Pharmacology of the Cardiovascular System: Drugs for Coagulation Disorders

hemostasis in injury to small vessels

- vessel spasm

- platelet plug forms

- platelet plug becomes fibrous clot with fibrin to stabilize it

activated platelets release these two mediators

- ADP

- Thromboxane A2

function of ADP and Thromboxane A2

- activate and attract more platelets to aggregate

- vasoconstriction

Thrombin

- enzyme that converts fibrinogen into fibrin in clotting

fibrin

the "scaffolding" of a clot --> structural stability of the clot

blood clotting pathways

extrinsic and intrinsic, meet at the common pathway with the activation of Xa

Extrinsic pathway

- triggered by tissue thromboplastin release from damaged cells outside of the circulation

- catalyzes the formation of Factor Xa

Intrinsic pathway

- triggered by exposed collagen in the damaged BV wall

- catalyzes the formation of Factor Xa

Common pathway

synthesis of factor Xa

Factor Xa

converts prothrombin to thrombin

fibrinolysis

- breakdown and removal of a clot by the body

- begins within 24-48 hours

- plasmin

tissue plasminogen activator (tPA)

- released from the cells adjacent to a clot

- converts plasminogen into plasmin to dissolve the clot

plasmin

digests fibrin and destroys clots

thromboembolic disorders

- formation of unhealthy, bad clots

- occlusion of vessels can cause CVA or MI

embolus

- traveling clot (unstable clots can break and travel)

- small bits of thrombi can break off and occlude small vessels and cause issues like kidney failure

bleeding disorders

- thrombocytopenia (low platelet count) (sometimes can be a side effect of heparin)

- hemophilia

anticoagulants

- prevent clot formation by inhibition of specific clotting factors

antiplatelet/anticoagulants

- prevent clot formation by inhibition of platelet action

thrombolytics

- breakdown of existing clots

antifibrinolytics

- interfere with the conversion of plasminogen to plasmin

- prevent the breakdown/dissolution of fibrin

- keep healthy clots in place

anticoagulant drug effects on clotting time

increase clotting time

prevention of non-therapeutic clots means:

- prevent thrombi from forming

- prevent thrombi from getting larger in veins and arteries

in cases of MI or CVA, how are anticoagulants administered?

IV or SC for rapid onset of action

once the disease state (MI or CVA) is stabilized, how do we give anticoagulants?

PO or SC usually

therapeutic effect of anticoagulant drugs

modulate the coagulation cascade and thrombin formation (and fibrin)

classes of anticoagulant drugs

- heparin (heparin)

- LMW heparins (enoxaparin, dalteparin)

- warfarin (coumadin)

- direct acting Factor Xa inhibitor (rivaroxaban, apixaban)

- direct thrombin inhibitors (dabigatran)

antidote for heparin

protamine sulphate

antidote for warfarin

vitain k

antidote for LMW heparin

protamine sulfate

antidote for direct thrombin inhibitors

praxbind

antidote for direct acting factor Xa inhibitors

andexanet (andexxa)

heparin MOA

- kind of an aggressive anticoag.

- catalyzes the inactivation of thrombin

- enhances the ability of antithrombin III to inactivate thrombin and clotting factor Xa

- thrombin will no longer be available to convert fibrinogen into fibrin

- inhibits factor Xa --> inhibition of the extrinsic and intrinsic pathways of the clotting cascade

heparin indications

used to prevent venous thrombosis, PE, disseminated intravascular coagulation, treatment in stroke and MI

adverse reaction to heparin

- thrombocytopenia (usually with an allergy)

- bleeding

does heparin cross the placenta?

no, its use is safe in pregnancy

low molecular weight heparin MOA

- same as normal heparin, but more specific to factor Xa

- produces a more stable response than unfractioned heparin since thrombin remains active (no direct thrombin effect)

- longer duration of action

- drug class of choice for DVT prophylaxis

Risks with LMWH

- less risk for thrombocytopenia

benefits of LMWH for patients

- can be self administered and less likely to bind to plasma proteins compared to heparin (more stable response)

Warfarin MOA

- blocks synthesis of clotting factors VIIa, IXa, Xa

- inhibits vit K epoxide reductase

- decreased vitamin K inhibits production of active coagulation factors

- as stores of previously active coag factors get depleted, we see the anticoag effects of warfarin

- clotting factors are made, but have less functionality due to under-carboxylation

how do clotting factors become activated

carboxylation (linked to oxidation of vitamin K to vitamin K epoxide)

vitamin K epoxide reductase

vitamin K epoxide is recycled to its reduced form by this enzyme

overlap period in transitioning from heparin to warfarin therapy

- 3 days of co-administration

- caution with super increased risk of bleeding

how long does warfarin's effect last

4-5 days

how much of warfarin is plasma protein bound?

- 95-99% (bad stuff can happen with another high affinity drug like ASA in the mix)

- lots of drug interactions with warfarin

drugs that increase anticoagulant effect of warfarin

acetaminophen, amiodarone, anabolic steroids, aspirin, cephalosporins, clopidogrel, heparin, macrolides, metronidazole, NSAIDs, penicillin, statins, thyroid hormone

drugs that decrease anticoagulant effect of warfarin

barbiturates, bile-acid sequestrants, oral contraceptives, rifampin

supplements and foods to avoid on warfarin

american ginseng, cranberry, ginkgo, green tea, vitamin E, vitamin K

contraindications of warfarin

- pregnancy/lactation

- hemorrhage history

- thrombocytopenia

drugs that potentiate the action of heparin

oral anticoag like warfarin

drugs that inhibit platelet aggregation and heparin

ASA, NSAIDs may induce bleeding in pts taking heparin

drugs that may inhibit anticoagulant effect of heparin

nicotine, digitalis, tetracyclines, antihistamines

dabigatran is contraindicated in these patients

patients with gastritis

Direct acting thrombin inhibitor MOA (dabigatran)

- directly binds to and inhibits thrombin

- prevents conversion of fibrinogen to fibrin, inhibiting clot formation

- bind to circulating thrombin and thrombin attached to fibrin clots

indications for direct thrombin inhibitors

- similar indications as heparin and LMWHs; reduce the risk of stroke and systemic embolism in ppl with Afib, DVT, and PE

use of direct thrombin inhibitors r/t adverse effects of other anticoags

- can be used in cases of heparin-induced thrombocytopenia

- equal efficiency to warfarin

antagonist for direct acting thrombin inhibitors

praxbind (IV)

indication for praxbind

life-threatening bleeding or uncontrolled bleeding and in cases of emergency surgery/emergent procedures; dabigatran binds to praxbind with higher affinity than thrombin

Direct acting factor Xa inhibitor MOA

- highly selective inhibition of factor Xa in both plasma and clots, no effect on platelets

- inhibits the formation of thrombin from both the intrinsic and extrinsic pathways

- reduces thrombin formation and development of thrombi; no direct effects on thrombin or platelets

indications for direct acting factor Xa inhibitors

- used for prevention of DVT and PE, and to reduce the risk of stroke or embolism in clients with non-valvular Afib

indication for andexxa

- used in life threatening bleeding or uncontrolled bleeding and in cases of emergency surgery/urgent procedure

- rivaroxaban binds to andexxa with higher affinity than factor Xa

current trends in use of anticoagulant medications

- direct acting thrombin and factor Xa inhibitors have begun to replace warfarin and some LMWHs

benefits to direct acting thrombin and Xa inhibitors

oral administration, predictable effect, less monitoring, fewer drug interactions

term of use for direct acting thrombin/Xa inhibitors

3 months therapy recommended as initial DVT or PE prophylaxis

caution for all anticoagulant drugs

hemorrhagic disorders, recent trauma, spinal puncture, GI ulcers, recent surgery, closed head injuries, increased bleeding/bruising while brushing teeth

common adverse effects of anticoagulants

- bleeding

INR

International normalized ratio - measures prothombin levels

Prothrombin time (PT)

time required for clotting to occur

antiplatelet drugs MOA

- exert anticoagulant effects by inhibiting platelet aggregation

- used to prevent clots in the arteries

types of antiplatelet drugs

1. irreversible COX inhibitors (ASA)

2. ADP receptor antagonists (Alopidogrel/Ticagrelor)

3. Glycoprotein IIb/IIIa receptor antagonists (IV only) (Abciximab, Tirofiban, Eptifibatide)

Aspirin

- irreversibly blocks COX1 and COX2 enzymes

- inhibits synthesis of prostaglandins, esp. Thromboxane A2

- low dose (81) sufficient to produce antiplatelet effect

- benefit for ppl with established CV disease

- secondary prevention of CV events

- for ppl with no CVD, the use of aspirin is not recommended due to bleeding risk

ADP receptor antagonist MOA

- irreversibly change the molecular conformation of ADP receptors present on platelets (no longer get the signal to clump)

- admin PO

CAPRIE trial

- clopidogrel vs ASA in pts at risk of ischemic events

- 8.7% reduction in relative risk of ischemic stroke, MI, or vascular death compared to aspirin

- Ticagrelor assoc. with faster onset, and greater efficacy

Glycoprotein IIb/IIIa

- receptor found on the surface of platelets

- activation causes platelets to change shape, bind fibrinogen, and become sticky

Glycoprotein IIb/IIIa inhibitor MOA

- antagonist activity at receptors prevents platelet aggregation and thrombus formation

- administered IV only

when are Glycoprotein IIb/IIIa inhibitors used?

prevention of thromboembolism during PCI; no evidence that they are more effective than aspirin for secondary prevention

Thrombolytic drugs

- promote fibrinolysis by converting plasminogen to plasmin

- dissolve insoluble fibrin within intravascular emboli and thrombi

- admin to dissolve pre-existing clots, not a preventative strategy (MI, PE, CVA, DVT)

- dissolve all clots (good and bad)

- follow up with anticoagulant therapy to prevent reformation of clots

Streptokinase

- thrombolytic

- can cause an immunological reaction, including allergy

- previous admin is a contraindication

- may result in systemic fibrinolysis bc it works relatively nonspecifically

Tissue plasminogen activator (tPA)

- identical to human derived tPA released by endothelial cells

- converts plasminogen to plasmin (dissolves clots)

- specific to fibrin bound plasminogen, systemic effects minimized

timeline for admin of tPA

post-MI: < 6 hours

post-CVA: < 3 hours

Tenecteplase

genetically engineered, longer half-life, greater fibrin specificity; improved reperfusion in CVA

thrombolytic drug contraindications

- any recent trauma or bleeding disorders

- surgery, active internal bleeding, obstetrical delivery (10 days post delivery)

how can the effects of thrombolytics be reversed

aminocaproic acid (antidote to tenecteplase)

what is aminocaproic acid? *consideration with giving it

- antidote for someone bleeding too much

- an enzyme inhibitor that inactivates plasmin

- orally active

- assess for excessive clotting with giving this

antifibrinolytic drugs

- used to facilitate blood clotting and shorten bleeding time

- prevent the dissolution of fibrin

- used post-op to reduce surgical site bleeding