anticoagulant, antiplatelet, and thrombolytic drugs - pharmacology

hemostatsis steps

• stage 1: formation of platelet plug

  • platelet aggregation, contact w exposed collagen of blood vessel and adhere to injury

• stage 2: coagulation

• production of fibrin, reinforces platelet plug

  • intrinsic coagulation pathway (longer, responds to internal damage)

  • extrinsic coagulation pathway (external trauma)

keeping hemostasis under control

• antithrombin forms a complex with clotting factors and inhibits their activity

  • antithrombin involved in heparin anticoagulant

physiologic removal of clots

• plasmin - enzyme degrades fibrin meshwork

  • produced by activation of plasminogen

  • fibrinolytic drugs promote conversion of plasminogen into plasmin

arterial thrombosis

• adhesion of platelets to the arterial wall

• stimulated by damage to wall or rupture if atherosclerotic plaque

• causes localized tissue injury bc of lack of perfusion

venous thrombosis

• develops sites where blood flow is slow

• stagnation of blood initiates coagulation cascade

• has long tail (embolus) that can break off and become lodged (pulmonary embolus)

anticoagulants

• reduce formation of fibrin

• 2 mechanisms of action

  • inhibits synthesis of clotting factors, factor X and thrombin (warfarin)

  • inhibits activity of clotting factors, factor Xa, thrombin, both

• heparin and enoxaparin are shots

• warfarin is a pill

herparin unfractioned

• enhances antithrombin (supresses formation of fibrin)

• sources

  • lungs of cattle

  • intestines of pigs

• is a rapid acting anticoagulant

• administerd by IV or SC/SQ

heparin unfractioned therapeutic uses

• preferred for PREGNANCY bc doesn’t cross placenta

• for pulmonary embolism and DVT

  • bc requires rapid onset if anticoagulant effects

• open heart surgery and renal dialysis

  • prevents coagulation in devices of extracorporeal circulated (heart-lung machines and dialyzers)

• low dose for postoperative prevention

• treats disseminated intravascular coagulation

  • condition where fibrin clots form throughout vascular systemin which bleeding tendencies may be present

• adjunct to thrombolytic therapy of acute myocardial therapy

• stroke evolving

unfractioned heparin adverse effects

• hemmorhage (should be monitored for blood loss)

• heparin-induced thrombocytopenia (HIT)

  • watch labs for low platelet count, would have to stop and give platelets

• hypersensitivity reactions

  • bc comes from animal

CONTRAINDICATED FOR

• thrombocytopenia (low WBC)

• uncontrollable bleeding

• during and immediately after surgery of eye, brain, or spinal cord

antidote for overdose of heparin

• protamine

watch labs for what when on unfractioned heparin?

• activated partial thromboplastin time (aPTT)

  • normal = 30-40 seconds

• partial thromboplastin time (PTT)

  • normal= 60-70 seconds

low molecular weight (LMW) heparins therapeutic uses

USES

• prevention of DVT after surgery

  • includes replacement of knee and hip, abdominal surgery

• treatment of DVT

• prevention of ischemic complications in pt. with unable angina, non-q-wave myocardial infarction (MI), and ST elevation MI (STEMI)

low molecular weight (LMW) heparins

• heparin preparations composed pf molecules that are shorter than those found in unfractioned heparin

• administered SubQ

• costs more than unfractioned heparin

• doesn’t require monitoring, can be given at home

LMW heparin dosage based on

body weight

low molecular weight (LMW) heparins ANTIDOTE

• protamine sulfate

low molecular weight (LMW) heparins adverse effects and interactions

• bleeding but less than with unfractioned heparin

• can cause immune mediated thrombocytopenia

• can cause severe neurologic injury incuding paralysis when given to pt. undergoing spinal puncture or spinal or epidural anesthesia

  • risk inc. by using concurrent use of antiplatelet drugs

other LMW heparins

• Enoxaparin (Lovenox)

• Dalteparin

• Tinzaparin

warfarin

• ORAL ANTICOAUGULANT

• og discovered when cattle were observed bleeding after ingesting spoiled clover silage

• used as rat poison

• failed suicide attempt w larger dose of rat poison brought renewed clinical interest

warfarin clinical MoA

• ORAL ANTICOAUGULANT

• delayed onset can take days for effect so gets bridged with heparin

• vit. K antagonist

  • inhibits enzyme needed to convert vit.K to active form

• blocks biosynthesis of factors VII, IX, and X and prothrombin

  • vit. K is needed to make these

warfarin therapeutic uses

• not useful in emergencies

• for long term prophylaxis of thrombosis

• prevention of venous thrombosis and PE

• prevention of thromboembolism (in pt. with prosthetic heart valves)

  • usually hear click in heart sounds, coumadin drug of choice for valves

• prevention of thrombosis during atrial fibrilation

values to know for warfarin

• Prothrombin time (PT)

  • 11-12.5 seconds

  • coagulation test is sensitive to vit. K factors

• internatiomal normalized ratio (INR)

  • normal = 1.0

  • therapeutic level = 2.0-3.5

• regular labs needed daily then weekly, hard for pt. to be compliant

warfarin adverse reactions

• hemorrhage

  • give vitamin K for toxicity subQ or IV

    • mayo, canola oil, soybean oil, green veggies

    • this is why u cant have an extra salad, have to tell nurse what you’ll eat and stick to it

• fetal hemorrhage and teratogenesis from use during pregnancy

• used during lactation (enters milk)

warfarin drug interactions

• drugs that inc, anticoagulant effects

• drugs that promote bleeding

• drugs that decrease anticoagulant effects

• heparin

• aspirin

• acetaminophen

contrasts between warfarin and heparin

• decrease fibrin formation by diff mechanisms

  • heparin inactivates thrombin and factor Xa

  • warfarin inhibits synthesis of factors

• time

  • heparin begins and ends fast

  • warfarin takes days to start but lasts days

• labs

  • aPTT used to monitor heparin

  • PT for warfarin

direct thrombin inhibitors

• direct inhibition of thrombin unlike heparin which enhances activity of antithrombin

• dabigatran etexilate (Pradaxa)

  • oral prodrug that undergoes conversion to dabigatran

advantages of Dabigatran etexilate

• rapid onset

• does NOT require monitoring of anticoagulation

• little risk of adverse interactions

• SAME DOSE CAN BE USED FOR ALL PT. REGARDLESS OF AGE AND WEIGHT

  • don’t have reverse agent

• disadvantage

  • expensive

Dabigatran etexilate therapeutic uses

• treatment of DVT and PE and for prevention of stroke and systemic embolism in pt. with nonvalvular atrial fibrillation

• knee/hip replacement

Dabigatran etexilate adverse effects

• bleeding

• no drug to reverse bleeding (antidote)

• GI disturbances (bleeding/upset)

direct factor Xa inhibitors

• all Xa’s oral

  • better for old people bc injections are hard on old people skin since they have thin skin and dec subQ tissue

• Produce selective inhibition of factor Xa

• rivaroxaban (Xarelto)

• apixaban (Eliquis)

• no labs needed outside of hospital

Rivaroxaban (Xarelto)

• binds directly with factor Xa to cause inactivatiom

• Oral

• prevents DVT and PE after total hip or knee replacement surgery

• prevents stroke in pt. w/ atrial fib

• treatment of DVT and PE unrelated to orthopedic surgery

• compared to warfarin has: fixed dosage, rapid onset, lower bleeding risk, fewer interactions, no need for INR monitoring

Apixaban (eliquis)

• selective inhibition of factor Xa

• oral

• inhibits free and clot bound factor Xa as well as prothrombinase activity

• prevents stroke and systemic embolism in pt., w NONVALVULAR A.FIB

antiplatelet drugs

• Asprinin (ASA)

  • inhibits cyclooxygenase (enzyme required to synthesize TXA (promotes platelet activation))

  • adverse effect: inc. risk of Gi bleeding, hemorrhage, and stroke

• Ticlopidine (Ticlid)

  • inhibits ADP mediated platelet aggregation by blocking receptor

  • adverse effects: hematologic effects

• Clopidogrel (Plavix)

  • ADP receptor antagonist, inhibits platelet aggregation

Aspirin therapeutic uses

• ischemic stroke

• transient uscgemic attack (bby stroke)

• chronic stable angina

• coronary stenting

• acute MI

• previous MI

• primary prevention of MI

aspirin (ASA) adverse effects

• bleeding

• GI bleeding and hemorrhagic stroke

• enteric-coated tablets may not reduce the risk of GI irritation/bleeding - depends on the person

clopidogrel (plavix)

therapuetic uses:

• Block P2Y12 ADP receptors on platelet surface, preventing ADP-stimulated aggregation

• prevents blockage of coronary artery stents

• reduces thromotic events in pt. with acute coronary syndromes

• prevents stenosis of coronary stents, secondary prevention of MI, ischemic stroke, and other vascular events

adverse effects similar to those of aspirin

use w caution in combination with other drugs that promote bleeding

other P2Y12ADP receptor antagonists

• prasugrel (effient)

• Ticagrelor (brilinta)

• Ticlopidine

*not as common as aspirin

glycoprotein (GP) IIb/IIIa receptor antagonists MoA and use

• most effectiive antiplatelet drug, called “super aspirins”

  • Abciximab / reopro

  • epitifibatide / integrilin

• cause reversible blckade of platelet GP IIB/IIIa receptors - inhibits final step in aggregation

  • therefore can prevent aggregation stimulated by all factors

THERAPUETIC USE

• acute coronary syndromes

  • symptoms (angina and non-STEMI) result from thrombosis triggered by disruption of atherosclerotic plaque, therefore reducing risk of ischemic complications when added to traditional ACS drugs (heparin,aspirin)

• percutaneous coronary interventions

  • reduce risk of coronary of rapid re-occlusion after coronary revascularization using PCI, bc PCI damages arterial wall, causing platelet aggregation

Abciximab (reopro)

• binds to platelets in vicinity of GP IIB/IIIa receptors, thereby preventing the receptors from binding to fibrinogen

• used w aspirin and heparin

• apprvied for SHORT TERM therapy of ACS and for pt undegoing PCI (clavix used more often)

• can acceleerate revascularization in pt. undergoing thrombolytic therapy for acute MI

• antiplatelet effects persist for 24-48 hours after infusion has stopped

Eptifibatide / Integrilin

• small peptide that causes reversible and highly selective inhibition of GP IIb/IIIa receptors

• ACS

• pt. undergoing PCI

• antiplatelet effects reverse within 4 hours of stopping infusion

thrombolytics (fibrinolytics) - Alteplase (TPA) MoA

• binds w plasminogen to form an active complex

• alteplase- plasminogen complex then catalyzes conversion of other plasminogen molecules into plasmin

  • plasmin= enzyme that digests the fibrin meshwork of clots

thrombolytics (fibrinolytics) - Alteplase (TPA) uses

do CAT scan fist to make sure not internally bleeding bc med is STRONG

• Myocardial infarction

• ischemic stroke

• massive pulmonary emboli

thrombolytics (fibrinolytics) - Alteplase (TPA) adverse effects

• BLEEDING

  • intracranial hemorrhage/bleeding higher than with streptokinase

    • plasmin can eliminate preexisting clots and interfere with coagulation and new clots

  • pt. who require blood replacement can be given whole blood or blood products (packed RBC, fresh-frozen plasma); blood replacement restores hemostasis

    • if this fails, fibrinolysis can be reversed with IV Aminocaproic acid (Amicar) - inhibits plasmin

• fever

thrombolytics (fibrinolytics) - Alteplase (TPA) advantages

• does not cause allergic reactions

• does not cause hypotension

Tenecteplase (TNKASE)

• variant of human tissue plasminogen activator (tPA, alteplase)

• approved only for ACUTE MI

• easier to use

Reteplase (Retavase)

• derivative of tPA produced by recombinant DNA technology

• short half life of 13-16min

• approved only for acute MI

minimizing risk of bleeding

• minimize physical manipulation of pt.

• avoid subQ and IM injections

• minimize invasive procedures

• minimize concurrent use of anticoagulants

  • hepatin, warfarin, dabigatran

• minimize concurrent use of antiplatelet drugs

  • aspirin, clopidogrel