papaverine

Papaverine
Systematic (IUPAC) name
1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline
Identifiers
CAS number	58-74-2 61-25-6 (hydrochloride)
ATC code	A03AD01 G04BE02
PubChem	4680
DrugBank	APRD00628
Chemical data
Formula	C20H21NO4
Mol. mass	339.385 g/mol[1]
Pharmacokinetic data
Bioavailability	80%[3]
Protein binding	~90%
Metabolism	Hepatic[3]
Half life	1.5–2 hours[3]
Excretion	Renal[3]
Therapeutic considerations
Pregnancy cat.	USA: C[4]
Legal status
Routes	Oral, intravenous, intramuscular, rectal,[5] intracavernosal

Papaverine (pronounced /pəˈpævəriːn/^[1]) is an opium alkaloid 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.^[3] While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the analgesic (morphine-related) opium alkaloids (opiates). In 1979, a Food and Drug Administration Advisory Committee evaluated studies on papaverine and concluded that there was a lack of objective data to support the therapeutic use of papaverine for these conditions. Papaverine remains available despite the committee's recommendation that it be withdrawn from the market.

Uses

Papaverine is approved to treat spasms of the gastrointestinal tract, bile ducts and ureter and for use as a cerebral and coronary vasodilator^[3] in subarachnoid hemorrhage (combined with balloon angioplasty)^[6] and coronary artery bypass surgery.^[7] Papaverine may also be used as a smooth muscle relaxant in microsurgery where it is applied directly to blood vessels.

It is also commonly used in cryopreservation of blood vessels along with the other glycosaminoglycans and protein suspensions.^[2][3] Functions as a vasodilator during cryopreservation when used in conjunction with verapamil, phentolamine, nifedipine, tolazoline or nitroprusside.^[4][5]

Papaverine is also being investigated as a topical growth factor in tissue expansion with some success.^[6]

Papaverine is also present in combinations of opium alkaloid salts such as Omnopon, Pantopon, Papaveretum, 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.^[7][8]

Side effects

Frequent side effects of papaverine treatment include polymorphic ventricular tachycardia, constipation, interference with sulphobromophthalein^[8] retention test (used to determine hepatic function), increased transaminase levels, increased alkaline phosphatase levels, somnolence, and vertigo.^[3]

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,^[3] and paradoxical aggravation of cerebral vasospasm.^[9]

Formulations and trade names

Papaverine is available as a conjugate of hydrochloride, codecarboxylate, adenylate, and teprosylate.^[10] 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.^[5] The teprosylate is available in intravenous, intramuscular, and orally administered formulations.^[11] The codecarboxylate is available in oral form, only,^[12] as is the adenylate.^[13]

The codecarboxylate is sold under the name Albatran,^[14] the adenylate as Dicertan,^[15] 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), Papaverin-Hamelin (Germany), Paveron (Germany), Spasmo-Nit (Germany),^[5] Cardiospan, Papaversan, Cepaverin, Cerespan, Drapavel, Forpaven, Papalease, Pavatest, Paverolan, Therapav (France^[16]), 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.^[17]. In Hungary papaverine and homatropine-methylbromide are used in mild drugs that help "flush" the bile (e.g. Neo-Bilagit).

References