Anticoagulants drugs interactions

1
Anticoagulants drugs interactions

• Oral anticoagulants
• Warfarin sodium (Marivan)
• It is a synthetic coumarine derivative oral
  anticoagulant
• Will absorbed orally (100) food decrease the
  rate but not the extent of warfarin absorption
• Pass BBB placenta,
• Highly bound to plasma proteins 99 therefore
  has a small volume of disribution (7-14L)
• Onset of action is delayed (1-2 days), duration
  of action is long (5-8) days
• The commercially avaialable warfarin is a
  mixture of L- isomer (S- form) and D- isomer
  (R-form) the former is 5 times more potent than
  the latter

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Metabolism is very complex - The more active S-
isomer (L) is metabolised primarly by Cytochrome
P450 2C9 (CYP2C9) - The less active R-warfarin
(D) is metabolised by 1A2 - R-warfarin is an
inhibitor of P450 2C9 - Only small amount appears
unchanged in urine (renal function has no effect
on warfarin) - Half life 20-50 h so steady state
obtained after approximately one week
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• Action
• - Both enantiomers act by inducing a functional
  deficiency of vitamin K (via inhibit of vit K
  Epoxide reductase resulting in decreased
  reactivation of vit K) and thus prevent the
  normal carboxylation of glutamic acid residues of
  the amino terminals of clotting factors (non
  functional clotting factors II, VII, IX, X)
• This explains the delayed onset of action of
  warfarin (as the onset depends on the rate of
  clearance of already carboxlated and previously
  syntheisized clotting factors )

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• 2- Dosage Control
• Initial dose 10mg daily for two days then
  maintenance dose 2-10 mg/day , this variability
  in dose requirement is related to genetic
  polymorphism of CYP2C9 mediating the rate of
  hepatic metabolism of S-warfarin
• so individuals with a variant isoform
  metabolise S-warfarin more slowly and needs lower
  doses

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• Control of dose
• PT, INR, Prothrombin activity, Guiac test ,
  urine analysis (hematuria)
• INR is the most accurate parameter
• - As it correlates PT of patient to that of
  control
• - It it is highly sensitive to factor II, VII, X
  the most important factors in the extrinsic
  pathway of metabolism
• - But the optimum therapeutic range of INR
  (target INR) varies according to the clinical
  conditions
• The lowest INR but consistent with therapeutic
  efficacy is the best to guard against haemorrhage
  
• - In majority of conditionn INR should be kept
  between 2 to 3 or 2.5 (British Committee for
  Standards Hematology 2006A)

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• Variability in response to warfarin or resistance
  
• May be related to genetic variation in the gene
  encoding the vit K epoxide reductase
  multi-protein complex (VKORC1 gene)

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• Side effects
• Hemorrhage, GIT upset, hypersensitivity,
  teratogenicity,
• sudden stop of warfarin results in TEM
  (thrombo-embolic manifistation)
• Skin reaction (warfarin induced necrosis is the
  most serious manifistation)
• - It occurs over the areas of adipose tissue
  specially in female (over breast) which is
  related to relative deficiency of protein C or S
  (anti-thrombotic vitamin k dependant protein),
  this deficiency of such protein result in an
  increased risk of thrombosis in small vesseles of
  skin (necrosis) when large initiating doses of
  warafrin are given and subjects suffering from
  protein C deficiency

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• Antagonists
• 1- Vit K 0.5 2.5 mg oral if there is a minor
  bleeding or a risk factors of bleeding
• 2- in case of major bleeding
• stop warfarin ,
• or Fresh blood transfusion
• or prothrombin complex 50 U/Kg
• or FFP 15 ml/Kg
• or 5 mg vit K I.V.

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Anticoagulants drugs interactions Warfarin
(Marivan) interactions

• 1- Drugs that increase potency of oral
  anticoagulants (increase both PT INR)
• In such case the dose of oral anticoagulant
  should be reduced otherwise bleeding occurs which
  requires treatment by vit K or other mesures
• A- inhibitors of vit K synthesis by gut flora (
  broad spectrum antimicrobials as aminoglycosides)
• B- Inhibitors of Vit K absorption by liquid
  paraffin
• C- Decreased reduction of vit K epoxide by
  certain cephalosporins specially Cefoperazone
  Cefamandole
• D- Hepatic microsomal enzyme inhibitors
  Cimitidine, Chloramphenichol, Clofibrate,
  Phenylbutazone, Sulfonamides, Amiodronre,
  Allopurinol, Ciprofloxacin, Norfloxacin,
  Ofloxacin,Erythromycin, Clarithromycin ,
  antifungal (Ketokenazole, Itraconazole,
  Fluconazole, Voriconazole)

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• E- Displacement from PBB sites Phenylbutazone,
  Salicylates, Sulfonamides, Clofibrate
• F- Inhibition of platelet aggregation with risk
  of increasing bleeding tendency (additive effect)
  NSAIDs including Aspirin at all doses,
  Dipyridamol,Clopidogrel, Moxalactam,
• G- Pharmacodynamic potentiation of anticoagulant
  effect (Anti-metabolites, Phenytoin, L-Thyroxine,
  Tamoxifen) These agents increase clotting
  factor turn over thus decrease the circulating
  conc of these factors
• H- Cessation of smoking when stabilised on
  warfarin

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Anticoagulants drugs interactions
2- Drugs that decrease potency of oral
anticoagulants (?PT ? INR) The dose of oral
anticoagulant must be increased to avoid
thrombosis, ishemic attacks, cerebrovascular
accidents,. A- Decreased absorption of oral
anticoagulant Cholystyramine,Colistipol,
sucralfate N.B long term treatment may impair
vit K absorption and enhance warfain effect B-
Hepatic microsomal inducers (Phenytoin,
Primidone, Phenobarbitone, Tobacco, Topiramate,
Carbamezipine, Rifampicin, Grisofulvin,st johns
wort,. C- Vit K supplement in green leafy
vegetables and enteral feeds
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• C- Pharmacodynamic antagonism of anticoagulant
  effect
• (oral contraceptives containing estrogen and
  progestrones,
• These O.C inhibit clotting factor metabolism thus
  increase circulating conc of clotting factors
  I,II, VII,VIII, IX,X This effect is dose related
  and consider more significant with the high (50
  µg) estrogen containing contraceptives pill than
  with the lower dose preparation
• D- Diuretics (spironolactone)
• by inducing hemoconcentration with subsequent
  concentration of clotting factors have been
  reported to decrease the effect of anticoagulant

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Warfarin sulfonyl-ureas interaction

• Warfarin may increase the activity and
  toxicity of chloropropamide and tolbutamide
  (hypoglycemia,hyponateremia,) by displacement
  reaction
• So,
• Careful monitoring of BG level and reduction
  of su doses are recommended when conncurrently
  taken with warfarin

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Warfarin Phenytoin interaction

• Both potentiation and of anticouglant effect
  have been reported with phenytoin
• This may be due to increase clotting factors
  turn over or induction of hepatic metabolism of
  warfarin by phenytoin
• So,
• Careful monitoring of PT, INR, is required
  together with regular urine examamination for
  hematuria (if any) and Guiac test

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Warfarin Valoproate

• Review anti-epileptic drug interaction

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warfarin Fluvoxamine (Luvox)

• Case study
• A 75 Y.O woman with a history of major
  depressive episoides ( no TTT for many years ago)
  was hospatilised due to deep venous thrombosis
  (DVT) on right thigh, she was initially treated
  by heparin and then shifted to warfarin 5mg daily
  (INR 2.4). After three weeks she experencie a
  recurrence of major depressive disorder for which
  fluvoxamine was titrated up to 100 mg daily.
  After one week , the patient accidently but
  lightly bumped her arm on the side of her bed and
  immediately developped a large and ugly bruise
  on her arm as a result. Her physian ordered the
  state of PT that revealed INR of 5.8 so
  antidepressant was immediately stopped but her
  INR not fall below 3 for another 1O days.
• Outcome mentioned above
• Mec
• Fluvoxamine is a strong inhibitor of 1A2,
  P 450 2C9 2C19, and moderate inhibitor for 3A4
• the addition of fluvoxamine leads to
  increase of INR by several mechanisms
• A- it impairs the ability of 2C9 to metabolise
  S-warfarin leading to increased blood level of
  S-warfarin
• B- it inhibits 1A2 resulting in increase of
  R-warfarin
• Even though, This isomer is less potent but
  it has anticoagulant activity
• In addition, it acts as an inhibitor for
  p450 2C9, it hinders the metabolism of highly
  potent S-warfarin, yeilding a higher S-warfarin
  level
• This combined influnces lead to a
  significant increase in the patient INR to
  almost 2.5 times thebase line value, which placed
  the patient on hypocoaulable stat in which she
  bruised very easily
• Management
• Stop fluvoxamine (done)
• Evaluate INR (done)
• Vit K I.V to adress the
  persistent high INR

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Warfarin st Johnns Wort

• Case study
• A 56 Y.O woman on warfarin therapy for
  atrial fibrillation with mild mitral stenosis
  appears to become resistance to warfarin after
  previously good control on 5 mg daily. Her INR
  dosnt arise above 1.4 even when her warfarin
  dose is increased to 20 mg daily. Her physiacn
  asked her about any medication which might have
  been introduced recentely, she said as she lives
  lonely her mood is down and her neighbour gave
  her some coktail of medicinal herb that improoves
  mood. After investigation ,the physcian
  discovered that this herbal coktail contains st
  Johns wort.
• Outcome Mentioned above
• Mec st Johns wort hypericum perforatum
  extracts which are effective in the treatment of
  modeate depression and have an enzyme inducing
  capacity )
• So, induce warfarin metabolism with
  subsequent reduction of its effect (decrease PT
  INR) with increased risk of thromosis

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Warfarin GINSING

• Case study
• A 65 Y.O man with a history of atrial
  fibrillation with regular rate and prior
  cerebral vascular accident was being maintained
  on warfarin 2.5 mg daily (INR 2.6). A freind told
  him about ginsing as a mean of improoving
  cognitive function and ones overall sens of
  well-being. He decided to purchase some ginsing
  and took it as directed by the herbalist. Three
  weeks later on, he awoke with tingling sensation
  over the lower left side of his face. He called
  the ambulance and was transported to the
  emergency room. He was found to be having a
  transient ischemic attack and his INR was only
  1.4
• Outcome Mentioned above
• Mec
• GINSING appears to have some procoagulant
  effects that decrease the INR, even though the
  nature of this is not well understood. The
  addition of ginsing to the warfarin antagonise
  some of warfarins anticoagulant efficacy, making
  the patient vulnerable to clot formation, which
  might lead to transient ischemic attachs or
  cerebrovascular accidents

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Anticoagulants drugs interactions

• Warfarin (Marivan) interactions (drug-diseases
  interactions)
• 1- Endogenous factors that enhance oral
  anticoagulantseffect
• Hepatic disorder (infectious hepatitis,
  jaundice)
• Hyperthyrodism, thyrotoxicosis, Gravesdisease
• Mal nutrition
• Vit K deficiency

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• 2- Endogenous factors that reducing the response
  to oral anticoagulants
• Carcinoma this may be related to expression of
  factor X activator or tissue factor (as in
  carcinoma of pancreas and all solid tumors)
• Edema
• Hyperlipemia
• D.M.
• Herdiditery resistance to oral anticoagulant
• Hypothyrodism (hashimotoss disease)
• N.B. patint with herdiditery resistance to oral
  anticoagulant also have an increased need for
  vit K why?
• Take in consideration the condition that might
  predispose a patient to a toxicity from higly
  protein bound drug include the following
• Hypoalbuminemia
• Hepatic disease
• Mal nutrition

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WARFARIN- GENETICS INTERACTION

• Variability in response to warfarin or resistance
  
• May be related to genetic variation in the gene
  encoding the vit K epoxide reductase
  multi-protein complex (VKORC1 gene)
• Variability in dose requirement is related to
  genetic polymorphism of CYP2C9 mediating the rate
  of hepatic metabolism of S-warfarin
• so individuals with a variant isoform metabolise
  S-warfarin more slowly and needs lower doses