used to prevent post-operative venousm thrombosis after surgery and those with acute MI • DOC for treating pregnant women • Do not require intense monitoring with LMWH, as does Heparin, saving lab costs and time • Useful for both inpatient and outpatient therapy

Uses for Heparin

-GIven SQ or IV -IV infusion, titrated to the desired level of anticoagulation according to aPTT or anti-Xa level -Works within minutes of IV dose [or 1-2 hours after SC dose] -Inactive metabolites eliminated in the urine

Pharmacokinetics of Heparin

Antidote for Heparin

Protamine SO4

ADEs: Bleeding (HIT), chills, fever, hives/anaphylaxis, and osteoporosis (long term use)

ADEs of Heparin

If HIT develops with Heparin what is the DOC to switch to?

Argatroban

Cannont be given to those with hypersensitivity to Heparin, bleeding disorders, alcoholism, or those who have had recent surgery of the brain, eye or spinal cord

Heparin and LMWH

-Direct thrombin inhibitor derived from L-arginine -Used for prevention or treatment of venous thromboembolism in those with HIT -Also approved for use in PCI in those at risk for HIT -Immediate effects; 1⁄2 life is 39-51 minutes -Hepatic metabolism; dose reduction in liver disease -Monitor H/H and PTT -ADEs—bleeding

Argatraban

-Anticoagulants derived from saliva of the leech -Selective direct thrombin inhibitors—reversibly inhibit catalytic site of free and clot- bound thrombin -With normal renal function, 1⁄2 life is 25 minutes; reduce dose in those with renal disease -ADE—bleeding

Bivalirudin and Desirudin

Is an alternative to Heparin in those having PCI who are at risk for HIT and those patients with unstable angina having angioplasty

Bivalirudin

Indicated for prevention of DVT in patients undergoing hip replacement

Desirudin

-Anticoagulant that selectively inhibits Factor Xa -Treat DVT, PE, and prevent DVT in those having ortho or abdominal surgery -Well absorbed SC; predictable response, so less monitoring than Heparin -Eliminated in the urine unchanged; elimination 1⁄2 life is 17-21 hours -CI in severe renal disease -ADE—bleeding; no antidote; HIT not likely, but is still possible

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