Carbimazole
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| Non-proprietary name | Carbimazole | ||||||||||||||||||
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| Molecular formula | C 7 H 10 N 2 O 2 S | ||||||||||||||||||
| Brief description |
white to yellowish white, crystalline powder |
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| Mechanism of action |
Iodization inhibitor |
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| Molar mass | 186.23 g · mol -1 | ||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
122-125 ° C |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Carbimazole is a cyclic thiourea - derivative which to the group of anti-thyroid drugs belongs and for the symptomatic treatment of an overactive thyroid ( hyperthyroidism is used). Carbimazole is a prodrug and is converted into its active form thiamazole immediately after absorption . It was patented as an anti-thyroid drug in 1954, 1957 and 1958 by Natural Resources Development Corporation and is commercially available as a generic drug for use in human and veterinary medicine .
Clinical information
Application areas (indications)
In hyperthyroidism there is an excess of thyroxine (T 4 ) and triiodothyronine (T 3 ) in the target organs of the thyroid hormone action, as the thyroid gland produces more thyroid hormones than the organism needs. One speaks of an "overfunction", which is most often caused by the autoimmune disease Graves' disease (with and without endocrine orbitopathy ) as well as by thyroid autonomy . Rare causes are de Quervain's thyroiditis and iatrogenic overdose of thyroid hormones.
- Carbimazole is suitable
- for the symptomatic treatment of hyperthyroidism in Graves' disease and in autonomy. A euthyroid thyroid function and, after a limited duration of therapy, a permanent remission are the goals of the therapy. A remission over 1 year can be achieved in less than half of the patients.
- in all forms of hyperthyroidism as preparation for surgery. Here, a limited duration of the pretreatment (about three to four weeks, in individual cases longer) can be used to create a euthyroid metabolic situation that lowers the risk of surgery.
- to prepare for a planned radioiodine therapy , especially in severe forms of hyperthyroidism (since in individual cases after radioiodine therapy of untreated hyperthyroidism, thyrotoxic crises have occurred).
- after radioiodine treatment to bridge the time until the radioiodine effect fully sets in (4–6 months).
- Exceptionally for long-term therapy of hyperthyroidism, when definitive treatment measures cannot be carried out due to the general condition of the patient and when carbimazole is well tolerated in low doses.
- For the preventive use of the drug in the case of a history of known or latent hyperthyroidism and autonomic adenomas , when iodine - containing X- ray contrast media are required for the diagnostic X - ray examination .
Contraindications (contraindications)
Treatment with carbimazole is contraindicated in a hypersensitivity to the drug , compared thiamazole or against other thiourea at a prior bone marrow damage after treatment with carbimazole or thiamazole , with a reduction of neutrophils in the blood ( neutropenia ) in the history of existing in cholestasis as well as during pregnancy with additional therapy with thyroid hormones. A contraindication is a retrosternal goiter due to the risk of compression of the trachea due to an increase in gland volume.
Drug interactions
- Anticoagulants, oral - antithyroid drugs
- In patients who have been stopped on oral anticoagulants , starting antithyroid drug treatment may weaken the anticoagulant effect over the course of a few days; thromboembolic complications can occur. No interaction is to be expected when oral anticoagulants are administered to patients who have been treated with anti-thyroid drugs.
- Whenever the thyroid hormone status changes due to the start or end of therapy with anti-thyroid drugs, radioiodine therapy or changes in the dosage of anti -thyroid drugs, the blood coagulation parameters ( INR ) must be monitored particularly closely and the dose of the anticoagulant adjusted as necessary.
- Cardiac glycosides - anti-thyroid drugs
- Hyperthyroid patients show a relative resistance to the effects of cardiac glycosides . You therefore need higher cardiac glycoside doses to achieve the same therapeutic effect. The elimination of cardiac glycosides may be accelerated in hyperthyroid patients. However, in one study, thiamazole did not cause changes in the pharmacokinetics of digoxin .
Use during pregnancy and breastfeeding
Hyperthyroidism is generally positively influenced by pregnancy . In the first trimester , treating an overactive thyroid is often unavoidable. During pregnancy, untreated hyperthyroidism can lead to serious complications such as premature births and malformations of the newborn. Maternal hypothyroidism also leads to increased abortion rates as a result of incorrectly dosed pharmacotherapy . The active metabolite of carbimazole crosses the placental barrier and reaches the same concentrations in the fetal blood as in the maternal serum, which can lead to the formation of a goiter and hypothyroidism in the fetus as well as a reduced birth weight if the dose is inadequate . There have been repeated reports of children born to mothers treated with thiamazole who were born with partial aplasia cutis congenita in the head area, which healed spontaneously after a few weeks. Thyrostatic therapy during pregnancy must therefore be given in the lowest effective dose.
Thiamazole passes into breast milk and can there reach a concentration corresponding to the maternal serum level, so that there is a risk of hypothyroidism in the infant. During breastfeeding , propylthiouracil is considered the drug of choice if there are strict indications , as the concentration in breast milk is at most one tenth of the maternal serum concentration due to higher protein binding in the blood. Particularly careful monitoring of the mother and child is required during pregnancy and breastfeeding. The TSH levels should be very low or not measurable, and the parameters of the free thyroid hormones should be in the upper normal range. A combination of carbimazole with thyroxine during pregnancy and breastfeeding is obsolete.
Adverse drug effects
Most side effects are dose-dependent and are therefore mainly observed in the first eight weeks of treatment and especially in the event of an overdose. Lighter reactions often regress even if thyrostatic therapy is continued. The following adverse drug reactions can occur with normal doses of carbimazole :
- Common: drug eruption , allergic skin reaction , pruritus (itching), hives (urticaria), nausea , headache , joint pain , mosquito-bite-like wheals
- Uncommon: edema , vasculitis , salivary gland swelling
- Rare: Ageusia , drug fever , impaired sense of taste , parageusia , agranulocytosis
- Very rare: alopecia , angiitis , hypoglycemia , generalized dermatitis , dysosmia , lupus erythematosus , gastrointestinal disorders , toxic hepatitis , cholestatic jaundice , insulin autoimmune syndrome (with a sharp drop in blood sugar levels), generalized lymphadenopathy , muscle pain , thrombopenia , pancytopathy , thrombopenia
Pharmacological properties
Mechanism of action (pharmacodynamics)
Carbimazole is a sulfur-containing thyreostatic agent and is a prodrug , which is rapidly and practically completely biotransformed during absorption and in the bloodstream - with splitting off of the labile ethoxycarbonyl group - to an equimolar amount of thiamazole (methimazole). Therefore, on a weight basis, 10 mg carbimazole is equivalent to approximately 6-7 mg thiamazole. This active metabolite acts as an iodization inhibitor , which competitively inhibits thyroid peroxidase (thyroid peroxidase) and thus, on the one hand, the oxidation of iodide to elemental iodine (iodization) and, as a consequence, the incorporation of iodine into the thyrosyl residues of the thyroglobulin and their combination to T 3 or T 4 prevented. In addition to these effects, which are typical for all thioimidazole derivatives, carbimazole also has a special property: it blocks the enzyme dehalogenase , which enables the recovery of organic iodine that has not been released. This gradually eliminates the intrathyroid iodine and leads to iodine avidity in the thyroid gland. Therefore, in cats, radioiodine therapy can be replaced with carbimazole at any time.
Absorption and distribution in the body (pharmacokinetics)
Orally administered carbimazole is quickly and 90-100% absorbed from the intestine and then biotransformed into its active form thiamazole in the bloodstream through hydrolysis and enzymatic decarboxylation . After ingestion of 60 mg carbimazole, maximum plasma levels of 0.2–1.0 μg / l are reached within 1–2 hours. The volume of distribution is approximately 0.5 l / kg and the plasma protein binding is given as 40%. The plasma half-life is - depending on the individual - 4 to 12 hours. After administration, thiamazole rapidly accumulates in the thyroid where it is slowly metabolized. In the thyroid gland, thiamazole is inactivated by sulfur oxidation and in the liver by glucuronidation . The metabolic products are mainly eliminated with the urine, but also in the biliary . In hepatic insufficiency, the plasma clearance is reduced due to a lower metabolism and the elimination half-life is prolonged.
Application in veterinary medicine
Carbimazole and its active metabolite thiamazole (trade names including Felimazole ® ad us. Vet. ) Are used for long-term therapy in feline hyperthyroidism and for preoperative stabilization in feline hyperthyroidism prior to thyroidectomy. The ATC vet is Q H03BB02 .
Law
"According to § 1 in conjunction with Appendix 1 of the ordinance on substances with a pharmacological effect, the use of" substances with a thyrostatic effect such as thiouracils, thioimidazoles, thiohydantoins for equidae, cattle, pigs, sheep, goats, rabbits, poultry, haired game and game birds for all areas of application "excluded. Therefore, there are no maximum permitted levels; Proof of residues leads to criminal prosecution regardless of the level of the finding. The misuse of thyreostatics as fattening aids is monitored within the framework of the National Residue Control Plan. "
Trade names
Carbistad (A), Néo-Mercazole (CH), as well as generics (D)
- Veterinary medicine
Vidalta
literature
- W. Forth et al .: General and Special Pharmacology and Toxicology . 9th edition. URBAN & FISCHER, Munich 2005, ISBN 3-437-42521-8 .
- Heinz Lüllmann, Klaus Mohr, Lutz Hein: Pharmacology and Toxicology . 16th edition. Thieme, Stuttgart 2006, ISBN 3-13-368516-3 .
Web links
- Entry on carbimazole at Vetpharm, accessed on August 11, 2012.
Individual evidence
- ↑ a b c d data sheet CARBIMAZOLE CRS (PDF) at EDQM , accessed on June 26, 2009.
- ↑ a b Data sheet Ethyl 3-methyl-2-thionoimidazoline-1-carboxylate, 97% from AlfaAesar, accessed on October 31, 2016 ( PDF )(JavaScript required) .
- ↑ Entry on carbimazole. In: Römpp Online . Georg Thieme Verlag, accessed on June 1, 2014.
- ↑ Specialist information carbimazole sanofi aventis .
- ↑ Treatment of hyperthyroidism in pregnancy . Medicines Letter 1999; 33, 20b.
- ↑ Tavintharan S. et al. Carbimazole-induced agranulocytosis - a report of 2 recent cases. Singapore Med J. 1997 Sep; 38 (9): 386-7. PMID 9407764 .
- ↑ Side effects with DocCheck Pillbox and SCHOLZ database .
- ↑ Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site The FASEB Journal . 2004; 18: 1574-1576.
- ^ Peterson ME, Aucoin DP. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Res Vet Sci. 1993 May; 54 (3): 351-5, PMID 8337482 .
- ↑ University of Leipzig: Pharmacology of the Thyroid ( Memento of the original from April 24, 2014 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 187 kB) .
- ↑ National Residue Control Plan for Food of Animal Origin ( Memento of September 27, 2014 in the Internet Archive ).
