Drugs Affecting Haemostasis Flashcards
Clotting Pathway
SEE NOTES
Endogenous clotting inhibitors
Heparin: activates antithrombin 3
Antithrombin 3: inactivates thrombin
Thrombomodulin: binds thrombin, removes it from
circulation
Tissue plasminogen activator: activates plasminogen; dissolves thrombus
Coagulation Defects
Genetically determined: Hemophilia A (lack of VIII) Hemophilia B (lack of XI) Hemophilia C (lack of XI) vW Disease (lack of vWF)
Acquired:
Liver Disease
Vit. K deficiency
Excessive oral anticoagulant th
Vitamin K
Importance
Clinical Use
Essential for formation of factors II,VII,IX,X (required as cofactor for carboxylase (without–> no binding X and II)
Antidote of Warfarin
Prevention of hemorrhagic diseases in babies
Th of vit K def (coeliacs, steatorrhea, lack of bile as require bile salts for absorption)
Given orally or parenterally
Vitamin K
Drug List
Menadiol Sodium Phosphate
water soluble–> doesn’t require bile salts for absorption
Anticoagulants and Antiplatelets
Drug Categories
Heparins
Coumarins
Acting in thrombocytes
Acting on surface of thrombocytes
Heparins
Mode of Action
How does LMWH compare
Found in granules of mast cells (GIT, lungs..) together with histamine
Inhibits intrinsic and extrinsic pathway via activation of antithrombin 3 and other serine proteases (bind to active serine sites–> change in conformation. Complex then can inhibit factors IIa, IXa, Xa!!!, XIa, XIIa (thrombin most sensitive)
LMWH
Only has one binding site–> increased action of AT3 on Xa but not on thrombin
Heparin
Pharmacokinetics
I.V. (acute sit.) or subcutaneously
T1/2: 40-90 min
Elim by liver–> better for renal failure patients than LMWH
NEVER I.M INJECTION (–> bleeding)
Requires regular blood test to possibly adjust dosage
LMWH
Pharmacokinetics
Subcutaneously
T1/2: longer than heparin, indep of dose (first order kinetics)–> effects more predictable
Renally excreted—> bad in renal failure
NEVER I.M INJECTION (–> bleeding)
Heparin and LMWH
Side Effects
Hemorrhages: Protamine sulfate inactivated heparin
Thrombosis: Heparin induced thrombocytopenia
during th: IgM or IgG bind to heparin-platelet factor 4 complex–> vascular injury causing thrombosis and DIC
Osteoporosis:
Long term th
LMWH
Drug List
Enoxaparin
Dalteparin
Fondaparinux
Direct Thrombin Inhibitor
Hirudin (found in salivary gland of medical leeches)
Dabigatran
Oral anticoagulant that does not require monitoring of
PT or INR
Used in atrial fibrillation as an alternative to warfarin
Coumarins
Mode of Action
Competitively inhibit vitamine K epoxide reduction (same as cyclosporins)–> vit K not active
Interfere with posttranslational gamma carboxylation of glutamic residues factors II/VII/IX/X (done by vit K)–> can’t bind Ca.
Require a few days to become active as need to degrade preformed factors–> combo with heparin
Can –> pro coagulant as coumarins inhibit protein C synthesis–> thrombosis.
Courmarins
Pharmacokinetics
Indications and Contraindications
Antidote
Pharmacokinetics good oral absorption strong PPB (drug-drug interactions!) inactivation in liver (CYP450) T1/2: 40 hrs Narrow th range
Indications
Thrombosis
Embolism prophylaxis
Contraindications
Pregnancy (can cross placenta–> teratogenic)
Liver/ Kidney insufficiency
Occult bleeding
Antidote
Vit K
Coumarin
Drug Interactions
Potentiation
Enzyme inhibitors (cimetidine, chloramphenicol, metronidazole, amiodarone)
Thrombocyte Inhibitors (NSAIDs)
Drugs that displace them from PP
Drugs that inhibit vit K reduction (some cephalosporins)
Drugs decreasing vit K availability (broad spectrum AB)
Decrease Coumarin effects
Vit K
Drugs that induce CYP450 (barbiturates, carbamazepine)
Drugs that reduce absorption–> bind coumarin in gut (cholestyramine)
Coumarins
Drug List
Dicumarol
Acenocumarol
Warfarin (false substrate for vit K reductase; used for prolonged therapy)
Aggregation Process of Platelets
Vascular damage–> adhesion via vWF bridging to glycoprotein Ib R (vWF R) on platelets.
Thrombocytes secrete granular contents (ADP, serotonin, thromboxane 2)–> vasoconstriction and aggregation.
Then: Thrombocytes express GPIIb and IIIa R–> bind fibrinogen–> linkage
Drugs acting in thrombocyte
Name, Mech of Action
Aspirin
Irreversible inhibition COX1 via acetylation of serine residue–> Inhibits thromboxane 2 synthesis
Meets thrombocytes in portal blood
Side Effects: GIT bleeding, Reye Syndrome in kiddies
Aspirin affects two substances involved in blood clotting; thromboxane A2 and prostacyclin. At low doses aspirin preferentially inhibits thromboxane A2 (which normally stimulates aggregation) thus prevents clotting. At high doses aspirin additionally inhibits prostacyclin (which normally inhibits aggregation) thus we lose antiplatelet effect
Dipyridamole
Inhibits phosphodiesterase–> increase cAMP–> inhibits aggregation
Drugs acting on thrombocyte
Drug names, Mech of Action
Clopidogrel, Ticlopidin
Inhibition of P2Y12 R (Gi) –> inhibits ADP dep aggregation
Side effect: Neutropenia
Abciximab
Ab against GP IIb-IIIa R
One time admin as immunological
Iloprost, Tirofiban
Synthetic prostacyclines
Antagonist: GPIIb-IIIa R
New Compound
Rivaroxaban
Anisindione
Rivaroxaban
Oral direct Xa inhibitor
No significant drug interactions
Anisindione
Synthetic, oral
Reduce prothrombin activity
Local Drugs for Haemostasis
Names and Mech of Action
Spongostan
Sterile gelatine sponge; big foreign surface activates extrinsic pathway
Thrombin Powder
IIa
Astingents: Potassium Aluminium Sulphate
Adrenaline
Vasopressin
Systemic Drugs for Haemostasis
Names and Mech of Action
Plasma Prep
Thrombocyte Conc
Coagulation Factors (VIIa, VIIIa, IX)
Vitamine K and analogs
Ethamsylat
increase thrombocyte aggregation and capillary resistance
Inhibition of parenchymal bleeding post surgery
Antifibrinolytics
Names and Mech of Action
Inhibit path. increased fibrinolytics
Transexamic Acid
Inhibits plasminogen activation; oral, parenteral
ex in DIC
Aprotinin
Inhibits proteolytic enzymes
Used for hyperplasminemia caused by fibrinolytic drug overdose
Fibrinolytics and Thrombolytics
Mech of Actions, Indications, Side Effects
Activate plasminogen, promote plasminogen plasmin transformation
AMI (under 12 hrs)
Stroke (Under 4.5 hrs)
Acute arterial thromboembolism
Side Effects
Bleeding
Allergy
Hypotension
Fibrinolytics and Thrombolytics
Names and characteristics
Streptokinase
Protein extracted from streptococci cultures (previous infection inhibit effect: Ag induce AB production)
Causes transient fever
Urokinase
Acts as tissue plasminogen activator
Duteplase, Alteplase, Reteplase
Recombinant tissue plasminogen activator
More active on fibrin bound plasminogen than plasma plasminogen
