Khaled A. Alrasheedi

PharmD, Clinical Toxicologist

Pharmacokinetics-Rapidly and completely absorbed after oral administration

-100% bioavailability

-High plasma protein binding capacity : 99%

-Crosses placenta TERATOGENIC

Metabolism: By liver , through the cytochrome P-450 system.

-Half-life is 36 to 42 hours

Dosage and Therapeutic Monitoring

Warfarin is dosed once daily orally and titrated to

an appropriate international normalized ratio (INR) for

different conditions.

Warfarin use is monitored by measuring PT and calculating the INR. The INR “normalizes” variations in PT measurement due to different sensitivities of reagents used by different laboratories.

OverdoseIn therapeutic over medication, warfarin should be held and indications for vitamin K administration should be reviewed in consultation with those monitoring therapeutic dosing.

Vitamin K is indicated for those with a significantly

elevated INR that does not decrease when warfarin is

withheld or when there is evidence of hepatic synthetic

dysfunction (e.g., a significant increase in liver transaminase

concentrations or in the INR).

Fresh frozen plasma is indicated for those with active bleeding.

Nonbleeding Complications

Warfarin use has been implicated in the rare

development of nonhemorrhagic skin lesions ranging

from simple ecchymosis and purpura to urticaria, purple

toes, and skin necrosis.

Warfarin should be discontinued in patients who acquire skin necrosis, and alternative anticoagulation should be started to prevent postcapillary thrombosis.

Purple toe syndrome is thought to be caused by

anticoagulant-induced bleeding into atherosclerotic

plaques releasing cholesterol crystal emboli.

Changing anticoagulation agents is thus unlikely to prevent or reverse progression

SUPERWARFARINS

• They are primarily used as rodenticides and have no role in human medical therapeutic anticoagulation.

• It is highly lipid soluble and are mostly concentrated in the liver.

• They are 100 times more potent than warfarin.

• In overdose, their elimination half-life is weeks to months.

• up to 60 times longer than warfarin’s half-life of 35 hours.

Ingestion

Management of superwarfarin ingestion should be based on amount ingested as related to circumstance of ingestion.

Patients who have ingested superwarfarins intentionally should undergo routine decontamination and have their PT and INR monitored 24 and 48 hours after ingestion.

In the acute phase, PT and INR should be reassessed every 6 hours if prolongation is observed.

There are no means of enhanced elimination of superwarfarins, and multidose activated charcoal has not shown any clear benefit.

In asymptomatic patients, vitamin K1 (phytonadione) may be administered orally at an initial dose of 5 to 15 mg/day

Children who ingest a small dose of a warfarin-based rodenticide (0.01%–0.005% strength) do not need to present to an emergency department.

If any symptoms develop, the child should have a routine medical screening examination and PT and INR drawn. Increases in PT and INR should be followed weekly until a downward trend is seen.

Guideline For Superwarfarin Ingestion Management

UNFRACTIONATED HEPARIN• UFH is only administered parenterally.

• UFH is an easily titratable medication because of its short halflife of 1 to 2.5 hours and short duration of action of 1 to 3 hours.

• Therapeutic monitoring is through the PTT.

• The goal PTT for most vaso-occlusive events as well as

thrombosis prophylaxis when heparin is used as a single

agent is 60 to 80 seconds..

Overdose• Initial treatment is discontinuation of the heparin infusion. For patients with active bleeding requiring quick reversal, protamine sulfate (derived from salmon sperm and testes) should be administered.• Protamine should be dosed as follows:

1 mg protamine per 100 U heparin■ Administer up to 50 mg intravenously over 10minutes (more rapid administration may result inhypotension or anaphylactoid reaction).■ Half the dose of protamine for each half-life of

heparin (about 90 minutes) that has passed sinceinitial administration.Watch for “rebound” hemorrhage: the half-life of protamine is shorter than that of heparin.

Nonbleeding Complications

Patients who experience a drop in platelet count after initiation of heparin therapy may have heparin-induced thrombocytopenia (HIT).

There are two forms of HIT:

1- HIT I is characterized by a mild and transient drop in platelet count occurring within 2 days of heparin administration and is usually asymptomatic, resolving spontaneously.

2- HIT II is more serious, leading to vascular thromboses and their complications.

LOW-MOLECULAR-WEIGHT HEPARINSPharmacokinetics

Their plasma half-life is 4 to 6 hours, with hepatic metabolism and renal elimination.

Patients receiving LMWH therapy do not routinely

undergo therapeutic monitoring

If a patient does suffer an overdose and has active bleeding, protamine should be administered using the same guidelines as for overdose of unfractionated heparin.

Since 1 mg of available LMWHs equals approximately 100 anti-Xa units, 1 mg of protamine should be given for every 1 mg of LMWH for Xaneutralization.

DIRECT FACTOR XA INHIBITORS(FONDAPARINUX)

• Representative of this emerging anticoagulant class, fondaparinux demonstrates 100% bioavailability and is 94% bound to ATIII.

• Peak plasma levels are seen in 2 hours. The volume of distribution (Vd) is 100 mL/kg.

• At least half of the drug is excreted unchanged in urine, and its elimination half-life is 17 to 21 hours.

• Plasma concentration of the drug can be quantified by serum anti–factor Xa activity when the anti–factor Xa assay is calibrated with fondaparinux.

• Plasma concentration of the drug can be quantified by serum anti–factor Xa activity when the anti–factor Xaassay is calibrated with fondaparinux.

• No specific reversal agent has been developed yet for fondaparinux. Because of its small volume of distribution.

• This anti–factor Xa drug is amenable to hemodialysis.

Direct Thrombin Inhibition

Overdose

• There is no specific melagatran or ximelagatran antagonist in the event of an overdose.

• Patients with active hemorrhage should be administered fresh frozen plasma for replacement of coagulation proteins or prothrombin concentrate.

• There have been no reports of hemodialysis to remove the drug, its small molecular weight and volume of distribution suggest that it could be effectively hemodialyzed.

Inhibition of Platelet Aggregation(Antiplatelet Anticoagulation Therapies)

GLYCOPROTEIN IIB/IIIA INHIBITION

The gpIIb/IIIa receptor is the most prevalent cell surface protein on platelets.

When used concomitantly with heparin, gpIIb/IIIa inhibitors should lower the PTT goal (to a range of either 50–70 or 40–60 seconds).

In overdose, the gpIIb/ IIIa infusion should be discontinued, and platelets should be administered for active bleeding or a platelet count of less than 20 × 109/L.

ADENOSINE DIPHOSPHATE–INDUCED PLATELET AGGREGATION INHIBITION

Platelet activation leads to release of ADP, a soluble factor that induces further platelet aggregation through their recruitment and activation.

There is no therapeutic monitoring for thienopyridine

use. However, routine quantitative platelet analysis

(e.g., through a complete blood count) is indicated for

patients taking thienopyridines because they can cause

neutropenia and thrombocytopenia.

OverdoseOverdose of thienopyridines remains a rare occurrence compared with other anticoagulant overdoses.

Although no thienopyridine antiplatelet reversal agent has yet been developed, DDAVP (desmopressin) administration may temporarily improve primary hemostasis.

Patients who overdose with clopidogrel or ticlopidine should undergo routine decontamination with activated charcoal and receive supportive measures.

platelet transfusion may be indicated for patients with active hemorrhage

BOTANICALS WITH ANTICOAGULANTPROPERTIES

Garlic has been shown to inhibit platelet aggregation, and patients with previously stable INRs on warfarin have had elevated INRs after adding garlic to their diets.

Ginger may inhibit platelet aggregation, but ingestion of up to 40 g of cooked ginger does not seem to affect platelet function.

Gingko may also affect platelet aggregation and has been implicated in increased bleeding complications in patients taking anticoagulants.

SNAKE VENOM

Almost all snakes have heparin-like substances that can lead to coagulopathy.

All patients with snake envenomations

should have PT, PTT, INR, and fibrin split products monitored for development of coagulopathies.