Tripelennamine

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Tripelennamine
Tripelennamine2.svg
Systematic (IUPAC) name
N,N-dimethyl-N-(phenylmethyl)-N-pyridin-2-ylethane-1,2-diamine
Clinical data
AHFS/Drugs.com Multum Consumer Information
MedlinePlus a601044
Legal status Prescription only
Routes Oral, Intravenous
Pharmacokinetic data
Metabolism Hepatic hydroxylation and glucuronidation
Half-life 4-6 hours[1]
Excretion Renal
Identifiers
CAS number 91-81-6 YesY
154-69-8 (monohydrochloride)
22306-05-4 (hydrochloride)
57116-36-6 (maleate)
6138-56-3 (citrate)
ATC code D04AA04 R06AC04
PubChem CID 5587
DrugBank DB00792
ChemSpider 5385 YesY
UNII 3C5ORO99TY YesY
KEGG D08645 YesY
ChEMBL CHEMBL1241 YesY
Chemical data
Formula C16H21N3 
Mol. mass 255.358 g/mol
 YesY (what is this?)  (verify)

Tripelennamine (sold as Pyribenzamine by Novartis) is a psychoactive drug and member of the pyridine and ethylenediamine classes that is used as an antipruritic and first-generation antihistamine. It can be used in the treatment of asthma, hay fever, rhinitus and urticaria, but is now less common as it has been replaced by newer antihistamines.

History[edit]

Tripelennamine was first synthesized in 1946 by Carl Djerassi, working in the laboratory of Charles Huttrer at Ciba, shortly after Djerassi got his B.S. It was his first patent.

Pharmacology[edit]

Tripelennamine acts primarily as an antihistamine, or H1 receptor antagonist. It has little to no anticholinergic activity. In addition to its antihistamine properties, tripelennamine also acts as a weak serotonin reuptake inhibitor (SRI) and dopamine reuptake inhibitor (DRI).[2][3][4] Because of its SRI properties, tripelennamine was used as the basis for the development of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Luvox).[5] Additionally, due to its DRI properties, it is occasionally abused as a recreational drug (see below).

Use in medicine[edit]

Where and when it is/was in common use, tripelennamine is used much like other mildly-anticholinergic antihistamines for treating conditions of the upper respiratory tract arising from illnesses and hay fever. It can be used alone or in combination with other agents to have the desired effect. Cough medicine of the general formula tripelennamine + codeine/dihydrocodine/hydrocodone ± expectorant ± decongestant(s) is quite popular where available. One example is the line of Pyribenzamine Cough Syrups which contains codeine and with and without decongestants listed in the 1978 Physicians' Desk Reference; the codeine-tripelennamine synergy is well-known and does make such mixtures more useful for their intended purposes.

Side effects[edit]

Tripelennamine is mildly sedating. Other side effects can include irritation, dry mouth, nausea, and dizziness.

Recreational use[edit]

Tripelennamine by itself is a primary euphoriant manifesting anxiolytic, sedative, dopaminergic, and quasi-tricyclic-anti-depressant actions; unlike diphenhydramine and the like, there is little to no anticholinergic action (given by one source as 7 per cent the muscarinic blocking power of atropine compared to 58 per cent for diphenhydramine and 25 per cent for chlorpheniramine), making the euphoria subjectively different from that of orphenadrine and its relatives as well as dexchlorpheniramine (Polaramine) and other alkylamine antihistamines. Anticholinergics like scopolamine, trihexyphenidyl, dicycloverine, orphenadrine, diphenhydramine, benztropine, cyclobenzaprine, etc. produce a characteristic mild to moderate euphoria by this mechanism, and alkylamines have elements of both. The relatively rapid onset of action by any route of administration is also part of the appeal.

Tripelennamine is used also for its tranquillising effects, which are stronger than those of its close chemical relative pyrilamine, which is used in OTC day-time sedatives such as Compoz® in many countries in the world.

The most common recreational use of tripelennamine is as a potentiator of narcotic analgesics. It both strengthens the opioid effects overall and changes the side effect profile of the drug in question by adding warmth and other qualities. The potentiating effect is also used clinically to increase the effectiveness of a given dose of painkiller; the most commonly used for this purpose are hydroxyzine, doxylamine, phenyltoloxamine, orphenadrine, cyclizine, meclozine, promethazine, and chlorpheniramine. The above list includes drugs from all five major families of first-generation antihistamines, which attain a similar objective by somewhat differing means.

Tripelennamine is sometimes abused recreationally in combination with the benzomorphan class synthetic opioid pentazocine (Fortral, Talacen, Talwin) in a mixture known as "T's & Blues",[6] or morphine ("Blue Velvet"), by preparing an injection containing both agents; heroin may also be used like this. The local anesthetic effects of the antihistamine manifest in the case of intramuscular and subcutaneous injections. The US manufacturers of Talwin began adding naloxone to the tablets in the late 1970s as the practice of Ts and Blues spread—injecting a solution made from the pills delivers the antagonist which does not enter the system in significant amounts if the pills are swallowed. This changed the name of the product in question to Talwin NX. Talwin PX, available in Canada, and some other US versions as well as a large majority of pentazocine used in other countries does not contain the antagonist.

Tripelennamine is also used orally with the aforementioned drugs as well as paregoric, opium in all its forms including powdered opium and DTO (laudanum), narcotic cough syrups containing codeine and its derivatives, and analgesic preparations containing opioids with much the same impact, albeit taking longer to develop etc.

This use of tripelennamine with mixed agonist–antagonist opioids such as pentazocine, phenazocine, dezocine, butorphanol (Stadol), buprenorphine (Temgesic, Subutex), nalbuphine (Nubain) and others has results that make it appear that the antihistamine changes the receptor-activation profile of these drugs in a way that makes them more euphoric, but it is unknown if tripelennamine operates in this way in a true, literal sense or if increased dopamine levels counteract the dysphoric action of antagonists and drugs affecting the kappa opioid receptor in particular, and to an unclear extent pure agonists with dysphoria-inducing metabolites such as pethidine (Dolantin, Demerol) and its relatives. The relatively small degree of additive anticholinergic action make non-parenteral analogues of Blue Velvet using opium-belladonna combinations feasible and all the more euphoric. Tripelennamine and drugs of the same type of course do not counteract the effects of the naloxone which is added to pentazocine tablets in some countries to discourage injection.

It is dangerous to combine an opiate with a sedating antihistamine via injection, although the use of antihistamines (usually by mouth) to reduce opioid requirements for pain relief is a well-known practice, which is done under medical supervision with tripelennamine, as well as hydroxyzine, cyclizine, promethazine, diphenhydramine, phenindamine, orphenadrine, meclozine, chlorpheniramine, cyproheptadine and others; this method is doubly useful when used with opioids which release a great deal of histamine when administered and therefore cause itching, redness of skin and other histamine-related effects.

Like many of the first-generation antihistamines of the ethanolamine and alkylamine classes, tripelennamine and other members of its chemical class (ethylenediamines) produces a marginal to moderate euphoria; triepelennamine has a euphoriant effect with a relatively rapid onset and up to eight hours in duration.

The euphoric effect of tripelennamine makes these combinations more than the sum of their parts, and it is qualitatively and quantitatively different from that of the ethanolamine antihistamines such as diphenhydramine and orphenadrine in that there is much less anticholinergic impact—the mixing of opioids and anticholinergics is vividly illustrated by the combination drugs Skophedal (scopolamine, ephedrine, and eucodal (oxycodone)) and Twilight Sleep (scopolamine and morphine) which are/were used particularly for nerve pain and produce very deep analgesia and are profoundly powerful euphoriants . The alkylamine antihistamines, including brompheniramine (Dimetapp), chlorpheniramine (Chlor-Trimeton), and dexchlorpheniramine (Polaramine), are therefore in between the ethanolamines and the ethylenediamines in this respect. Anticholinergics change the dopamine to acetylcholine ratio in the CNS, whereas this is much less prominent with tripelennamine, which causes an increase in the absolute levels of dopamine by means of reuptake inhibition without a lot of effect on acetylcholine. The opioid-potentiating effects of other antihistamines such as hydroxyzine, cyclizine etc. appear to be directly due to additive sedation, and promethazine also has metabolic effects on codeine and the like, namely increasing the percentage of codeine that the liver converts to morphine in most people.

An episode of Joe Frank's NPR radio show, Somewhere Out There, was devoted to Pyribenzamine and its recreational devotees.

Synthesis[edit]

Tripelennamine synthesis:[7][8][9]
  1. 2-Benzylaminopyrridine is synthesized by reduction of a Schiff base between 2-aminopyrridine and benzaldehyde.
  2. 2-benzylaminopyrridine with 2-dimethylaminoethylchloride in the presence of sodium amide.

See also[edit]

References[edit]

  1. ^ Lewis R. Goldfrank; Neal Flomenbaum (2006). Goldfrank's toxicologic emergencies. McGraw-Hill Professional. p. 787. ISBN 978-0-07-147914-1. Retrieved 27 November 2011. 
  2. ^ Oishi R, Shishido S, Yamori M, Saeki K (February 1994). "Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain". Naunyn-Schmiedeberg's Archives of Pharmacology 349 (2): 140–4. doi:10.1007/bf00169830. PMID 7513381. 
  3. ^ Sato T, Suemaru K, Matsunaga K, Hamaoka S, Gomita Y, Oishi R (May 1996). "Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice". Japanese Journal of Pharmacology 71 (1): 81–4. doi:10.1254/jjp.71.81. PMID 8791174. [dead link]
  4. ^ Yeh SY, Dersch C, Rothman R, Cadet JL (September 1999). "Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats". Synapse 33 (3): 207–17. doi:10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8. PMID 10420168. 
  5. ^ ), David Healy (MRC Psych (January 2004). Let them eat Prozac: the unhealthy ... - Google Books. ISBN 978-0-8147-3669-2. 
  6. ^ McGwier BW, Alpert MA, Panayiotou H, Lambert CR (June 1992). "Acute myocardial infarction associated with intravenous injection of pentazocine and tripelennamine". Chest 101 (6): 1730–2. doi:10.1378/chest.101.6.1730. PMID 1600804. 
  7. ^ Ch.P. Huttrer, C. Gjerassi, C.R. Scholz, U.S. Patent 2,406,594 (1946).
  8. ^ R.J. Horclois, U.S. Patent 2,502,151 (1950).
  9. ^ Huttrer, C. P.; Djerassi, C.; Beears, W. L.; Mayer, R. L.; Scholz, C. R. (1946). "Heterocyclic amines with antithistaminic activity". Journal of the American Chemical Society 68 (10): 1999. doi:10.1021/ja01214a037. PMID 21001124.  edit]]