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38 Cards in this Set

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  • Back
What's the aim of preventing and reversing abnormal hemostasis?
inhibit primary and secondary hemostasis and activate fibrinolysis via plasmin to breakdo insoluble fibrin.
Antiplatelet dru do what?
blcok signaling systmes that trigger platelet activation or proteins that mediate their adhesion or aggregation.
What are the major drug targets
Cyclooxygenase I (synthesizer for Thromboxane A2 (a vasoconstrictor and platelet activator/aggregator)).

The ADP receptor

The GPIIb/IIIA surface antigen, which bind fibrinogen and promote aggregation.
Aspirin (acetylsalicylic acid, ASA)
irreversibly inhibits COX1 for life of platelet (7-10 dz) whom can't synthesize new protein. They can't synthesize Thromboxane A2 (TXA2).

Decreases: risk of CHD, prevent strokes and stroke related mortality in ischemic stroke.

Used in Tx of unstable angina.

Negatives: GI bleeding and peptic ulcers.

Use 81mg baby aspirin. Higher dose doesn't provide additional antiplatelet activity but enhances side effects.
Thienopyridine class: The ADP receptor antagonists
are PRO drugs: clopidogrel (plavix), ticlopidine (ticlid).

P2Y1, P2Y12-R Irreversible antagonists

Drug of choice in pts allergic to aspirin.

Normally used in combo with aspirin. Slow onset b/c requires activation of pro drugs by p450 (3-5dz), peak efficacy at 8-11dz.

No benefit over aspirin alone but increased risk of bleeding and higher cost.

side effects: neutropenia and thrombocytopenia, monitor pts on this therapy.

2nd highest selling drug in the world!
How does ADP-R antagonist work.
Normally acitvation of P2Y1 and 12 receptors on platelet surface increases IP3 and decrease cAMP; both signals promote GPIIb/IIIa (fibrinogen receptor) on surface.

thienopyridine drugs block this from happening.
increases cAMP by inhibition of cAMP phosphodiesterase... so simila effect as thienopyridines (via blocking signals that promote expression of GPIIb/IIIa).

Different than thienopyridines in that it is also a VASODILATOR, and its efficacy is SUPERIOR to aspirin alone.

indicated as propylaxis of thromboemboli in heart valves, recurrence of stroke.
Role of fish oils as antiplatelet drug
unlike other fats, causes production of Thromboxane 3 (TXA3) which is a VASODILATOR, and also blocks platelet activation and aggregation.

Requires intact Cox enzyme, so aspirin would prevent TXA3 synthesis.
Parenteral Antiplatelet Drugs: abciximab, eptifibatide, tirofiban
abciximab: Fab fragement of antibody against GPIIb/IIIa which mediates platelet adhesion and aggregation. Abciximab block platelet-vasculature interraction for upto a day.

IV during angioplasty, reduce risk of re-stenosis. Expensive.

Eptifibatide: cyclic peptide, also inhibits GPIIb/IIIa.

Tirofiban: reversible, non-peptide inhibitor of GPIIb/IIIa.
Pharm of coagulation cascade
Secondary hemostasis, formation of fibrin clot, is targeted. Anticoagulants block acitivity or synthesis of: antithrombin, thrombin, and vitamin K epoxide reductase.
Activities inhibited by Heparin?
It inhibits the active forms: i.e. XIIa, XIa, IXa, Xa, IIa (thrombin)
Activities inhibited by LMWH?
Synthesis inhibited by Warfarin?
VII, IX, X, II (prothrombin)
What labs are used for heparin and warfarin
Use intrinsic pathway (PTT or aPTT) for Heparin.

Use extrinsic pathway (PT) for Warfarin. INR for PT is the standard.
Heparin and Heparin Sulfate
natural compound secreted by mast cells. Consist of neg. charged mucopolysaccharides.
Heparin: Mech of action
Normally antithrombin III, glycoprotein secreted by liver, binds thrombin (IIa) with low affinity.

Heparin act as an ENZYMATIC surface, allows antithrombin and thrombin plus other factors to 'meet' alteast with a thousand fold increase.

Antithrombin III makes a 1:1 complex with thrombin or the other coagulation factors, and are both permanently out of commission. Heparin can leave and catylyze formation of additional complexes.

Antithrombin III inhibits factors Xa, IXa, XIa, XIIa and Kallikrein but not factor VII.
Heparin vs. Low Molecular Weight Heparin: What's the difference
Heparin has a 18 monosaccharide units or larger which is required for Factor, Heparin and Antithrombin III (all 3 components) to come together all at once.

However, Factor Xa doesn't require the 3 components to come together all at once.

This is important b/c LMWH doesn't have the 18 units but rather only 5 monosaccharide units and can not bind antithrombin (IIa).
Mech of action: LMWH
It induces a conformational change in antithrombin III exposing the reactive site to Factor Xa.

So it only inhibits Factor Xa, and not thrombin (IIa) or the other factors.
Pharmacokinetics: Heparin and LMWH
Heparin: half life increases with increasing doses b/c of both saturable and unsaturable processes (complicated pharmakokinetics).

LMWH: greater bioavailability, longer plasma half-life, and simpler pharmkokinetics. Self-admin. syringes available.
Heparin Administration?
NEVER give I.M. b/c risk of hematoma

Dose Unit: amt of hep needed to prevent 1 ml sheep plasma from clotting for 1 hr following addition of .2 ml of CaCl2.

LD: 5000-10000 U as I.V. w maint dose: 900-1600 U/hr.

Can be SQ at 5000 U per 8-12 hrs.

Goal: get aPTT 1.5 to 2.5x. Not monitored with LMWH.

Large Dose req'd for pulmonary embolism due to increased heparin clearance.
Heparin Toxicity

transient thrombocytopenia: assoc w/ paradoxical thrombotic complications b/c thrombocytopenia is an immune reaction and results in IgG mediated platelet activation. Less freq w/ LMWH

Can be used during pregnancy w/ caution: no placenta crossing.
Heparin Clinical indications
First line: prev and tx of venous thromboembolism

i.e following post surgeries MIs etc.
Some LMWH?
enoxaparin, dalteparin, tinzaparin (all end in -parin).

Enoxaparin and dalteparin following hip repl or abd surgeries.

also recomm for prev of recurrent angina or MIs.
Heparin contraindications?
pts undergoing brain, sp. cord, or eye surgery bc even minor bleeding may cause major problems.
Heparin antidote
mild bleeding reversed by mere termination of therapy within hours.

Severe bleeding due to heparin: use PROTAMINE SULFATE.

basic protein tightly binds and neutralizes heparin (which is acidic).

Protamine sulfate has weak anticoagulant effects so use minimal dose (1 mg for every 100 U of heparin).
first synthetic selective inhibitor of factor Xa. Indiacted by prophylaxis of deep vein thrombosis.
Lepirudin, bivalirudin
reversible, direct thrombin inhibitors.

from salivary glands of leeches.

cleared by kidney so use w/ caution in pts with renal failure. Monitor aPTT.
also direct reversible thrombin inhibitor. But different from 'iuridins' in that cleared by Hepatic 450. Monitor aPTT.
most freq. used oral anticoagulant.
Coumadin: Mech of Action
glutamate residues of factor II, VII, IX and X undergo carboxylation to turn inactive decarboxy- form of proteini into active coag factors. Vit K is a cofactor for decarboxylation during which it goes from hydroquinone form to an epoxide.

Coumadin inhibits conversion of the epoxide form of VitK back to hydroquinone form, therefore resulting in depletion of this cofactor.

No effect on synthesis of the coag cofactors, just prevents their activation.
Coumadin Pharmakokinetics
nearly 100% bioavailability but highly plasma albumin bound (99%).

small VD and long plasma half life.

inactivated by kidney and liver.

S-form 4x more potent than R-form.
Coumadin Administration
no need for LD b/c of its mech of action. Started off with small initial doses and increased as indicated by PT/INR.

No effect on carboxylated coag factors. Therefore, degradation rate of coag factor will determine when drug exerts its full effect. PT quickly prolonged due to faster breakdown of Factor VIII.

Primary aim: prolong PT to 25% of normal clotting activity. Translates to INR of 2.5-3.5 (PT of 1.6).
Coumadin: clinical indications
Acute MI: preve of stroke or pulm embolism

Prev of stroke

Atrial fibrillation: reduce stroke rate

Prosthetic heart valve: reduce thromboembolims

Prophyl. or tx of venous thromboembolism
Drug Interraction: Warfarin

See p. 8, lect 45 and 46.
Coumadin: Contraindication
birth defects and abortion, do not use in pregnancy.

Extreme caution in pts with hepatic or renal dz or GI tract lesion.
Clot busters
Thrombolytics enhance fibrinolysis by promoting covernsion of plasminogen to plasmin.
Thrombolytic drugs
urokinase, streptokinase, anistreplase, tissue plasminogen activator (t-PA).

t-PA does not induce system activation, activates plasminogen to plasmin only in presence of fibrin.
Thrmobolytic drugs: indications
multiple pulmonary emboli, central DVTs, acute MI in only selected pts

Contraindicated for: surgery, GI tract bleeding, aneurysm, hypertension, active bleeding etc.