Phenprocoumon

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Phenprocoumon
Clinical data
Trade namesMarcoumar, Marcumar, Falithrom
AHFS/Drugs.comInternational Drug Names
MedlinePlusa699003
Pregnancy
category
  • Contraindicated
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Hydroxyl derivatives, glucuronides
Elimination half-life6–7 days
ExcretionKidney
Identifiers
  • (RS)-4-hydroxy-3-(1-phenylpropyl)-2H-chromen-2-one
JSmol)
Melting point177–181 °C (351–358 °F)
SMILES
  • OC=1c3ccccc3OC(=O)C=1C(CC)c2ccccc2
  • InChI=1S/C18H16O3/c1-2-13(12-8-4-3-5-9-12)16-17(19)14-10-6-7-11-15(14)21-18(16)20/h3-11,13,19H,2H2,1H3 checkY
  • Key:DQDAYGNAKTZFIW-UHFFFAOYSA-N checkY
  (verify)

Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting

St John's Wort. It is the standard coumarin used in Germany,[3] Austria,[4] and other European countries.[5]

Medical uses

cm
)

Phenprocoumon is used for the prophylaxis and treatment of thromboembolic disorders after

congestive cardiomyopathy (enlarged heart).[1]

Dosing

When phenprocoumon therapy is started, the clotting tendency of the blood is measured daily by determining the

international normalized ratio (INR). After the desired INR has been reached, which typically takes five to six days, intervals between measurements are increased to twice or three times a week for a week or two, then to two to four weeks if the patient is stable. INR monitoring continues throughout the therapy, often for life.[1][4] This is necessary because people need different doses depending on the genetic makeup of their enzymes, activity of coagulation factors, vitamin K concentrations in the body, other drugs, and diet.[2][6]

If a fast onset of action is needed, as after an acute thromboembolism, phenprocoumon therapy has to be accompanied with a subcutaneous or intravenous low-molecular-weight heparin (LMWH) for the first 36 to 72 hours. Similarly, if the blood thinning effect has to be stopped before a surgery, phenprocoumon is paused up to two weeks beforehand, and the therapy gap is "bridged" with LMWH until after the surgery. Alternatively, phenprocoumon can be antagonised with vitamin K, for example before an unplanned surgery, or when severe bleeding occurs after overdosing.[1][4]

Contraindications

Phenprocoumon is contraindicated when bleeding risks exceed the potential benefits, for example in people with severe

brain surgery. During pregnancy, it is contraindicated except to prevent coagulation in women with life-threatening heparin intolerance.[4]

Adverse effects

The most common adverse effect is bleeding. It occurs in 5–25% of patients and ranges from harmless nosebleeds to life-threatening bleeding in the brain, gut wall,

purple toe syndrome, and allergic rashes.[1][4] A rare but severe adverse effect is warfarin necrosis of the skin and subcutaneous tissue during the first days of treatment.[7][8]

Overdose

Mild cases of overdosing are characterised by minor bleeding and/or bruising; they can usually be controlled by reducing the dose. Taking a large amount of phenprocoumon at once can lead to

brain edema during the first 24 hours, followed by reduced blood clotting and (possibly severe) bleeding, including blood in the stool or urine. Bleeding into the brain can lead to disorientation or unconsciousness, calling for immediate medical intervention.[4] Overdosing for an extended time period is toxic for the liver parenchyma, the kidneys' glomeruli, and blood vessels.[1]

Interactions

Due to its narrow therapeutic index, the fact that it can only be eliminated from the body after inactivation by the liver enzymes CYP2C9 and CYP3A4, and its high plasma protein binding (see below), phenprocoumon has significant interactions with a large number of other drugs and with some kinds of food. Some examples are:[4][6]

Pharmacology

Mechanism of action

Further information: Vitamin K antagonist § Mechanism of action

Phenprocoumon is an inhibitor of the enzyme

X[9] and the anticoagulation factors protein C and protein S,[10] in which process it turns into vitamin K 2,3-epoxide. This is then recycled to vitamin K in a process involving VKOR. Inhibiting this enzyme effectively creates a vitamin K deficiency, blocking activation of the coagulation factors. After 36 to 72 hours, the available activated factors have been depleted (used up) by the coagulation system, and the anticoagulation takes effect.[1]

Pharmacokinetics

Metabolism of S(−)‑phenprocoumon: known positions of hydroxylation by liver enzymes[11]

The drug is taken by mouth and quickly and completely absorbed from the gut. When in the bloodstream, 99% are bound to plasma proteins (mainly

terminal half-life is 150 hours (6 to 7 days) on average with large differences between people.[9]

The long half-life means that drug concentrations take about four weeks to reach a steady state after therapy is started; the anticoagulation lasts at least 7 to 10 days after therapy is stopped; and dose changes need several days to take effect.[3][4]

The drug passes the placenta and also into breast milk.[8]

Pharmacogenomics

Genetic polymorphisms of CYP2C9 can change the metabolization speed of phenprocoumon.[4] Polymorphisms of VKORC1, the gene coding for subunit 1 of vitamin K epoxide reductase, can influence the dose needed to achieve the desired INR.[13]

Chemistry

1:1 mixture of both.[1]

Phenprocoumon, a 4-hydroxycoumarin structurally similar to warfarin, is a white to off-white crystalline powder with a characteristic smell. It is practically insoluble in water, but soluble in chloroform, ethanol, methanol, and aqueous alkali hydroxide solutions. It is an acid (pKa = 4.2) and melts between 177 and 181 °C (351 and 358 °F).[1] The substance is used as a racemic mixture; the S(−)-form is significantly more potent as an anticoagulant.[9]

Comparison with other anticoagulants

Warfarin

Warfarin and phenprocoumon have the same mechanism of action, similar uses, side effects and interactions, and are also chemically similar. For both drugs, the INR needs to be carefully monitored. Both are racemates, and the S(−)-

pharmacokinetic differences: Warfarin is predominantly metabolized via the enzyme CYP2C9, while for phenprocoumon CYP3A4 plays the more important role. The average half-life of warfarin is 40 hours, that of phenprocoumon 150 hours, almost four times as long. Both drugs show large differences in half-life between individuals.[4][9][14]

Direct factor Xa inhibitors

Direct factor Xa inhibitors (xabans) such as rivaroxaban and apixaban are a newer class of blood thinners. They have been in therapeutic use since about 2010, while phenprocoumon was developed in the 1950s.[4] Xabans have a fast onset and cessation of action, wide therapeutic index, and relatively low potential for interactions with other drugs and food. There are standard dosing schemes, and INR monitoring is neither necessary nor meaningful.[15][16]

On the other hand, forgetting one phenprocoumon dose does not change the INR much because of its long half-life, while forgetting a xaban dose means the patient is not reliably anticoagulated for about a day. INR monitoring under phenprocoumon makes it easier to detect problems such as medication errors or interactions with drugs or food. Also, there have been concerns that patients' therapy adherence may not be as reliable if they are not regularly monitored by their physicians. Finally, xabans are significantly more expensive than phenprocoumon and warfarin.[3][15][16]

Low-molecular-weight heparins

LMWHs also have a fast onset of action, wide therapeutic index, standard dosing schemes, and a very low potential for interactions. They can, however, only be given by injection or infusion, rendering them impractical for long-term use at home.[17]

History

The substance was developed in 1953 by

Hoffmann-La Roche.[18]

References

  1. ^
    ISBN 978-3-7741-9846-3
    .
  2. ^
    PMID 10327214
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  3. ^
    ISBN 978-3-8047-3747-1
    .
  4. ^ a b c d e f g h i j k l m n Haberfeld H, ed. (2021). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Marcoumar-Tabletten. Text available here.
  5. ^ Phenprocoumon International Drug Names. Accessed 2021-08-25.
  6. ^ a b c "mediQ (paywalled)" (in German). Psychiatrische Dienste Aargau AG. Retrieved 2021-08-24.
  7. S2CID 44842896
    .
  8. ^
    ISBN 9783982122311
    .
  9. ^
    ISBN 978-3-8047-1763-3
    .
  10. S2CID 11522770
    .
  11. S2CID 13730692
    .
  12. S2CID 13730692
    .
  13. ^ "Clinical Annotation for rs9923231 (VKORC1); phenprocoumon (level 1A Dosage)". PharmGKB. Retrieved 2021-08-25.
  14. ^ Warfarin Monograph. Accessed 2021-08-24.
  15. ^
    S2CID 27830280
    .
  16. ^
    PMID 24319220
    .
  17. ^ Haberfeld H, ed. (2021). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Lovenox 4.000 IE (40 mg)/0,4 ml Injektionslösung in einer Fertigspritze.
  18. ^ Entry on Phenprocoumon. at: Römpp Online. Georg Thieme Verlag, retrieved 2019-07-23.
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