Papaverine is an
opiumOpium is a narcotic formed from the latex released by lacerating the immature seed pods of opium poppies . It contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade...
alkaloidAlkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of...
used primarily in the treatment of visceral
spasmA spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
,
vasospasmVasospasm refers to a condition in which blood vessels spasm, leading to vasoconstriction. This can lead to tissue ischemia and death . Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to...
(especially those involving the
heartThe heart is a muscular organ found in all vertebrates that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
), and occasionally in the treatment of
erectile dysfunctionErectile dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis sufficient for satisfactory sexual performance....
. While it is found in the
opium poppyThe Opium Poppy, Papaver somniferum, is the type of poppy from which opium and many refined opiates, including morphine, thebaine, codeine, papaverine, and noscapine, are extracted. The binomial name means, loosely, the "sleep-bringing poppy", referring to its narcotic properties. The seeds are...
, 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 is an
opiumOpium is a narcotic formed from the latex released by lacerating the immature seed pods of opium poppies . It contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade...
alkaloidAlkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals and are part of...
used primarily in the treatment of visceral
spasmA spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
,
vasospasmVasospasm refers to a condition in which blood vessels spasm, leading to vasoconstriction. This can lead to tissue ischemia and death . Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to...
(especially those involving the
heartThe heart is a muscular organ found in all vertebrates that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and the
brainThe brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as jellyfish and starfish have a decentralized nervous system without a brain, while sponges lack any nervous system at all...
), and occasionally in the treatment of
erectile dysfunctionErectile dysfunction is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis sufficient for satisfactory sexual performance....
. While it is found in the
opium poppyThe Opium Poppy, Papaver somniferum, is the type of poppy from which opium and many refined opiates, including morphine, thebaine, codeine, papaverine, and noscapine, are extracted. The binomial name means, loosely, the "sleep-bringing poppy", referring to its narcotic properties. The seeds are...
, 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 ductA bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
s and
ureterIn human anatomy, the ureters are muscular ducts that propel urine from the kidneys to the urinary bladder. In the adult, the ureters are usually long....
and for use as a cerebral and coronary vasodilator in
subarachnoid hemorrhageA subarachnoid hemorrhage is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain...
(combined with balloon angioplasty) and
coronary artery bypass surgeryCoronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
. Papaverine may also be used as a smooth muscle relaxant in
microsurgeryMicrosurgery is a general term for surgery requiring an operating microscope. The most obvious developments have been procedures developed to allow anastomosis of successively smaller blood vessels and nerves which have allowed transfer of tissue from one part of the body to another and...
where it is applied directly to blood vessels.
It is also commonly used in
cryopreservationCryopreservation is a process where cells or whole tissues are preserved by cooling to low sub-zero temperatures, such as 77 K or −196 °C . At these low temperatures, any biological activity, including the biochemical reactions that would lead to cell death, is effectively stopped...
of blood vessels along with the other glycosaminoglycans and protein suspensions. Functions as a vasodilator during cryopreservation when used in conjunction with
verapamilVerapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
,
phentolaminePhentolamine is a reversible nonselective alpha-adrenergic antagonist. -Mechanism:Its primary action is vasodilation due to α
1 blockade....
,
nifedipineNifedipine is a dihydropyridine calcium channel blocker. Its main uses are as an antianginal and antihypertensive, although a large number of other uses have recently been found for this agent, such as Raynaud's phenomenon, premature labor, and painful spasms of the esophagus in cancer and...
,
tolazolineTolazoline is a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to treat spasms of peripheral blood vessels...
or nitroprusside.
Papaverine is also being investigated as a topical growth factor in tissue expansion with some success.
Papaverine is also present in combinations of opium alkaloid salts such as Omnopon,
PantoponPantopon is a preparation of opiates made up of all of the alkaloids present in opium in their natural proportions as hydrochloride salts. It can sometimes be tolerated by persons who are allergic to morphine....
,
PapaveretumPapaveretum is a preparation containing a mixture of hydrochloride salts of opium alkaloids. Since 1993, papaveretum has been defined in the British Pharmacopoeia as a mixture of 253 parts morphine hydrochloride, 23 parts papaverine hydrochloride, and 20 parts codeine hydrochloride...
, and others along with
morphineMorphine is a highly potent opiate analgesic psychoactive drug, is the principal active ingredient in Papaver somniferum , is considered to be the prototypical opioid. Like other opioids, e.g...
,
codeineCodeine or methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties.-History:Codeine is an alkaloid found in opium and other poppy saps like Papaver bracteatum, the Iranian poppy, in concentrations ranging from 0.3 to 3.0 percent...
, and in some cases
noscapineNoscapine is a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without significant painkilling properties. This agent is primarily used for its antitussive effects. It has also been shown to have anticancer activity...
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
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
phosphodiesterase causing elevation of cyclic AMP levels is significant. It may also alter mitochondrial
respirationCellular respiration is one of the key ways a cell gains useful energy. It is the set of the metabolic reactions and processes that take place in organisms' cells to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products...
.
Papaverine has also been demonstrated to be a selective
phosphodiesterase inhibitorA phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase , therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE...
for the PDE
10A subtype found mainly in the
striatumThe striatum also known as striate body or striate nucleus is a subcortical part of the telencephalon/cerebrum. It is the major input station of the basal ganglia system...
of the brain. When administered chronically to mice it produced motor and cognitive deficits and
increased anxietyAn anxiogenic substance is one that causes anxiety. Anxiogenic effects can be measured by, for example, the hole-board test in rats and mice. A number of agents are used to provoke anxiety or panic in experimental models...
, but conversely may produce an
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
effect.
Side effects
Frequent side effects of papaverine treatment include polymorphic
ventricular tachycardiaVentricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
, constipation, interference with sulphobromophthalein retention test (used to determine hepatic function), increased
transaminaseIn biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. Specifically, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to...
levels, increased
alkaline phosphataseAlkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation. As the name suggests, alkaline phosphatases are most...
levels,
somnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, and
vertigoVertigo is a specific type of dizziness, a major symptom of a balance disorder. It is the sensation of spinning or swaying while the body is actually stationary with respect to the surroundings.The effects of vertigo may be slight...
.
Rare side effects include flushing of the face,
hyperhidrosisHyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...
(excessive sweating), cutaneous eruption, arterial
hypotensionIn physiology and medicine, hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the opposite of hypertension, which is high blood...
, tachycardia, loss of appetite,
jaundiceJaundice, also known as icterus , is a yellowish discoloration of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia...
,
eosinophiliaEosinophilia is the state of having a high concentration of eosinophils in the blood. The normal concentration is between 0 and 0.5 x 109 eosinophils per litre of blood...
, thrombopenia, mixed
hepatitisHepatitis implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, headache, allergic reaction, chronic active hepatitis, and paradoxical aggravation of cerebral vasospasm.
Formulations and trade names
Papaverine is available as a
conjugateA conjugated system occurs in an organic compound where atoms covalently bond with alternating single and multiple bonds and influence each other to produce a region called electron delocalization. In this region electrons do not belong to a single bond or atom, but rather a group...
of
hydrochlorideIn chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base...
, codecarboxylate,
adenylateAdenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is found in RNA. It is an ester of phosphoric acid and the nucleoside adenosine...
, 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), Papaverin-Hamelin (Germany), Paveron (Germany), Spasmo-Nit (Germany), Cardiospan, Papaversan, Cepaverin, Cerespan, Drapavel, Forpaven, Papalease, Pavatest, Paverolan, Therapav (France), 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
HungaryHungary , in English officially the Republic of Hungary , is a landlocked country in the Carpathian Basin of Central Europe, bordered by Austria, Slovakia, Ukraine, Romania, Serbia, Croatia, and Slovenia. Its capital is Budapest. Hungary is a member of OECD, NATO, EU, V4 and is a Schengen state...
papaverine and
homatropineHomatropine is an anticholinergic medication that inhibits muscarinic acetylcholine receptors and thus the parasympathetic nervous system. It is used in eye drops as a cycloplegic, to temporarily paralyze accommodation, and as a mydriatic, to dilate the pupil.Homatropine is less potent than...
-methylbromide are used in mild drugs that help "flush" the
bileBile or gall is a bitter yellowish, blue and green fluid secreted by hepatocytes from the liver of most vertebrates. In many species, bile is stored in the gallbladder between meals and upon eating is discharged into the duodenum where the bile aids the process of digestion of lipids by...
(e.g.
Neo-Bilagit).