Drugs that affect Drugs that affect hemostasishemostasis

Ahmad Shihada Silmi Msc, FIBMSIUG

Faculty of SciencesMedical Technology Dep.

Drugs Affecting

Hemostasis

Drugs are categorized according to the process they target.

An injured blood vessel Contracts Forms a platelet plug (1º hemostasis) Forms a protein clot (2º hemostasis) Once healed, solubilizes the clot

(fibrinolysis)

Drugs that affect Drugs that affect hemostasishemostasis

Anticoagulants

Therapeutic overview

Heparin and heparin derivatives

Coumarins (warfarin)

Directly acting thrombin inhibitors

hirudin

bivalirudin

argatroban

arterial thrombosis

atrial fibrillation

cardiomyopathy

cerebral emboli

heart valve disease

hip surgery

vascular prostheses

Venous thromboembolism

Oral anticoagulants4-Hydrdroxycoumarin and indan-1,3-dione are the parent molecules.

MechanismDrugs Affecting Hemostasis

Warfarin

Interferes with the synthesis of the vitamin K-dependent clotting factors

Drugs Affecting

Hemostasis

Vitamin KVitamin K

Synthesis Synthesis of of

Functional Functional CoagulatioCoagulation Factorsn Factors

VIIVII

IXIX

XX

IIII

Mechanism of ActionMechanism of ActionInterferes with liver synthesisInterferes with liver synthesis

CC

SS

ZZ

Synthesis Synthesis of Anti- of Anti-

coagulatiocoagulation Proteinsn Proteins

Drugs Affecting

Hemostasis

Vitamin K ActionVitamin K Action

Drugs Affecting

Hemostasis

Warfarin Mechanism of Warfarin Mechanism of ActionAction

Drugs Affecting

Hemostasis

Warfarin Warfarin PharmacokineticsPharmacokinetics

ABSORPTION: Rapid, complete. Used orally.

DISTRIBUTION: Vd is small; plasma protein binding ≈ 99%.

[Maternal] = [Fetal]. Warfarin is not found in breast milk; other coumadins are!

ELIMINATION: T1/2 = 40 hr.

ONSET: 2-3 days.

DURATION: 2-5 days.

Drugs Affecting

Hemostasis

Warfarin: Adverse Warfarin: Adverse

ActionsActions BleedingBleeding is the is the mainmain concern concern

vitamin K, clotting factors, fresh vitamin K, clotting factors, fresh frozen plasmafrozen plasma

Crosses the placenta and is Crosses the placenta and is teratogenic during weeks 6-12teratogenic during weeks 6-12

Alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramps, anorexia, skin necrosis

Drugs Affecting

Hemostasis

Drug Interactions

Drug interactions are particularly important with oral anticoagulants, and the result may be either an increase or a decrease in the effect of the anticoagulant. Frequent monitoring of the prothrombin time is essential when administering another drug with warfarin, and changing the dose of warfarin may be necessary.

Drugs increase anticoagulation by

1. Displacement of protein bound warfarin. Because of the high degree of warfarin bound to plasma proteins, even a small decrease in the amount bound can lead to significant increases in free drug levels. Examples: salicylates such as aspirin.

2. Inhibition of the liver microsomal enzyme system that metabolizes warfarin will increase the availability of warfarin. Example: quinidine.

3. Increasing the warfarin “receptor site” affinity will increase the efficacy of a given plasma level of warfarin. Example: d-thyroxine.

4. Reducing the availability of vitamin K. Example: broad spectrum antibiotics, laxatives.

5. Inhibiting platelet function. Example, aspirin.

Drugs depress anticoagulation by

1. Stimulation of the hepatic microsomal enzyme system. This decreases plasma half-life of warfarin. Example: barbiturates.

2. Stimulation of clotting factor synthesis. This antagonizes the effect of warfarin. Example: vitamin K, estrogens.

3. Inhibition of absorption. Example: cholestyramine.

Drugs Affecting

Hemostasis

HeparinHeparin 2-40 kDa MW, naturally occurring N- & O-

sulfated sugars polymerized by glycoside bonds found in the secretory granules of mast cells.

Drugs Affecting

Hemostasis

Heparin 2-40 kDa MW, naturally occurring N- & O-sulfated

sugars polymerized by glycoside bonds found in the secretory granules of mast cells.

Lower MW polymers possess most of the biological activity.

Active in vitro as well as in vivo.

The most acidic organic acid in the body.

Is not absorbed following oral administration.

Drugs Affecting

Hemostasis

Mechanism of ActionMechanism of Action

Accelerates the inactivation of factors IIa, Accelerates the inactivation of factors IIa, Xa, IXa, XIa and XIIa by the serine protease Xa, IXa, XIa and XIIa by the serine protease inhibitor, antithrombin III (AT III).inhibitor, antithrombin III (AT III).

Drugs Affecting

Hemostasis

Mechanism of ActionMechanism of Action Unique pentasaccharide sequence binds to Unique pentasaccharide sequence binds to

antithrombin III (AT III) with high affinity but a antithrombin III (AT III) with high affinity but a polysaccharide of at least 18 units is required polysaccharide of at least 18 units is required (5 for LMWH).(5 for LMWH).

Drugs Affecting

Hemostasis

AT III + HeparinAT III + Heparin

SerineSerineproteaseprotease

Ternary complexTernary complexInactiveInactive

Drugs Affecting

Hemostasis

LMW Heparin MW 4,000 - 6,000 Preferentially binds to factor Xa T1/2 2x > standard heparin Less bleeding Less effect on platelet activation

and factor XIII activation Clinically effective - e.g.,

enoxaparin

Drugs Affecting

Hemostasis

AT IIIAT III

Heparin

IIaIIa

HeparinHeparin

ATAT IIIIII

HeparinHeparin

LMWHLMWH

AT IIIAT IIIXaXa

< 18 monosaccharide units

> 18 monosaccharide units

Drugs Affecting

Hemostasis

Heparin Heparin PharmacokineticsPharmacokinetics

No oral absorption; IV or subQ.

Vd is small due to extensive binding. Binding can influence the effect of heparin.

Onset: IV, immediate; subQ, 20-60 min

Drugs Affecting

Hemostasis

Heparin Adverse ActionsHeparin Adverse Actions Bleeding is the main concern. Antidote: protamine sulfate.

Thrombocytopenia (<5%, within a few days). Disappears with cessation of therapy.

Rapid and profound thrombocytopenia (<5%, 8-10 days) with paradoxical arterial or venous thrombosis. Results from the formation of anti-heparin antibodies. Heparin-Ab bind to platelets causing inappropriate aggregation and thrombus formation. May be life-threatening.

Reversible osteoporosis (6 months). If it occurs, it is usually after 6 months therapy with >15,000 U/day.

Drugs Affecting

Hemostasis

Antiplatelet DrugsAntiplatelet Drugs

Therapeutic overviewPlatelet aggregation inhibitors

AspirinCerebrovascular accident, stroke, coronary bypass surgery, coronary angioplasty/stenting or thrombolysis, myocardial infarction, transient ischemic attack

ClopidogrelCoronary artery disease, cerebrovascular accident, stroke, peripheral arterial disease

Glycoprotein IIb/IIIa inhibitors

Acute coronary syndromes, after coronary artery stenting

Drugs Affecting

Hemostasis

Aspirin Mechanism of Aspirin Mechanism of ActionAction

Aspirin irreversibly inactivates cyclooxygenase by covalent acetylation.

Aspirin inhibits

Aspirin inhibits

Drugs Affecting

Hemostasis

Selectivity of aspirin for platelet COXSelectivity of aspirin for platelet COX

1. Platelet COX is acetylated in the portal circulation before aspirin is deacylated in the liver.

2. The systemic vasculature is unaffected because platelets are not affected by salicylate.

Drugs Affecting

Hemostasis

Aspirin PharmacokineticsAspirin Pharmacokinetics ABSORPTION: 70% DISTRIBUTION: at low doses most is

protein bound in plasma; at high doses a smaller percentage is bound and more is available to tissues

ELIMINATION: hepatic metabolites (75%) and parent compound excreted in urine. At low doses half-life is 4 hr and is 1st order. High doses show saturation kinetics and half-life is 15 hr. Faster in alkaline urine.

ONSET: 30 min DURATION: 7-10 daysDURATION: 7-10 days

Drugs Affecting

Hemostasis

Aspirin Adverse ActionsAspirin Adverse ActionsPrimarily gastrointestinal Epigastric pain, heartburn, nausea

GI blood loss

Gastric ulcer

Others: rash, tinnitus, nasal polyps, gout, acid-base disturbances

Drugs Affecting

Hemostasis

Aspirin Drug InteractionsAspirin Drug Interactions

Decreases the effectiveness of antihypertensives: usually not a problem with low doses.

Increases the effect of warfarin.

Attenuates the actions of uricosuric agents, e.g. probenecid.

Drugs Affecting

Hemostasis

Ticlopidine and ClopidogrelTiclopidine and Clopidogrel

P2Y2 purine receptor antagonists.

Drugs Affecting

HemostasisDaniel, J. L. et al. J. Biol. Chem. 1998;273:2024-2029

clopidogrel

P2Y1R

P2Y2R AC

Other Antiplatelet DrugsTiclopidine and Clopidogrel: P2Y2 purine

receptor antagonists

Drugs Affecting

Hemostasis

ClopidogrelClopidogrel Reduces the incidence of stroke and

myocardial ischemia.

Particularly effective combined with aspirin.

Currently the drug of choice in the prophylaxis of subacute stent thrombosis and post ischemic stroke treatment.

Drugs Affecting

Hemostasis

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

GP IIb/IIIa is a platelet surface integrin (IIb3)

GP IIb/IIIa is the receptor for fibrinogen and von Willebrand factor.

Thrombin, collagen, TXA2 activate platelets exposing binding sites for vWf and fibrinogen.

Basal platelet with GP IIb/IIIa

receptors in inactive state

AgonisAgonistt

Activated Activated platelet with platelet with functional GP functional GP

IIb/IIIa receptorsIIb/IIIa receptorsFibrinog

en

Fibrinogen mediated platelet

aggregation

GP IIb/IIIa antagonis

t ()

Fibrinogen binding to platelets blocked

by GP IIb/IIIa receptor antagonist

Drugs Affecting

Hemostasis

Glycoprotein IIb/IIIa InhibitorsGlycoprotein IIb/IIIa Inhibitors

AbciximabAbciximab -- Fab fragment directed to the GPIIb/IIIa receptor. Can be used only once.

EptifibatideEptifibatide -- a cyclic peptide

TirofibanTirofiban -- a nonpeptide inhibitor

Drugs Affecting

Hemostasis

FibrinolyticsFibrinolytics

Restore blood flow to an injured area by lysing the thrombus into soluble fibrin degradation products.

Drugs Affecting

Hemostasis

Alteplase (rtPA)Urokinase

StreptokinaseAnistreplase

Site of action of drugs acting on the fibrinolytic system. Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products.

© 2005 Elsevier

Drugs Affecting

Hemostasis

Plasminogen tPA

L LL

Fibrin Clot

Plasmin

tPA

LL L

Fibrin Clot

Plasmin

PI

Soluble fibrin digestion products

Plasminogen tPA

Plasmin

tPA, tissue plasminogen activator

L, lysine binding sites

PI, plasmin inactivator

Drugs Affecting

Hemostasis

Treatment Goals

Rapid reperfusion of the infarcted area to preserve more tissue.

Drugs Affecting

Hemostasis

Fibrinolytic success is dependent upon the time lapse between the onset of symptoms and administration of the fibrinolytic.

• DVT: < 7 days

• Pulmonary embolism: < 2 days

• Myocardial infarction: 2 - 4 hr

• Stroke: < 3 hr

Drugs Affecting

Hemostasis

Fibrinolytics: Adverse Fibrinolytics: Adverse ActionsActions

Unwanted BLEEDING is the MAJOR side effect.

Drugs Affecting

Hemostasis

The The EndEnd