Protriptyline is available as 5 mg and 10 mg tablets.[7] Doses range from 15 to 40 mg per day and can be taken in one daily dose or divided into up to four doses daily.[7] Some people with severe depression may require up to 60 mg per day.[7]
In adolescents and people over age 60, therapy should be initiated at a dose of 5 mg three times a day and increased under the supervision of a physician as needed.[7] Patients over age 60 who are taking daily doses of 20 mg or more should be closely monitored for side effects such as rapid heart rate andurinary retention.[7]
Like all TCAs, protriptyline should be used cautiously and with close physician supervision. This is especially so for persons withglaucoma, especiallyangle-closure glaucoma (the most severe form) or urinary retention, for men withbenign prostatic hyperplasia (enlarged prostate gland), and for the elderly. Before starting treatment, people should discuss the relative risks and benefits of treatment with their doctors to help determine if protriptyline is the right antidepressant for them.[8]
Protriptyline may increase heart rate and stress on the heart.[9] It may be dangerous for people with cardiovascular disease, especially those who have recently had a heart attack, to take this drug or other antidepressants in the same pharmacological class.[9] In rare cases in which patients with cardiovascular disease must take protriptyline, they should be monitored closely for cardiac rhythm disturbances and signs of cardiac stress or damage.[9]
When protriptyline is used to treat the depressive component ofschizophrenia, psychotic symptoms may be aggravated. Likewise, inmanic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Paranoid delusions, with or without associated hostility, may be exaggerated.[7] In any of these circumstances, it may be advisable to reduce the dose of protriptyline or to use anantipsychotic drug concurrently.[7]
Protriptyline shares side effects common to all TCAs.[5] The most frequent of these are dry mouth, constipation, urinary retention, increased heart rate, sedation, irritability, decreased coordination, anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal problems.[7] Other more complicated side effects include; chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; sudden numbness or weakness, especially on one side of the body; sudden headache, confusion, problems with vision, speech, or balance;hallucinations, orseizure (convulsions); easy bruising or bleeding, unusual weakness; restless muscle movements in your eyes, tongue, jaw, or neck; urinating less than usual or not at all; extreme thirst with headache, nausea, vomiting, and weakness; or feeling light-headed or fainting.[7]
Dry mouth, if severe to the point of causing difficulty speaking or swallowing, may be managed by dosage reduction or temporary discontinuation of the drug.[5] Patients may also chew sugarless gum or suck on sugarless candy in order to increase the flow of saliva. Someartificial saliva products may give temporary relief.[5] Men with prostate enlargement who take protriptyline may be especially likely to have problems with urinary retention.[7] Symptoms include having difficulty starting a urine flow and more difficulty than usual passing urine.[7] In most cases, urinary retention is managed with dose reduction or by switching to another type of antidepressant.[7] In extreme cases, patients may require treatment with bethanechol, a drug that reverses this particular side effect.[7]
A common problem with TCAs issedation (drowsiness, lack of physical and mental alertness), but protriptyline is considered the least sedating agent among this class of agents.[8] Its side effects are especially noticeable early in therapy.[8] In most people, early TCA side effects decrease or disappear entirely with time, but, until then, patients taking protriptyline should take care to assess which side effects occur in them and should not perform hazardous activities requiring mental acuity or coordination.[10] Protriptyline may increase the possibility of having seizures.[10]
Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation;hypomania; exacerbation ofpsychosis;insomnia, panic, and nightmares.[5]
Gastrointestinal: Nausea and vomiting; anorexia; epigastric distress; diarrhea; peculiar taste;stomatitis; abdominal cramps; black tongue.[5]
Endocrine:Impotence, increased or decreased libido:gynecomastia in the male; breast enlargement andgalactorrhea in the female; testicular swelling; elevation or depression of blood sugar levels.[5]
Other:Jaundice (simulating obstructive); altered liver function;parotid swelling;alopecia; flushing; weight gain or loss; urinary frequency,nocturia; perspiration.[5]
Deaths may occur fromoverdose with this class of drugs.[10] Multiple drug ingestion (includingalcohol) is common in deliberate TCA overdose.[10] As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.[5] Signs and symptoms of toxicity develop rapidly after TCA overdose, therefore, hospital monitoring is required as soon as possible.[10]
Critical manifestations of overdose include:cardiac dysrhythmias,severe hypotension, convulsions, and CNS depression, including coma.[7] Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of TCA toxicity.[7]Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes,stupor, drowsiness, muscle rigidity, vomiting,hypothermia,hyperpyrexia.[7]
The side effects of protriptyline are increased when it is taken with central nervous system depressants, such as alcoholic beverages, sleeping medications, other sedatives, orantihistamines, as well as with other antidepressants including SSRIs, SNRIs ormonoamine oxidase inhibitors.[10] It may be dangerous to take protriptyline in combination with these substances.[10]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
Protriptyline acts by decreasing thereuptake ofnorepinephrine and to a lesser extentserotonin (5-HT) in the brain.[9] Its affinity for the humannorepinephrine transporter (NET) is 1.41 nM, 19.6 nM for theserotonin transporter and 2,100 nM for thedopamine transporter.[19] TCAs act to change the balance of naturally occurring chemicals in the brain that regulate the transmission ofnerve impulses between cells. Protriptyline increases the concentration of norepinephrine and serotonin (both chemicals that stimulate nerve cells) and, to a lesser extent, blocks the action of another brain chemical,acetylcholine.[9] The therapeutic effects of protriptyline, like other antidepressants, appear slowly. Maximum benefit is often not evident for at least two weeks after starting the drug.[9]
Protriptyline is a TCA.[7] It was thought that TCAs work byinhibiting the reuptake of theneurotransmittersnorepinephrine andserotonin byneurons.[7] However, this response occurs immediately, yet mood does not lift for around two weeks.[7] It is now thought that changes occur in receptor sensitivity in thecerebral cortex andhippocampus.[7] The hippocampus is part of thelimbic system, a part of the brain involved in emotions. TCAs are also known as effectiveanalgesics for different types of pain, especiallyneuropathic orneuralgic pain.[7] A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-painopioid systems in thecentral nervous system via an indirectserotonergic route. TCAs are also effective in migraineprophylaxis, but not in abortion of acute migraine attack.[7] The mechanism of their anti-migraine action is also thought to be serotonergic, similar topsilocybin.[7]
Metabolic studies indicate that protriptyline is well absorbed from the gastrointestinal tract and is rapidly sequestered in tissues.[5] Relatively low plasma levels are found after administration, and only a small amount of unchanged drug is excreted in the urine of dogs and rabbits.[5] Preliminary studies indicate that demethylation of the secondary amine moiety occurs to a significant extent, and that metabolic transformation takes place in the liver.[5] It penetrates the brain rapidly in mice and rats, and moreover that which is present in the brain is almost all unchanged drug.[5]Studies on the disposition of radioactive protriptyline in human test subjects showed significant plasma levels within 2 hours, peaking at 8 to 12 hours, then declining gradually.[5]
Urinary excretion studies in the same subjects showed significant amounts of radioactivity in 2 hours.[5] The rate of excretion was slow.[5] Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.[5]
Protriptyline has uniquely low dosing among TCAs, likely due to its exceptionally longterminal half-life.[20] It is used in dosages of 15 to 40 mg/day, whereas most other TCAs are used at dosages of 75 to 300 mg/day.[20] The maximum dose is 60 mg/day.[20] Therapeutic levels of protriptyline are typically in the range of 70 to 250 ng/mL (266-950 nmol/L), which is similar to that of other TCAs[21][22][23]
Protriptyline was developed byMerck.[32] It was patented in 1962 and first appeared in the literature in 1964.[32] The drug was first introduced for the treatment of depression in 1966.[32][33]
Protriptyline is theEnglish andFrenchgeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, whileprotriptyline hydrochloride is itsUSANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia, andBANMTooltip British Approved Name.[30][31][34][35] Its generic name inSpanish andItalian and itsDCITTooltip Denominazione Comune Italiana areprotriptylina, inGerman isprotriptylin, and inLatin isprotriptylinum.[31][35]
Protriptyline is or has been marketed throughout the world under a variety of brand names including Anelun, Concordin, Maximed, Triptil, andVivactil.[30][31]
^Schmidt, H. S., Clark, R. W., & Hyman, P. R. (1977). Protriptyline: An effective agent in the treatment of the narcolepsy-cataplexy syndrome and hypersomnia.The American Journal of Psychiatry, 134(2), 183–185.https://doi.org/10.1176/ajp.134.2.183
^abcdefghijklmnopqrstuDURAMED PHARMACEUTICALS, INC., . (Ed.). (2007). Protriptyline drug facts. Pomona, New York : Barr Pharmaceuticals, Inc.
^ULTRAM, . (Ed.). (2007). Protriptyline. Ortho-McNeil Pharmaceutical Inc.
^abcdefghijklmnopqrstuvwAmerican Society of Health-System Pharmacists.AHFS Drug Information 2002. Bethesda: American Society of Health-System Pharmacists, 2002.
^abcdefgDeVane, C. Lindsay, Pharm.D. "Drug Therapy for Mood Disorders." In Fundamentals of Monitoring Psychoactive Drug Therapy. Baltimore: Williams and Wilkins, 1990.
^Sériès F, Cormier Y (October 1990). "Effects of protriptyline on diurnal and nocturnal oxygenation in patients with chronic obstructive pulmonary disease".Ann. Intern. Med.113 (7):507–11.doi:10.7326/0003-4819-113-7-507.PMID2393207.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved7 May 2022.
^abcTatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".Eur. J. Pharmacol.340 (2–3):249–58.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^abWander TJ, Nelson A, Okazaki H, Richelson E (1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro".Eur. J. Pharmacol.132 (2–3):115–21.doi:10.1016/0014-2999(86)90596-0.PMID3816971.
^abcdeRichelson E, Nelson A (1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro".J. Pharmacol. Exp. Ther.230 (1):94–102.doi:10.1016/S0022-3565(25)21446-X.PMID6086881.
^Bylund DB, Snyder SH (1976). "Beta adrenergic receptor binding in membrane preparations from mammalian brain".Mol. Pharmacol.12 (4):568–80.doi:10.1016/S0026-895X(25)10785-2.PMID8699.
^abcdAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H1R, H2R, H3R, and H4R receptors with 34 antidepressants and antipsychotics".Naunyn-Schmiedeberg's Arch. Pharmacol.385 (2):145–70.doi:10.1007/s00210-011-0704-0.PMID22033803.S2CID14274150.
^abcAndersen J, Kristensen AS, Bang-Andersen B, Strømgaard K (2009). "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters".Chem. Commun. (25):3677–92.doi:10.1039/b903035m.PMID19557250.
