Phenprocoumon

Structural formula
1: 1 mixture of ( R ) -form (top) and ( S ) -form (bottom)
General
Non-proprietary name	Phenprocoumon
other names	( RS ) -4-Hydroxy-3- (1-phenylpropyl) coumarin ( IUPAC ) Phenprocoumonum ( Latin )
Molecular formula	C 18 H 16 O 3
External identifiers / databases
CAS number 435-97-2 EC number 207-108-9 ECHA InfoCard 100.006.464 PubChem 54680692 DrugBank DB00946 Wikidata Q267896
Drug information
ATC code	B01 AA04
Drug class	anticoagulant
Mechanism of action	Vitamin K - antagonist
properties
Molar mass	280.32 g · mol -1
Physical state	firmly
Melting point	179-180 ° C
pK s value	4.20
solubility	very poor in water (12.9 mg · l −1 at 25 ° C); soluble in alkali hydroxide solutions, in chloroform and in methanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
Toxicological data	200 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Phenprocoumon , also known under the trade names Marcumar and Falithrom , is a chemical compound from the group of 4-hydroxycoumarins that is used as a medicinal substance to inhibit plasmatic blood coagulation ( anticoagulation ). The active ingredient was developed by Alfred Winterstein and his team in 1953 and patented by Hoffmann-La Roche in 1955 .

application

Phenprocoumon is in the context of long-term thrombosis - prophylaxis or -Rezidivprophylaxe (following a heparin therapy or alternatively with heparin intolerance), after the implantation of artificial heart valves / artificial vascular grafts (fem-pop / Y prosthesis, etc.), ventricular assist devices (Assist -Device) or used in atrial fibrillation to prevent thrombus formation and the resulting embolism .

During the adjustment phase with tablets (3 mg each) of about 5–7 days, blood is drawn from the patient every 2nd to 3rd day, every 2–4 weeks if the setting is stable, and then the next dose of phenprocoumon is determined. With stable attitudes and suitability (physically and mentally capable of doing so), the patient can carry out regular control measurements and adjustment of the drug dose ( coagulation self-management) himself after training . The procedure and measuring devices are similar to the well-known sugar self-tests.

effect

The anticoagulant effect resulting from the reduction of the amount of available functional clotting factors II , VII , IX and X . As an indirect vitamin K antagonist warfarin acts like warfarin by inhibiting the carboxylation of these clotting factors as well as protein C and protein S .

Phenprocoumon acts as a competitive inhibitor of the enzyme vitamin K epoxide reductase, which means that a smaller amount of vitamin K in reduced form is available as a cofactor for the enzyme γ-glutamyl carboxylase . This results in non- carboxylated or only partially carboxylated coagulation factors, which are inactive or only active to a limited extent . The effect only sets in when the remaining coagulation factors have been used up (after about 48–72 hours). Therefore, it is not used in an emergency, but only in the further course of an illness. The plasma half-life is approximately 160 hours (6 to 7 days). In addition to the delayed coagulation inhibition, increased coagulation can occur because the anti-coagulative proteins C and S, which are vitamin K-dependent, are inhibited. The practice of basically carrying out a bridging therapy with low-molecular-weight heparins or unfractionated heparin during surgical interventions is being abandoned more and more. Large observational studies and, most recently, a placebo-controlled double-blind study have shown that bridging is associated with a considerably increased risk of bleeding and is of no benefit with regard to thromboembolic events.

The concentration that is decisive for the effect and its fluctuation is determined by the rhythm of intake, the individual absorption capacity, the decay curve and the patient's constitution. The half-lives for uptake are 1–12 hours and for decay ( elimination half-life ) around 160 hours. Due to the long degradation time constants - in relation to a daily intake - compliance with the exact daily rhythm is less than the intake dose when prescribed regularly.

Therapy (in the case of acute thrombosis or embolism, necessarily with simultaneous administration of heparin!) Is usually started with a loading dose ( e.g. two tablets per day for three days) and continued to be dosed depending on the response. The daily dose is usually 1/4 to 2 tablets, on average around 2/3 tablets. Older people need lower doses than younger people, women slightly lower than men.

The effect is influenced by the vitamin K content of the food. A small amount of vitamin K-rich foods is therefore important for a constant effect. Nevertheless, on average only about 70% of the values ​​are in the therapeutic range.

unwanted effects

Very common (over 10%) are hematomas after injuries, nosebleeds or bleeding gums, as well as blood in the urine, liver inflammation occurs frequently (up to 10%), occasionally (under 1%) internal bleeding occurs as an undesirable effect (especially cerebral haemorrhage - 0.5 %) on.

In addition, increased but reversible hair loss and a decrease in bone density can occur with long-term therapy. The severe bleeding that can occur, especially in the event of an overdose and simultaneous high blood pressure , is feared (see assessment of the risk of bleeding ).

Livid (pale gray) discoloration of the skin, erythematous dermatitis, or acute urticaria have been observed very rarely . Individual cases of olfactory disorders have been observed, and fracture healing may possibly take longer.

In very rare cases an inflammation of the liver was found, which led to liver failure and subsequent transplantation, and very rarely retroperitoneal bleeding with impairment of nerves and fulminant skin bleeding were also reported.

Another rare but dreaded complication of anticoagulation with coumarin derivatives is so-called coumarin necrosis , in which necrosis of the skin, subcutaneous tissue and soft tissues occurs. Overweight women are particularly at risk if therapy is started after the onset of menopause (postmenopausal) and immediately after the birth of a child (postpartum).

Cancellation of the effect

After stopping the drug, it takes 10-14 days for the coagulation factors necessary for normal coagulation to be synthesized. This time can be shortened to 6–10 hours by administering high doses of vitamin K; in an emergency, the missing coagulation factors can be replaced at short notice by administering a coagulation factor concentrate ( PPSB ).

Before an operation, blood thinning is usually switched from the poorly controllable phenprocoumon to more controllable heparins. This means that the heparin can be paused shortly before the operation in order to ensure normal coagulation at the time of the operation. This bridging therapy with heparins is called "bridging" and begins with a pause of the phenprocoumon and regular INR controls. As soon as the INR falls below 2, the overlapping administration of heparins should be started. In high-risk patients such as B. in the presence of a mechanical mitral valve, bridging is usually carried out in a stationary manner.

Contraindications

Relative contraindications include malignant therapy-resistant hypertension, diabetic retinopathy, bacterial endocarditis, gastrointestinal lesions (ulcers, diverticula, polyps, tumors, esophageal varices), head and brain trauma, intracerebral aneurysms, major operations in the last two weeks or planned operations in the past two weeks coming two weeks, pregnancy and alcoholism.

Interactions

Phenprocoumon patients should refrain from self-medication, especially with analgesics (painkillers); the intake of acetylsalicylic acid is critical because of its platelet aggregation-inhibiting effect.

Possible combinations with phenprocoumon:

• Analgesics: opioids , metamizole , paracetamol
• Antiphlogistics: with close coagulation control

Therapeutic area

In general, the dose of phenprocoumon is determined by the coagulation values (old: Quick value ; new: International Normalized Ratio , INR). The therapeutic INR value is between 2.0 and 3.5 depending on the indication, if the INR falls below the target range, the risk of thrombosis or embolism increases, if the INR rises above these values, the risk of bleeding increases (from approx INR 5, the risk of bleeding increases quite rapidly).

Patients who need permanent anticoagulation can learn to measure the INR themselves and to dose phenprocoumon themselves ( coagulation self-management ). The costs for this (device, test strips, training in special centers) are usually borne by the health insurance companies. It should be noted that changing the tablet dose will only affect the INR after a few days. Mechanism of action and side effect mechanism see: Coumarins .

Stereoisomerism

Phenprocoumon contains a stereocenter, the ( R ) - and ( S ) - enantiomers are interconverted by the keto-enol equilibrium . All commercial preparations contain the drug as a racemate .

Trade names

Monopreparations : Falithrom (D), Marcoumar (A, CH), Marcumar (D), Marcuphen (D), Phenpro (D), Phenprogamma (D) and a generic (D, A).

literature

• Jörg Braun: Blood, blood products and coagulation disorders. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 539-579, here: pp. 558 f. ( Phenprocoumon, warfarin ).

Web links

• Laborlexikon.de: Patient information on the Quick value (= thromboplastin time = TPZ) and the INR (International Normalized Ratio)

Individual evidence

1. ^ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals , 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; P. 1253, ISBN 978-0-911910-00-1 .
2. ↑ ^{a b c} Entry on Phenprocoumon. In: Römpp Online . Georg Thieme Verlag, accessed on July 23, 2019.
3. ↑ ^{a b} Entry on phenprocoumon in the ChemIDplus database of the United States National Library of Medicine (NLM) .
4. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
5. ↑ Jörg Braun: Blood, blood products and coagulation disorders. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 539–579, here: p. 559.
6. ↑ ^{a b c d e f g} Fachinfo Marcumar (PDF; 84 kB) Retrieved on February 9, 2013.
7. ↑ Jörg Braun (2016), p. 558.
8. Jump up ↑ Jack Ansell, Jack Hirsh, Leon Poller, Henry Bussey, Alan Jacobson, Elaine Hylek: The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy . In: Chest . tape 126 , 3 Suppl, September 2004, pp. 204S – 233S , doi : 10.1378 / chest.126.3_suppl.204S , PMID 15383473 ( online ).
9. ↑ ^{a b c d} Björn Lemmer , Georges Fülgraff: Pharmacotherapy, clinical pharmacology: with 192 tables. [the textbook on the cross-sectional subject] . 14., revised. and updated edition. Springer, Heidelberg 2010, ISBN 978-3-642-10540-1 .
10. ^ "[...] but also the anticoagulant factors (proteins C and S) are inhibited" Marlies Michl, Hematology BASICS 3rd edition.
11. ↑ James D. Douketis, Alex C. Spyropoulos, Scott Kaatz, Richard C. Becker, Joseph A. Caprini, Andrew S. Dunn, David A. Garcia, Alan Jacobson, Amir K. Jaffer, David F. Kong, Sam Schulman, Alexander GG Turpie, Vic Hasselblad, Thomas L. Ortel, BRIDGE Investigators: Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation . In: The New England Journal of Medicine . June 22, 2015, doi : 10.1056 / NEJMoa1501035 , PMID 26095867 .
12. ↑ G. Schulz: On the inhibition of blood coagulation by phenprocoumon . (PDF; 115 kB) Seminar paper.
13. ↑ Vitamin K content of foods . Retrieved February 9, 2013.
14. ↑ S. Nöldeke u. a .: Coumarin necrosis: pathophysiology, clinic and therapy. In: Gefäßchirurgie , Edition 6, 2001, pp. 129–135, doi: 10.1007 / s007720100143 .
15. ↑ Michael Korenkov: General surgery patients in the family doctor's practice . Springer Berlin Heidelberg, City 2015, ISBN 978-3-662-47906-3 .
16. ↑ Phenprocoumon “ratiopharm” 3 mg tablets Information for professionals (PDF; 70 kB). Accessed on May 27, 2013.
17. ↑ Red List Online, as of August 2009.
18. ↑ Swiss Medicines Compendium , as of August 2009.
19. ↑ AGES-PharmMed, as of August 2009.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !