Piretanid

Structural formula
General
Non-proprietary name	Piretanid
other names	3- (aminosulfonyl) -4-phenoxy-5-pyrrolidin-1-ylbenzoic acid
Molecular formula	C 17 H 18 N 2 O 5 S
External identifiers / databases
CAS number 55837-27-9 EC number 259-852-9 ECHA InfoCard 100.054.394 PubChem 4849 ChemSpider 4683 DrugBank DB02925 Wikidata Q3905617
Drug information
ATC code	C03 CA03
Drug class	Loop diuretics
Mechanism of action	Inhibitors of the Na-K-2Cl cotransporter
properties
Molar mass	362.4 g · mol
Melting point	225-227 ° C
pK s value	3.85
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	618 mg kg −1 ( LD 50 ,  mouse ,  iv ) 2000 mg kg −1 ( LD 50 ,  mouse ,  oral ) 700 mg kg −1 ( LD 50 ,  rat ,  iv ) 5601 mg kg −1 ( LD 50 ,  rat ,  oral ) > 1000 mg kg −1 ( LD 50 ,  dog ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Piretanide is a drug from the group of loop diuretics that is used in the treatment of high blood pressure (hypertension) and edema . It was developed and patented by the pharmaceutical manufacturer Hoechst in the 1970s .

Clinical information

Application areas (indications)

Piretanide is approved for the elimination of edema, for heart failure to relieve the strain, for edema caused by kidney or liver disease and for the treatment of high blood pressure (hypertension). Monotherapy with piretanide is possible for the treatment of mild to moderate hypertension. In severe hypertension piretanide is used in combination with other non- diuretic acting antihypertensive agents used.

Contraindications (contraindications)

The use of piretanide is in kidney failure with anuria , coma and hepatic Praecoma , severe hypokalemia , severe hyponatremia , hypovolemia or dehydration contraindicated . Due to its structural similarity to sulfonamides , piretanide must not be used in the case of known piretanide or sulfonamide intolerance.

Relative restrictions of use exist in hypotension , diabetes mellitus , gout , urinary flow obstruction, liver cirrhosis with simultaneous renal impairment, hypoproteinemia , cerebrovascular circulatory disorders and coronary heart disease . Here piretanide should only be used under strict medical supervision.

There are insufficient clinical data on the safety of piretanide in pregnancy . Animal experiments did not give any indications of negative effects on pregnancy, embryonic and fetal development , parturition or development afterwards. Nevertheless, the use of piretanide in the first trimester of pregnancy is considered contraindicated for safety reasons. In the later phases of pregnancy, a short-term use of the lowest effective dose is possible after weighing the risk-benefit ratio. Piretanide is contraindicated during breastfeeding as it passes into breast milk and effects on the infant cannot be excluded.

Drug interactions

Piretanid can increase the kidney-damaging effects of potentially nephrotoxic drugs, such as some antibiotics from the aminoglycoside , cephalosporin and polymyxin groups. Likewise, the hearing-damaging effects of potentially ototoxic drugs, especially aminoglycosides and cisplatin , can be increased. By inhibiting excretion, the cardio- and neurotoxic effects of lithium are increased. Increased potassium excretion with simultaneous use of glucocorticoids , ACTH , potassium uretic diuretics, laxatives or frequent consumption of licorice can lead to increased potassium losses and even hypokalaemia. The toxic effect of cardiac glycosides and high-dose salicylates is intensified by piretanide. With simultaneous use with drugs that prolong the QT interval , an increased risk of cardiac arrhythmias is to be expected. The muscle relaxant effect of muscle relaxants of the curare type is enhanced or prolonged.

Piretanide can reduce the effects of many active substances, including insulin , oral anti-diabetic drugs , allopurinol, and sympathomimetics .

The antihypertensive effects of piretanide can be increased by other antihypertensive drugs such as nitrates , barbiturates , phenothiazines , tricyclic antidepressants , vasodilators, and alcohol. On the other hand, probenecid and nonsteroidal anti-inflammatory drugs reduce the effect of piretanid.

Adverse effects (side effects)

Based on its mechanism of action, which primarily includes increased excretion of sodium and chloride as well as secondary water, potassium , calcium and magnesium , piretanide can lead to a disruption of the fluid and mineral balance (1 to 10%). As a result of sodium loss, hyponatremia with symptoms such as apathy , weakness, leg cramps, loss of appetite, vomiting, tiredness and confusion can occur. Hypokalaemia can occur as a result of potassium losses, especially when the potassium intake is reduced at the same time. The losses of magnesium and calcium can lead to hypomagnesaemia or hypocalcemia . The development or worsening of metabolic alkalosis is possible based on the loss of minerals and fluids.

Headache, dizziness, visual disturbances, dry mouth, thirst, hypotension and orthostatic regulation disorders can be symptoms of excessive water loss . Elderly patients in particular are at risk of hypovolemia and dehydration with haemoconcentration due to the excretion of water . As a result, the risk of thrombosis is increased in these patients and in the presence of venous disease .

In contrast, an increase in other urinary substances, especially creatinine and urea , can be observed in the blood. Frequently (1 to 10%) there is an increase in the uric acid level , which can lead to an attack of gout in pre-stressed patients . The blood sugar level and glucose tolerance can also be influenced.

Occasionally (0.1 to 1%) allergic skin and mucous membrane reactions and thrombocytopenia can occur. Gastrointestinal complaints, vasculitis , leukopenia and febrile conditions are rare (0.01 to 0.1%). Disturbances of the liver and biliary tract are very rare (0.001 to 0.1%) .

Erectile dysfunction can occur as a result of lowering blood pressure .

Pharmacological properties

Mechanism of action (pharmacodynamics)

Piretanide is a loop diuretic. It is about five to seven times more potent than furosemide . Like the other representatives of this group of substances, it mediates its effect via a reversible inhibition of the Na-K-2Cl cotransporter on Henle's loop , a part of the urine-producing system of the kidneys. In this way the uptake of sodium and chloride ions in the ascending limb of Henle's loop is inhibited. As a result, there is an increased excretion of osmotically bound water and an increased excretion of potassium ions and protons in the distal tubule. The secretion of calcium and magnesium ions is also increased.

In addition to lowering arterial blood pressure, piretanide also lowers venous tone and pulmonary artery pressure .

Absorption and distribution in the body (pharmacokinetics)

After release from tablet or sustained-release capsule formulations , about 80 to 90% of piretanide is absorbed by the body. Intravenous administration (with an onset of action within a few minutes and a maximum effect after about an hour) is also possible. 90% or more of it is bound to serum proteins in the bloodstream . A metabolism plays only a minor role, so only a few hydroxylation and conjugates can be found in the waste products. Excretion is largely unchanged via the kidneys (40 to 70%). The elimination half-life is 1 to 1.7 hours; in the case of renal insufficiency, it can be extended to up to 9 hours.

chemistry

Piretanide is structurally related to the loop diuretics bumetanide and furosemide. As a common structural feature, they have a 3-aminosulfonylbenzoic acid partial structure.

synthesis

The synthesis of piretanide starts from 4-chloro-3-chlorosulfanyl-5-nitrobenzoic acid and corresponds in the first steps to the synthesis of bumetanide. In a first step, 4-chloro-3-chlorosulfanyl-5-nitrobenzoic acid is converted into the corresponding sulfonamide with ammonia , which is converted in a nucleophilic substitution reaction with sodium phenolate to the biphenyl ether 5-aminosulfonyl-3-nitro-4-phenoxybenzoic acid. After protective esterification with methanol and catalytic reduction of the nitro group , methyl 3-amino-5-aminosulfonyl-4-phenoxybenzoate is obtained. The pyrrolidine ring is built up by reaction with succinic anhydride and subsequent reduction using sodium borohydride and boron trifluoride . After subsequent alkaline hydrolysis of the protective group , the end product piretanide is obtained.

Trade names

Monopreparations

Arelix (D), Generics (D)

Combination preparations

• In combination with Ramipril : Arelix ACE (D), Trialix (CH), Generika (D)
• In combination with penbutolol : Betarelix (D)

Individual evidence

1. ↑ ^{a b} Entry on Piretanid. In: Römpp Online . Georg Thieme Verlag, accessed on July 24, 2019.
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ↑ ^{a b c d e f} Jürgen Engel, Axel Kleemann, Bernhard Kutscher, Dietmar Reichert: Pharmaceutical Substances. Syntheses, Patents and Applications of the most relevant APIs , 5th edition, Georg Thieme Verlag, 2014, ISBN 3-13-179275-2 , p. 1103.
4. ↑ Dieter Bormann, Wulf Merkel, Roman Muschaweck (1974). DE2419970: Tertiary cyclic amines and processes for their preparation.
5. ↑ ^{a b c d e f g h i j k l m n o} Sanofi-Aventis: Technical information Arelix ^® mite 3 mg tablets, Arelix ^® 6 mg tablets, Arelix ^® RR 6 mg prolonged-release capsule. As of March 2010.
6. ^ SP Clissold, RN Brogden: Piretanide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy . In: Drugs . 29, No. 6, June 1985, pp. 489-530. PMID 3891305 .
7. ↑ ^{a b c} Anne Paschen: Heart. In: Jörg Braun, Roland Preuss (Ed.): Clinic Guide Intensive Care Medicine. 9th edition. Elsevier, Munich 2016, ISBN 978-3-437-23763-8 , pp. 185–283, here: p. 246 ( Piretanid ).

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 !