cerespan

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papaverine hydrochloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/23 16:01:15」(JST)

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Papaverine

Systematic (IUPAC) name
1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline
Clinical data
Trade names	Pavabid
AHFS/Drugs.com	monograph
MedlinePlus	a682707
Pregnancy category	AU: A US: C (Risk not ruled out)
Routes of administration	Oral, intravenous, intramuscular, rectal, intracavernosal
Legal status
Legal status	AU: S4 (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	80%
Protein binding	~90%
Metabolism	Hepatic
Biological half-life	1.5–2 hours
Excretion	Renal
Identifiers
CAS Number	58-74-2 Y 61-25-6 (hydrochloride)
ATC code	A03AD01 (WHO) G04BE02
PubChem	CID 4680
DrugBank	DB01113 Y
ChemSpider	4518 Y
UNII	DAA13NKG2Q Y
KEGG	D07425 Y
ChEBI	CHEBI:28241 N
ChEMBL	CHEMBL19224 Y
Chemical data
Formula	C20H21NO4
Molar mass	339.385 g/mol
SMILES COc1ccc(cc1OC)Cc2c3cc(c(cc3ccn2)OC)OC
InChI InChI=1S/C20H21NO4/c1-22-17-6-5-13(10-18(17)23-2)9-16-15-12-20(25-4)19(24-3)11-14(15)7-8-21-16/h5-8,10-12H,9H2,1-4H3 Y Key:XQYZDYMELSJDRZ-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Papaverine /pəˈpævəriːn/ (Latin papaver, "poppy") is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasm, vasospasm (especially those involving the heart and the brain), and occasionally in the treatment of erectile dysfunction. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the analgesic (morphine-related) opium alkaloids (opiates).

History

Capsule of Papaver somniferum showing latex (opium) exuding from incision. Papaverine occurs naturally in opium.

Papaverine was discovered in 1848 by Georg Merck (1825–1873). Merck was a student of the German chemists Justus von Liebig and August Hofmann, and he was the son of Emanuel Merck (1794–1855), founder of the Merck corporation, a major German chemical and pharmaceutical company.

Uses

Papaverine is approved to treat spasms of the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary vasodilator in subarachnoid hemorrhage (combined with balloon angioplasty) and coronary artery bypass surgery. Papaverine may also be used as a smooth muscle relaxant in microsurgery where it is applied directly to blood vessels.

Papaverine is used as an erectile dysfunction drug, alone or sometimes in combination. Papaverine, when injected in penile tissue causes direct smooth muscle relaxation and consequent filling of the corpus cavernosum with blood resulting in erection. A topical gel is also available for ED treatment.

It is also commonly used in cryopreservation of blood vessels along with the other glycosaminoglycans and protein suspensions. Functions as a vasodilator during cryopreservation when used in conjunction with verapamil, phentolamine, nifedipine, tolazoline or nitroprusside.

Papaverine is also being investigated as a topical growth factor in tissue expansion with some success.

Papaverine is used as an off label prophylaxis (preventative) of migraine headaches. It is not a first line drug such as a few beta blockers, calcium channel blockers, tricyclic antidepressants, and some anticonvulsants such as divalproex, but rather when these first line drugs and secondary drugs such as SSRIs, angiotensin II receptor antagonists, etc. fail in the prophylaxis of migraines, have intolerable side effects or are contraindicated.

Papaverine is also present in combinations of opium alkaloid salts such as papaveretum (Omnopon, Pantopon) and others, along with morphine, codeine, and in some cases noscapine and others in a percentage similar to that in opium, or modified for a given application.

Mechanism

The in vivo mechanism of action is not entirely clear, but an inhibition of the enzyme phosphodiesterase causing elevation of cyclic AMP levels is significant. It may also alter mitochondrial respiration.

Papaverine has also been demonstrated to be a selective phosphodiesterase inhibitor for the PDE_10A subtype found mainly in the striatum of the brain. When administered chronically to mice, it produced motor and cognitive deficits and increased anxiety, but conversely may produce an antipsychotic effect, even though not all studies support this view.

Side effects

Frequent side effects of papaverine treatment include polymorphic ventricular tachycardia, constipation, interference with sulphobromophthalein retention test (used to determine hepatic function), increased transaminase levels, increased alkaline phosphatase levels, somnolence, and vertigo.

Rare side effects include flushing of the face, hyperhidrosis (excessive sweating), cutaneous eruption, arterial hypotension, tachycardia, loss of appetite, jaundice, eosinophilia, thrombopenia, mixed hepatitis, headache, allergic reaction, chronic active hepatitis, and paradoxical aggravation of cerebral vasospasm.

Formulations and trade names

Papaverine is available as a conjugate of hydrochloride, codecarboxylate, adenylate, and teprosylate. It was also once available as a salt of hydrobromide, camsylate, cromesilate, nicotinate, and phenylglycolate. The hydrochloride salt is available for intramuscular, intravenous, rectal and oral administration. The teprosylate is available in intravenous, intramuscular, and orally administered formulations. The codecarboxylate is available in oral form, only, as is the adenylate.

The codecarboxylate is sold under the name Albatran, the adenylate as Dicertan, and the hydrochloride salt is sold variously as Artegodan (Germany), Cardioverina (countries outside Europe and the United States), Dispamil (countries outside Europe and the United States), Opdensit (Germany), Panergon (Germany), Paverina Houde (Italy, Belgium), Pavacap (United States), Pavadyl (United States), Papaverine (Israel), Papaverin-Hamelin (Germany), Paveron (Germany), Spasmo-Nit (Germany), Cardiospan, Papaversan, Cepaverin, Cerespan, Drapavel, Forpaven, Papalease, Pavatest, Paverolan, Therapav (Canada), Vasospan, Cerebid, Delapav, Dilaves, Durapav, Dynovas, Optenyl, Pameion, Papacon, Pavabid, Pavacen, Pavakey, Pavased, Pavnell, Alapav, Myobid, Vasal, Pamelon, Pavadel, Pavagen, Ro-Papav, Vaso-Pav, Papanerin-hcl, Qua bid, Papital T.R., Paptial T.R., Pap-Kaps-150. In Hungary, papaverine and homatropine methylbromide are used in mild drugs that help "flush" the bile.

References

English Journal

• Effects of levosimendan on isolated human internal mammary artery and saphenous vein: concurrent use with conventional vasodilators.

• Ertuna E1, Turkseven S1, Amanvermez D2, Ayik F2, Yagdi T2, Yasa M1.
• Fundamental & clinical pharmacology.Fundam Clin Pharmacol.2016 Jun;30(3):226-34. doi: 10.1111/fcp.12185. Epub 2016 Feb 26.
• Graft spasm is a common problem in coronary artery bypass grafting (CABG). In this study, we aimed to investigate the interaction of levosimendan, a novel inodilator, with vasodilator agents that are clinically used for the treatment of graft spasm and with endogenous vasoconstrictors that are thoug
• PMID 26839979

• Metamizole: an effective solution for vasospasm.

• Kaya B1, Elçin Işılgan S1, Serel S1, Ergün H2.
• Journal of plastic surgery and hand surgery.J Plast Surg Hand Surg.2016 Jun;50(3):151-5. doi: 10.3109/2000656X.2015.1137924. Epub 2016 Feb 6.
• OBJECTIVE: Vasospasm is a major problem during microsurgery, and a variety of pharmacological agents are used to alleviate vasospasm. This study aimed to demonstrate the effect of metamizole on vasospasm and to compare it with lidocaine and papaverine, both of which are commonly used to correct vaso
• PMID 26854097

• Crystal structure of norcoclaurine-6-O-methyltransferase a key rate-limiting step in the synthesis of benzylisoquinoline alkaloids.

• Robin AY1, Giustini C1, Graindorge M1, Matringe M1, Dumas R1.
• The Plant journal : for cell and molecular biology.Plant J.2016 May 27. doi: 10.1111/tpj.13225. [Epub ahead of print]
• The growing pharmaceutical interest in benzylisoquinoline alkaloids (BIA) coupled with their chemical complexity make metabolic engineering of microbial to create alternative platforms of production increasingly attractive. However, precise knowledge of rate-limiting enzymes and negative feedback in
• PMID 27232113

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