Pharmacology

Drugs Used Coagulation D/O (katzung)

19 February 08

Chapter 34 Drugs Used in Disorders of Coagulation Endogenous anticoagulants

Outline Antithrombin
I. Blood Coagulation - SERPIN inactivates IIa, IXa, Xa. XIa, XIIa
a. Mechanism Protein C & S
b. Cascade - attenuate blood clotting cascade by proteolysis of Va & VIIIa
II. Anticoagulant Drugs
a. Indirect Thrombin Inhibitors Defects in natural anticoagulant – increased risk of venous
b. Direct Thrombin Inhibitors thrombosis
c. Warfarin & Coumarin - most common is Factor V (Leiden) defect
III. Fibrinolytic Drugs
IV. Antiplatelet Agents
a. Aspirin Fibrinolysis - Process of fibrin digestion by plasmin
b. Clopidogrel & Ticlopidine 1. In response to injury, endothelial size synthesize & release
c. GLP IIB/IIIA Receptor Blockers tPA (converting plasminogen to plasmin)
V. Drugs Used to prevent clotting 2. plasmin remodels thrombus, limits its extension by
VI. Drugs used in Bleeding Disorders proteolytic digestion of fibrin
a. Vitamin K
b. Plasma Fractions Negative regulators
c. Fibrinolytic Inhibitors: Aminocaproic Acid 1. Endothelial cells also release Plasminogen Activator Inhibitor
d. Serine Protease Inhibitors: Aprotinin – inhibits tPA
2. A2-antiplasmin – inactivate any plasmin not clot-bound

Blood Coagulation Disseminated Intravascular Coagulation (DIC)

Mechanism - pathologically activated coagulation & fibrinolytic systems,
1. Vascular injury exposes reactive subendothelial matrix generalized intravascular clotting & bleeding
proteins (collagen & vWf) - may follow massive tissue injury, advanced cancers, OB
2. platelet adherence, activation, secretion and synthesis of emergencies
vasoconstrictors & platelet-recruiting & activating molecules - tx is to control the underlying disease process
(TXA2, ADP, 5HT)
3. conformational change in IIB/IIIA receptors enabling it to Activators of Fibrinolytic system (for thrombotic disease)
bind fibrinogen Tissue plasminogen activator
4. Aggregation & platelet plug formation Urokinase
Streptokinase
• Simultaneous with these events:
1. coagulation cascade activated Inhibitors of Fibrinolysis
2. thrombin generation & fibrin clot, stabilizing the platelet Aminocaproic Acid
plug

Diagnostic Significance: Anticoagulant Drugs

• Defects in primary hemostasis (formation of platelet plug)
– bleed from mucosal sites with injury
• Defects in secondary hemostasis (clotting) – bleed in
deep tissues often with no apparent inciting event, may
recur unpredictably
White Vs Red thrombi
White – platelet-rich (arterial thrombi – limb amputation or
organ failure)
Red – fibrin-rich, contain large number of trapped RBC (venous
thrombi – pulmonary embolism)
Cascade
Initiation of Clotting: Tissue Factor-VIIa Complex
1.exposure of TF on damaged epithelium binds TF to VIIa
(regulated by TFPI)
2.complex formed activates IX , X
3.Xa with Va (prothrombinase complex) convert II to thrombin
4.thrombin activates V, VIII, XI resulting in amplification of
thrombin generation
Clinical Significance:
• Patients with Factor VIII & IX deficiency (hemophilia A &
B) have severe bleeding disorder
Indirect Thrombin Inhibitors
Heparin (Unfractionated, Low-Molecular-Weight, & Fondaparinux)
- biologic activity dependent upon antithrombin
- functions as a cofactor without being consumed
- bind to antithrombin, cause conformational change, exposes
active site to proteases, protease complex formed, heparin
is released to bind to more antithrombin
- Monitoring: aPTT & Protamine titration (UFH)
- Major ADR: bleeding (women & renal failure px more prone)
- Other ADR: allergy (animal source), alopecia,
- osteoporosis, spontaneous fractures, mineralocorticoid
deficiency (long term)
- Heparin-Induced Thrombocytopenia (HIT) – systemic,
hypercoagulable state; tx by discontinuing heparin & direct
thrombin inhibitor or fondaparinux
- Consider:
o Platelet counts done frequently
o Thrombocytopenia and new thrombus suspicious for
HIT
- Contraindication: HIT, hypersensitivity, active bleeding,
hemophilia, significant thrombocytopenia, purpura,
intracranial hemorrhage, severe HPN, infective endocarditis,
active TB, GIT ulcer, threatened abortion, visceral

Elyu, Brim & Virns 1 of 3

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carcinoma, advanced hepatic/renal disease, undergone Clopidogrel & Ticlopidine

surgery or lumbar puncture, anesthesia
- No placental transfer but used only in pregnant women
when clearly indicated
Direct Thrombin Inhibitors
- directly binds to active site of thrombin, inhibiting its effects
- Hirudin & Bivalirudin – bivalent DTIs binding both in active &
substrate recognition site
- Argatroban & Melagatran – active site only
1. Hirudin
- specific, irreversible thrombin inhibitor from leech saliva
- available in recombinant form – Lepirudin
- independent of antithrombin (reach & inactivate fibrin-
bound thrombin in thrombi)
- aPTT monitoring
- excreted by kidney (caution in renal insufficiency);
anaphylaxis
- -
2. Bivalirudin – inhibits platelet activation; for percutaneous
coronary angioplasty
3. Argatroban – used in px with HIT with or without
thrombosis; coronary angioplasty in px with HIT
4. Ximelagatran (prodrug of melagatran)
- predictable PK & Bioavailability (for fixed dosing &
predictable anticoag response)
- no need for monitoring; no interaction with P450-
interacting drugs
- hepatic toxicity
- inhibit ADP pathway of platelets
- ADR of ticlopidine – nausea, dyspepsia, diarrhea,
hemorrhage, leucopenia, TTP
- ADR of clopidogrel – fewer ADR, associated with
neutropenia, TTP, preferred over ticlopidine
GLP IIB/IIIA Receptor Blockers
- acute coronary syndromes
- inhibit platelet IIb/IIIa receptor complex
- persons lacking this receptor – Glanzmann’s
thrombasthenia (platelet aggregation)
- Abciximab – directed against the receptor &
vibronectin receptor
- Eptifibatide and Tirofiban – inhibit ligand binding to
the receptor by occupancy of the receptor but not the
vibronectin
Dipyridamole
Vasodilator
- inhibit adenosine uptake & cGMP phosphodiesterase
activity
- In combination with aspirin to prevent cerebrovascular
ischemia
- With warfarin – primary prophylaxis of thromboemboli
in px with prosthetic heart valves
Cilostazol
- newer phosphodiesterase inhibitor
- promotes VD and inhibition of platelet aggregation
- treating intermittent claudication

Warfarin (Coumarin) Drugs Used to Prevent Clotting

- 100% bioavailability; as Na salt Venous Thrombosis
- block γ-carboxylation of factors II, VII, IX, X (vitamin K A. Inherited
dependent) as well as endogenous anticoagulant (protein C - tendency to form thrombi from normal anticoagulant
and S) abnormalities thrombophilia
- crosses the placenta
- should never used during pregnancy B. Acquired
- monitoring: Prothrombin time - thromboembolism associated with atrial fibrillation &
- the most serious drug interactions with warfarin – increase placement of mechanical valves, prolonged bed rest, high-
anticoagulant effect & risk of bleeding risk surgical procedures, cancer, Antiphospholipic Antibody
- interactions with pyrazolones phenylbutazone & syndrome, and drugs (synergistic risk factor)
sulfinpyrazone – hypoprothrombinemia and inhibit platelet
function, may induce PUD Prevention
- heparin & warfarin to prevent venous thrombosis
Fibrinolytic Drugs - SC admin of low-dose unfractionated heparin, LMWH, or
- conversion of plasminogen to plasmin fondaparinux – prophylaxis (also warfarin but requires
monitoring of Prothrombin Time)
1. Streptokinase- protein synthesized by strep
2. Urokinase – human enzyme synthesized by kidney, directly Tx of Established Disease
converting plasminogen to plasmin - initiated with unfractionated of LMW Heparin for first 5-7
3. Anistreplase – complex of human plasminogen & bacterial days, with an overlap of warfarin
streptokinase - pregnant women – subcutaneous heparin (warfarin crosses
placenta)
4. t-PA - endogenous
5. Alteplase & Reteplase – recombinant human t-PA Arterial Thrombosis
6. Tenecteplase – mutant form of t-PA - activation of platelets considered an essential process
- TIA, strokes, unstable angina, acute MI
Indications (through IV route): o Tx: PLATELET-INHIBITING DRUGS (aspirin, clopidogrel,
- pulmonary embolism with hemodynamic instability ticlopidine)
- severe deep venous thrombosis (SVC syndrome) - In angina & infarction: used in conjunction with B-blocker,
- ascending thrombophlebitis Ca Channel Blockers, Fibrinolytic drugs

Antiplatelet Agents Drugs used in Bleeding Disorders

Aspirin Vitamin K
- inhibits synthesis of TXA2 - K2 menaquinone (found in human tissues)
- primary prophylaxis of MI - K3 menadione should never be used in therapeutics
- Vitamin K1 phytonadione (found in food)
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o Available in oral or parenteral forms

o IV infusion should be slow (dyspnea, chest & back pain,
death)
o In newborns (prevent HDN associated with Vit K
deficiency)

Plasma Fractions (see table 34-3 pp 557)

Fibrinolytic Inhibitors: Aminocaproic Acid (EACA)

- Chemically similar to lysine
- synthetic inhibitor of fibrinolysis
- competitively inhibits plasminogen activation
- rapidly absorbed orally, cleared by kidney
- Tranexamic acid – analog of EACA
- Adjunct tx for hemophilia
- Tx for bleeding from fibrinolytic tx
- Prophylaxis for rebleeding from intracranial aneurysms
- ADR: intravascular thrombosis from inhibition of
plasminogen activator, Hypotension, myopathy, abdominal
discomfort, diarrhea, nasal stuffiness
- CI: DIC, upper GUT bleeding because of potential excessive
clotting

Serine Protease Inhibitors: Aprotinin

- inhibits fibrinolysis
- inhibits plasmin-streptokinase complex
- reduce bleeding by 50% (surgical)
- ADR: MI, stroke, renal damage, anaphylaxis (small test dose
done first)

Special thanks kina anne.. for sharing sa paggwa nito..

Detox corner…

Do What Heart Says . . .

Horror gripped the heart of a World War-I soldier, as he saw his lifelong
friend fall in battle. The soldier asked his Lieutenant if he could go out to
bring his fallen comrade back. "You can go," said the Lieutenant, "but
don't think it will be worth it. Your friend is probably dead and you may
throw your life away.."

The Lieutenant's words didn't matter, and the soldier went anyway.
Miraculously, he managed to reach his friend, hoisted him onto his
shoulder and brought him back to their company's trench. The officer
checked the wounded soldier , then looked kindly at his friend.

"I told you it wouldn't be worth it..," he said. "Your friend is dead and you
are mortally wounded.." " It was worth it, Sir," said the soldier..

"What do you mean by worth it?" responded the Lieutenant. " Your friend
is dead." "Yes Sir," the soldier answered, " but it was worth it because
when I got to him,he was still alive and I had the satisfaction of hearing
him say...." Jim...I knew you'd come..."

Many times in life, whether a thing is worth doing or not, really depends
on how u look at it. Take up all your courage and do something your heart
tells you to do so that you may not regret not doing it later in your life . .