pharmacology anticoagulation

Anticoagulant

Clotting Cascade

Anticoagulant:

An anticoagulant is a substance that prevents coagulation; that is, which stops blood from clotting

Anticoagulants reduce blood clotting.

This prevents Deep vein thrombosis, Pulmonary embolism, Myocardial infarction  

Stroke.

PT and INR

Prothrombin time (PT) evaluates the ability of blood to clot properly, it can be used to help diagnose

bleeding.

When used in this instance, it is often used in conjunction with the PTT to evaluate the function of

all coagulation factors. the test may be used to screen patients for any previously undetected bleeding

problems prior to surgical procedures.

Prothrombin Time (PT)

• Historically, a most reliable and “relied upon” clinical testHowever:– Proliferation of thromboplastin reagents with

widely varying sensitivities to reduced levels of vitamin K-dependent clotting factors has occurred

– Concept of correct “intensity” of anticoagulant therapy has changed significantly (low intensity)

– Problem addressed by use of INR (International Normalized Ratio)

INR: International Normalized Ratio• A mathematical “correction” (of the PT ratio)

for differences in the sensitivity of thromboplastin reagents

• Relies upon “reference” thromboplastins with known sensitivity to antithrombotic effects of oral anticoagulants

• INR is the PT ratio one would have obtained if the “reference” thromboplastin had been used

• Allows for comparison of results between labs and standardizes reporting of the prothrombin time

(( ))Patient’s PT in SecondsPatient’s PT in SecondsMean Normal PT in SecondsMean Normal PT in Seconds

INR =INR =ISIISI

INR = International Normalized Ratio ISI = International Sensitivity Index

INR Equation

The International Normalized Ratio (INR) is used to monitor the effectiveness of blood thinning drugs

such as warfarin (Coumadin).

These anti-coagulant drugs help inhibit the formation of blood clots. They are prescribed on a long-term basis to patients who have experienced recurrent

inappropriate blood clotting. 

The test result for PT depends on the method used, with results measured in seconds and compared to the average value in

healthy people.

Most laboratories report PT results that have been adjusted to the International Normalized Ratio (INR) for patients on anti-

coagulant drugs.

These patients should have an INR of 2.0 to 3.0 for basic "blood-thinning" needs. For some patients who have a high risk of clot formation, the INR needs to be higher - about 2.5 to 3.5.

Prothrombin Time Blood Test-PT:

This test is done to evaluate the blood for its ability to clot.

It is often done before surgery to evaluate how likely the patient is to have a bleeding or clotting problem during or after surgery.Normal PT Values:  10-12 seconds

Partial Thromboplastin Time Blood Test-PTTThis test is performed primarily to determine if heparin (blood thinning) therapy is effective. It can also be used to detect the presence of a clotting disorder. It does not show the effects of drugs called “low molecular weight heparin” Normal PTT Values: 30 to 45 seconds Extended PTT times can be a result of anticoagulation therapy, liver problems, lupus and other diseases that result in poor clotting.

International Normalized Ratio Blood Test-INR

Normal INR Values: 1 to 2

The INR is used to make sure the results from a PT test is the same at one lab as it is at another lab.

Common drugs influencing INR values :

INR / PT decreases INR /PT increases

amoxicillin

kinolons

cephalosporins

makrolid antibiotics

paracetamol

salicylate

amiodaron

allopurinol

omeprasol

heparine

NSAID & COX2 inh.

tricyclic antidepressants

rifampin

antihistamin

barbiturat

carbamazepin

digoxin

diuretics

pills

coffein

pentoxiphyllin

Vitamin K

CLASSIFICATION:

• Heparin, Low Molecular Weight Heparin

• Heparinoids– Heparan Sulfates

• Danaparoid

• Lepirudin

• Ancrod

Low-Molecular-Weight Heparinand

Unfractionated Heparin

The Coagulation Cascade

• Central to the coagulation cascade is the generation of thrombin (factor IIa)

• thrombin is generated from prothrombin by the action of activated factor X (Xa)

• thrombin then acts on fibrinogen to generate fibrin clot

Vitamin KVitamin K

Synthesis of Synthesis of Functional Functional

Coagulation FactorsCoagulation Factors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Clotting Factors

Coagulation CascadeCoagulation Cascade

XIIa

XIa

IXa

Intrinsic Pathway(surface contact)

Xa

Extrinsic Pathway(tissue factor)

VIIa

Thrombin (IIa)

Thrombin-FibrinClot

aPTT

PT

Heparin / LMWH(AT-III dependent)

Hirudin/Hirulog(direct antithrombin)

Courtesy of VTI

THROMBOSISCollagen XIa

Tissue Factor IXa

Platelet Clumping

Thrombus Formation

Thrombus Growth

HEMOSTASIS

Tissue Factor &Collagen

Platelet Aggregation

Platelet-richHemostatic Plug

Xa

FluidThrombin

HEPHEP

HEP & HIRHEP & HIR

Heparin Inhibits HemostasisHeparin Inhibits Hemostasis

Only approximately one third of an administered dose of heparin binds to AT, and this fraction is responsible for most of its anticoagulant effect. The remaining two thirds has minimal anticoagulant activity at therapeutic concentrations, but at concentrations greater than those

usually obtained clinically, both high- and lowaffinity heparin catalyze the AT effect of a second

plasma protein, heparin cofactor II

The heparin-AT complex inactivates a number of coagulation enzymes, including thrombin factor

(IIa) and factors Xa, IXa, XIa, and XIIa. Of these, thrombin and factor Xa are the most responsive to inhibition, and human thrombin is  10-fold more sensitive to inhibition by the heparin-AT complex

than factor Xa 

For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, but binding to the enzyme is less important for inhibition of activated

factor X (factor Xa ) Molecules of heparin with fewer than 18 saccharides do not bind simultaneously to

thrombin and AT and therefore are unable to catalyze thrombin inhibition. In contrast, very small heparin

fragments containing the high-affinity pentasaccharide sequence catalyze inhibition of factor Xa by AT.

By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced

activation of factor V and factor VIII

Low-molecular-weight heparin

• UH (mw 3k - 30k) is a heterogeneous mixture of polysacchride chains (glycosaminoglycans)

• LMWH (mw 5k) is obtained by alkaline degradation of heparin benzyl ester

• LMWH molecules are enriched with short chains with higher anti-Xa:IIa ratio

Mechanism of Action

• Both UH and LMWH exert their anticoagulation activity by catalyzing antithrombin (AT or AT III)

• catalyzed AT is accelerated in its inactivation of the coagulation enzymes thrombin (factor IIa) and factor Xa.

• prolongs aPTT

AT

HC II

++++- - -

-

Interaction of Heparin Co-Factors with Thrombin

Interaction of Heparin Co-Factors with Thrombin

ThrombinHF

S C

ThrombinHF

S C

Heparin has a higher affinity for AT than for HC II and there is more AT in plasma than HC II

AT

Free Thrombin

Antithrombin and Free ThrombinAntithrombin and Free Thrombin

AT alone does not inactivate free-thrombin

ThrombinHF

S C

Heparin binds to antithrombin and increases the rate of thrombin inactivation

AT

Heparin

Inactivation of Thrombin byHeparin-AT Complexes

Inactivation of Thrombin byHeparin-AT Complexes

ThrombinHF

S C

AT

Fibrin-Bound Thrombin

The rate at which AT inactivatesfibrin-bound thrombin is reduced 50-fold

Effect of Antithrombin on Fibrin-Bound Thrombin

Effect of Antithrombin on Fibrin-Bound Thrombin

ThrombinHF

S C

Inactivation of Thrombin by Heparin-AT Complexes

Inactivation of Thrombin by Heparin-AT Complexes

When thrombin binds to fibrin, it becomes resistant to inactivation by heparin.

AT

HeparinFibrin

ThrombinHF

S C

Mechanism of Action

• Summary– Catalyzes ATIII – Specific for fluid-phase thrombin– Prolongs aPTT by inactivating thrombin and blocking

Xa generation

Differences in Mechanism of Action

• Any size of heparin chain can inhibit the action of factor Xa by binding to antithrombin (AT)

• In contrast, in order to inactivate thrombin (IIa), the heparin molecule must be long enough to bind both antithrombin and thrombin

• < half the chains of LMWH are long enough

AT

Unfractionated Heparin

Differential inhibitory activity against factor Xa and IIa activity

Differential inhibitory activity against factor Xa and IIa activity

Thrombin (IIa)HF

S C AT

LMWH

Thrombin (IIa)HF

S C

By binding to AT, most UH and LMWH can inhibit Xa activity.Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity.

Low-Molecular-Weight HeparinsAnti-Factor Xa : Anti - Factor IIa Ratios

Agent Trade Xa:IIa Mol Wt (d)

Enosaparin Lovenox 3.8 : 1 4,200

Dalteparin Fragmin 2.7 : 1 6,000

Ardeparin Normiflo 1.9 : 1 6,000

Nadroparin 3.6 : 1 4,500

Reviparin 3.5 : 1 4,000

Tinzaparin 1.9 : 1 4,500

METHOD OF ADMINISTRATION FREQUENCYRECOMMENDED DOSE (based on

150 lb [68 kg] patient)

Deep Subcutaneous (Intrafat) Injection

Initial Dose 5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously

A different site should be used for each injection to prevent the development of massive hematoma

Every 8 hours or 8,000 to 10,000 units of a concentrated solution

Every 12 hours 15,000 to 20,000 units of a concentrated solution

Intermittent Intravenous Injection

Initial Dose 10,000 units, either undiluted or in 50 to100 mL of 0.9% Sodium Chloride Injection, USP

Every 4 to 6 hours 5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

Intravenous Infusion Initial Dose 5,000 units by IV injectionContinuous 20,000 to 40,000 units/24 hours in

1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

5/98 MedSlides.com 34

Each mL of the 1,000 Units per mL preparation contains: 1,000 USP Heparin Units (porcine); 9 mg sodium chloride; Water for Injection q.s. Made isotonic with sodium chloride. Hydrochloric

acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).

Heparin Sodium Injection, USP (porcine), preserved with benzyl alcohol, is available as follows:

Each mL of the 5,000 Units per mL preparation contains: 5,000 USP Heparin Units (porcine); 6 mg sodium chloride; 15 mg benzyl alcohol (as a preservative); Water for Injection q.s.

Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment (5.0-7.5).

Side Effects :Hemorrhage:

Hemorrhage is the chief complication that may result from heparin therapy . An overly prolonged clotting time or minor bleeding during therapy can usually be

controlled by withdrawing the drug .

Bleeding can occur at any site but certain specific hemorrhagic complications may be difficult to detect:

Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during anticoagulant therapy. Therefore, such treatment should be

discontinued in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of corrective therapy should not depend on laboratory confirmation of the diagnosis, since any delay in an

acute situation may result in the patient'sOvarian (corpus luteum) hemorrhage developed in a number of women of

reproductive age receiving short- or long-term anticoagulant therapy. This complication, if unrecognized, may be fatal.

Retroperitoneal hemorrhage.

Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis (HITT) and Delayed

Onset of HIT and HITT

HypersensitivityGeneralized hypersensitivity reactions have been reported,

with chills, fever and urticaria as the most usual manifestations, and asthma, rhinitis  lacrimation ,headache , nausea and vomiting, and anaphylactoid reactions, including shock,

occurring more rarely. Itching and burning, especially on the plantar side of the feet, may occur painful, ischemic and cyanosed limbs have in the past been attributed to allergic

vasospastic reactions. Whether these are in fact identical to the thrombocytopenia-associated complications, remains to be

determined.

Local IrritationLocal irritation, erythema, mild pain, hematoma or ulceration may follow deep subcutaneous injection of heparin sodium. These complications are

much more common after intramuscular use, and such use is not recommended.

MiscellaneousOsteoporosis following long-term administration of high doses of heparin,

cutaneous necrosis after systemic administration, suppression of aldosterone synthesis, delayed transient alopecia, priapism, and rebound

hyperlipemia on discontinuation of heparin sodium have also been reported.

Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and healthy

subjects) who have received heparin.

Platelet Inhibitors

Drugs such as acetylsalicylic aci d, dextran, phenylbutazone, ibuprofen, indomethacin,

dipyridamole, hydroxychloroquine and others that interfere with platelet- aggregation reactions (the main

hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in

patients receiving heparin sodium.

Other Interactions

Digitalis, tetracyclines, nicotine or antihistamines may partially counteract the anticoagulant action of heparin sodium.

Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with

subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of

heparin and intravenous nitroglycerin.

Advantages of LMWH over UH

• Decreased “heparin resistance”– pharmacokinetics of UH are influenced by its bindings

to plasma protein, endothelial cell surfaces, macrophages, and other acute phase reactants

– LMWH has decreased binding to nonanticoagulant-related plasma proteins

Advantages of LMWH over UH

• No need for laboratory monitoring– when given on a weight-adjusted basis, the LMWH

anticoagulant response is predictable and reproducible

• Higher bioavailability - 90% vs 30%

• Longer plasma half-life– 4 to 6 hours vs 0.5 to 1 hour– renal (slower) vs hepatic clearance

Advantages of LMWH over UH

• Less inhibition of platelet function– potentially less bleeding risk, but not shown in clinical

use

• Lower incidence of thrombocytopenia and thrombosis (HIT syndrome)– less interaction with platelet factor 4– fewer heparin-dependent IgG antibodies

Monitoring of LMWH• Unnecessary in majority of patients• May be useful in specific instances

– renal insufficiency (creatinine >2.0 mg/dl)– obese patients with altered drug pK– major bleeding risk factors

• aPTT not useful - low anti-IIa activity• anti-factor Xa assay is more appropriate, but not

widely available

ORAL ANTICOAGULANTS

CLASSIFICATION:• 1. Coumarin Derivatives:

• Bishydroxycoumarin• Warfarin sod.• Acenocoumarol• Ethylbiscoumacetate

• 2. Indandione derivative :

• Phenindione

Objectives

• Mechanism of Action

• Dosing/Target INRs

• Drug/Food Interactions

• Managing Elevated INRs

• Patient Counseling

• Other Considerations

Mechanism of Action

• Inhibits Vitamin K-dependent coagulation factors II, VII, IX, & X as well as anticoagulant proteins C & S

• Does not have an effect on already-synthesized coagulation factors; therefore, the therapeutic effects are not seen until these factors are depleted

• 3-4 days until effect is seen

Mechanism of Action

Elimination Half-Lives of Vitamin K-dependent

clotting factors:

• II 42-72 hours• VII 4-6 hours• IX 21-30 hours• X 27-48 hours

Dosing

• Response to warfarin is highly dependent upon the individual.

• When initiating warfarin in a patient, close PT/INR monitoring is key.

-PT vs. PTT vs. INR• Target INRs will vary based on indication, but

an INR > 4 typically confers no additional therapeutic benefit to justify the increased risk of bleeding.

Dosing: Initiation

• In patients without known enhanced response to warfarin:

-Various dosing strategies have been outlined, typically starting with 2-10 mg/day, titrated to the appropriate INR.

-5 mg PO initially is thought to carry minimal risk of bleeding and will bring INR to >/= 2 within 4-5 days

Dosing: Initiation

• Other strategies:

7.5-10 mg PO x 2 days to achieve rapid INR, then maintenance dose based on INR. **The problem with this is that often INR is overshot due to the half lives of the clotting factors.**

Large initial doses (>/= 20 mg/day) do not provide more rapid anticoagulation and are not recommended.

Dosing: Initiation

• If rapid anticoagulation is desired, may bridge with heparin/LMWH until INR is therapeutic.

• Special considerations It may be prudent to start with a lower initial dose (ex: 2 mg) in the following patient populations due to increased risk of bleeding:-elderly -children/adolescents-malnourished -patients with hepatic failure -debilitated -patients with heart failure

• May consider larger initial dose (ex: 7.5 mg) in healthy, young adults with no interacting medications and a low bleeding risk or those who have required a higher dose in the past.

Dosing: Maintenance

• In general, maintenance doses are 4-5 mg daily (range: 2-10 mg) but should be determined by INR monitoring.

• Adjusting doses (up or down) should be done in 5-20% increments depending on how far the INR is from target with close monitoring of INR.

• Duration of therapy will also be determined by indication (see handout--attached).

Dosing

• Always take into consideration the likelihood of compliance when initiating/changing daily doses.

• Stick to one tablet strength if possible.

• Avoid complicated dosing regimens especially in the elderly.

• Available tablet strengths: 1 mg, 2 mg, 2.5 mg, 3 mg, 4mg, 5 mg, 6 mg, 7.5 mg, 10 mg

INR Monitoring

Initiating Therapy

-Check INR within 2-3 days (outpatient).

-Daily INR/PT in hospital until therapeutic x2 days.

-Check one week after initiation steady state.

-Monitor weekly during first month of therapy.

INR Monitoring

• Maintenance Therapy:-If you have to hold a dose, recheck within 1-2

days-If you change a dose, recheck within 1-2 weeks.-Routine follow up for stable, reliable patients is

every 4 weeks (may consider 6 weeks in some patients), more often (every 1-2 weeks) in less reliable or unstable patients.

Target INRs for Various Indications

IndicationIndication Target INRTarget INR Target INR Target INR RangeRange

Acute MI (high risk)Acute MI (high risk) 2.52.5 2-32-3

Atrial fibrillationAtrial fibrillation 2.52.5 2-32-3

Prosthetic valve*Prosthetic valve* ---- 2-3.52-3.5

Mechanical valve + risk factorsMechanical valve + risk factors 33 2.5-3.52.5-3.5

Mechanical valve with systemic Mechanical valve with systemic embolism despite adequate embolism despite adequate anticoagulationanticoagulation

33 2.5-3.52.5-3.5

Venous thromboembolismVenous thromboembolism 2.52.5 2-32-3

Dosing

• A note about IVC filters…

-thrombosis at the insertion site has been reported in 50% of patients

-4-11% will have IVC thrombosis

-there is evidence of increased incidence of DVT with these filters prophylaxis is recommended if not otherwise contraindicated

Factors that Can Influence INR

• Drug Interactions• Diet• Alteration of intestinal

flora (increase INR)• Fever (increase INR)• Hepatic failure (increase

INR)

• Thyroid function (hypo decrease INR, hyper increase INR)

• Stress (increase INR)• Smoking (may decrease

INR)• Noncompliance

(increase or decrease INR)

Management of Warfarin During Invasive Procedures

• For subtherapeutic or normal INR: Hold warfarin for 3–5 days pre-procedure

• Low Dose Heparin (LDH): Low-dose heparin (5,000 IU SQ BID); hold warfarin 3–5 days pre-procedure and begin LDH therapy 1–2 days pre-procedure

• Adjusted Dose Heparin (AdjDH): Same as LDH but higher doses of heparin (between 8,000–10,000 IU BID or TID) to achieve an aPTT in upper range of normal or slightly higher midway between doses

• Full Dose Heparin (FDH): full doses of heparin, IV continuous infusion, to achieve a therapeutic aPTT (~1.5–2x control); implement as for LDH

• Restart heparin or warfarin post-op when considered safe to do so

Current Daily Dose (mg)Current Daily Dose (mg)

2.0 2.0 5.05.0 7.5 7.5 10.010.0 12.512.5WarfarinWarfarin

INRINR Dose Adjustment*Dose Adjustment* Adjusted Daily Dose (mg) Adjusted Daily Dose (mg)1.0-2.01.0-2.0 Increase x 2 daysIncrease x 2 days 5.05.0 7.57.5 10.010.0 12.512.5 15.015.02.0-3.02.0-3.0 No changeNo change —— —— — — — — — —3.0-6.03.0-6.0 Decrease x 2 daysDecrease x 2 days 1.251.25 2.52.5 5.05.0 7.57.5 10.010.0

6.0-10.06.0-10.0†† Decrease x 2 daysDecrease x 2 days 00 1.251.25 2.52.5 5.05.0 7.57.510.0-18.010.0-18.0§§ Decrease x 2 daysDecrease x 2 days 00 00 00 00 2.52.5

>18.0>18.0§§ Discontinue warfarinDiscontinue warfarin and consider hospitalization/reversal and consider hospitalization/reversalof anticoagulationof anticoagulation

† † Consider oral vitamin K, 2.5–5 mgConsider oral vitamin K, 2.5–5 mg§§ Oral vitamin K, 2.5–5 mg Oral vitamin K, 2.5–5 mg* Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or * Allow 2 days after dosage change for clotting factor equilibration. Repeat prothrombin time 2 days after increasing or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decreasing warfarin dosage and use new guide to management (INR = International Normalized Ratio). After increase or decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, decrease of dose for two days, go to new higher (or lower) dosage level (e.g., if 5.0 qd, alternate 5.0/7.5; if alternate 2.5/5.0, increase to 5.0 qd).increase to 5.0 qd).

Dosage Adjustment Algorithm

Drug Interactions with Warfarin: Potentiation

Level of Evidence Potentiation

Alcohol (if concomitant liver disease) amiodarone (anabolic steroids, cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600 mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam, propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)

Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram, itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen, tetracycline, flu vaccine

Acetylsalicylic acid, disopyramide, fluorouracil, ifosflhamide, ketoprofen, iovastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin, propoxyphene, sulindac, tolmetin, topical salicylates

Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole

I

II

III

IV

Drug Interactions with Warfarin: Inhibition

Level of Evidence Inhibition

Barbiturates, carbamazepine, chlordiazepoxide, cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate

Dicloxacillin

Azathioprine, cyclosporine, etretinate, trazodone

I

II

III

IV

Drug Interactions with Warfarin: No Effect

Level of Evidence No Effect

Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine‡

Ibuprofen, ketoconazole

Diltiazem, tobacco, vancomycin

I

II

III

IV

Effective Patient Education

• Teach basic concepts of safe, effective anticoagulation

• Discuss importance of regular INR monitoring

• Counsel on use of other medications, alcohol

• Develop creative strategies for improving compliance

Drug Interactions

• Problems with drug interactions are not as significant when warfarin is being added to the profile.

• The critical time is when other interacting agents are initiated or discontinued. Monitor INR depending on interaction, may consider monitoring weekly until stable (ex: amiodarone).

Drug Interactions: Increased INR

• Thyroid products

• Metronidazole

• Fluconazole/azole antifungals

• 2nd, 3rd generation cephs

• Broad spectrum antibiotics

• Alcohol*

• Amiodarone*

• Azithromycin

• Statins

• Omeprazole

• Phenytoin

• Bactrim

• Heparin

• Gemfibrozil

• Fluoroquinolones*

• Cimetidine

Drug Interactions: Decreased INR

• Estrogens• Vitamin K (vitamins, etc)• Alcohol*• Carbamazepine• Barbiturates• Phenytoin• Rifabutin• Rifampin• Ritonavir

Drug Interactions: No INR Effect

• Aspirin

• Clopidogrel

• COX 2 inhibitors

• Glycoprotein IIb/IIIa antagonists

• NSAIDs*

• Ticlopidine

Interaction Comments

• Quinolones

• Amiodarone

• Alcohol

• NSAIDs

Interactions with Natural Products

• Cranberry• Dong Quai• Ginseng• Fish Oil• Gingko biloba• Soy• St. John’s Wort• Green Tea

• Glucosamine• Chondroiton• Vitamin E• Seaweed• Garlic• Ginger• Saw Palmetto

Food Interactions• Asparagus• Avacado• Broccoli• Brussel Sprouts• Kale• Spinach• Collard Greens• Cole slaw• Turnip greens• Watercress• Liver• Green Tea

• Endive• Green Beans• Green Onions• Soybeans• Cauliflower• Lettuce• Peas• Pickles• Sauerkraut• Cabbage• Mustard greens• Mayonnaise

Management of Drug Interactions

• Choose another agent in the same class that does not interact (ex: pravastatin, famotidine, 1st gen. cephalosporin).

• Monitor INR closely upon initiation or discontinuation of interacting agent.

• Inform the patient of the signs/symptoms of excessive anticoagulation and instruct them to call if experiencing these signs.

Managing Elevated INRs

• Will depend upon INR as well as symptoms.

• If necessary, oral or IV Vitamin K may be given to reverse anticoagulation.

Vitamin K

• 2.5 mg PO: will correct within 24-48 hours• Bigger doses are NOT better, because it can

cause prolonged warfarin resistance.• 0.5-1 mg IV: will correct in 24 hours—this may

be a good option for anticoagulation prior to invasive procedures.

• 10 mg IV (high dose): will correct within 6-12 hours, but may have to start all over with heparin/bridge therapy.

Indications for anticoagulant treatment

Deep Vein ThrombosisPulmonary EmbolismMyocardial InfarctionUnstable AnginaRheumatic Heart Diseases; Atrial FibrillationCerebrovascular DiseasesDefibrination SyndromeVascular Surgery, Prosthetic Heart Valves, Retinal Vessel

Thrombosis, Extracorporeal Circulation, Haemodialysis

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