Drugs that affect hemostasis
Download
1 / 42

Drugs that affect hemostasis - PowerPoint PPT Presentation


  • 667 Views
  • Updated On :

Drugs that affect hemostasis. Ahmad Shihada Silmi Msc, FIBMS IUG Faculty of Sciences Medical Technology Dep. Drugs that affect hemostasis. Drugs are categorized according to the process they target. An injured blood vessel Contracts Forms a platelet plug (1 º hemostasis)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Drugs that affect hemostasis' - brad


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Drugs that affect hemostasis l.jpg

Drugs that affect hemostasis

Ahmad Shihada Silmi Msc, FIBMS

IUG

Faculty of Sciences

Medical Technology Dep.


Slide2 l.jpg

Drugs that affect 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 Affecting Hemostasis



Slide4 l.jpg

Oral anticoagulants

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


Warfarin l.jpg
Warfarin

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

MechanismDrugs Affecting Hemostasis


Mechanism of action interferes with liver synthesis l.jpg
Mechanism of ActionInterferes with liver synthesis

Vitamin K

VII

Synthesis of Functional Coagulation Factors

IX

X

II

C

Synthesis of Anti- coagulation Proteins

S

Z

Drugs Affecting Hemostasis


Vitamin k action l.jpg
Vitamin K Action

Drugs Affecting Hemostasis


Warfarin mechanism of action l.jpg
Warfarin Mechanism of Action

Drugs Affecting Hemostasis


Warfarin pharmacokinetics l.jpg
Warfarin Pharmacokinetics

  • 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 actions l.jpg
Warfarin: Adverse Actions

  • Bleeding is the main concern

    • vitamin K, clotting factors, fresh frozen plasma

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

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

Drugs Affecting Hemostasis


Slide11 l.jpg

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

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.

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

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

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

Inhibiting platelet function. Example, aspirin.

Drugs depress anticoagulation by

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

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

Inhibition of absorption. Example: cholestyramine.

Drugs Affecting Hemostasis


Heparin l.jpg
Heparin

  • 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


Heparin13 l.jpg
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 action l.jpg
Mechanism of Action

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

Drugs Affecting Hemostasis


Mechanism of action15 l.jpg
Mechanism of Action

  • Unique pentasaccharide sequence binds to antithrombin III (AT III) with high affinity but a polysaccharide of at least 18 units is required (5 for LMWH).

Drugs Affecting Hemostasis


Slide16 l.jpg

AT III + Heparin

Serine

protease

Inactive

Ternary complex

Drugs Affecting Hemostasis


Lmw heparin l.jpg
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


Slide18 l.jpg

AT III

IIa

Heparin

> 18 monosaccharide units

Heparin

ATIII

< 18 monosaccharide units

Heparin

AT III

Xa

LMWH

Drugs Affecting Hemostasis


Heparin pharmacokinetics l.jpg
Heparin Pharmacokinetics

  • 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 actions l.jpg
Heparin 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


Slide21 l.jpg

Antiplatelet Drugs

Drugs Affecting Hemostasis



Aspirin mechanism of action l.jpg
Aspirin Mechanism of Action

Aspirin irreversibly inactivates cyclooxygenase by covalent acetylation.

Drugs Affecting Hemostasis


Slide24 l.jpg

Aspirin inhibits

Aspirin inhibits


Slide25 l.jpg

Selectivity of aspirin for platelet COX

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

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

Drugs Affecting Hemostasis


Aspirin pharmacokinetics l.jpg
Aspirin 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 days

Drugs Affecting Hemostasis


Aspirin adverse actions l.jpg
Aspirin Adverse Actions

Primarily gastrointestinal

  • Epigastric pain, heartburn, nausea

  • GI blood loss

  • Gastric ulcer

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

Drugs Affecting Hemostasis


Aspirin drug interactions l.jpg
Aspirin 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


Slide29 l.jpg

Ticlopidine and Clopidogrel

P2Y2 purine receptor antagonists.

Drugs Affecting Hemostasis


Slide30 l.jpg

Other Antiplatelet Drugs

Ticlopidine and Clopidogrel: P2Y2 purine receptor antagonists

clopidogrel

P2Y1R

P2Y2R

AC

Drugs Affecting Hemostasis

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


Clopidogrel l.jpg
Clopidogrel

  • 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 inhibitors l.jpg
Glycoprotein IIb/IIIa Inhibitors

GP IIb/IIIa is a platelet surface integrin (aIIb3)

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

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

Drugs Affecting Hemostasis


Slide33 l.jpg

Basal platelet with GP IIb/IIIa receptors in inactive state

Activated platelet with functional GP IIb/IIIa receptors

Fibrinogen

Agonist

GP IIb/IIIa antagonist ()

Fibrinogen mediated platelet aggregation

Fibrinogen binding to platelets blocked by GP IIb/IIIa receptor antagonist


Slide34 l.jpg

Glycoprotein IIb/IIIa Inhibitors

  • Abciximab--Fab fragment directed to the GPIIb/IIIareceptor. Can be used only once.

  • Eptifibatide--a cyclic peptide

  • Tirofiban--a nonpeptide inhibitor

Drugs Affecting Hemostasis


Fibrinolytics l.jpg
Fibrinolytics

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

Drugs Affecting Hemostasis


Slide36 l.jpg

Alteplase (rtPA)

Urokinase

Streptokinase

Anistreplase

Drugs Affecting Hemostasis


Slide37 l.jpg

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


Slide38 l.jpg

tPA, tissue plasminogen activator Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products.

L, lysine binding sites

PI, plasmin inactivator

Drugs Affecting Hemostasis


Treatment goals l.jpg
Treatment Goals Fibrinolytic drugs accelerate the conversion of plasminogen to plasmin, which is a protease that breaks down fibrinogen and fibrin to degradation products.

Rapid reperfusion of the infarcted area to preserve more tissue.

Drugs Affecting Hemostasis


Slide40 l.jpg

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 actions l.jpg
Fibrinolytics: Adverse Actions between the onset of symptoms and administration of the fibrinolytic.

Unwanted BLEEDING is the MAJOR side effect.

Drugs Affecting Hemostasis


Slide42 l.jpg

The End between the onset of symptoms and administration of the fibrinolytic.

Drugs Affecting Hemostasis


ad