Chemistry:Pindolol

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Short description: Chemical compound
Pindolol
Skeletal formula of pindolol
Space-filling model of the pindolol molecule
Clinical data
Trade namesVisken, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa684032
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50% to 95%
MetabolismHepatic
Elimination half-life3–4 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC14H20N2O2
Molar mass248.326 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
 ☒N☑Y (what is this?)  (verify)

Pindolol, sold under the brand name Visken among others, is a nonselective beta blocker which is used in the treatment of hypertension.[1][2] It is also an antagonist of the serotonin 5-HT1A receptor, preferentially blocking inhibitory 5-HT1A autoreceptors, and has been researched as an add-on therapy to various antidepressants, such as clomipramine and the selective serotonin reuptake inhibitors (SSRIs), in the treatment of depression[3][4][5] and obsessive-compulsive disorder.[6][7]

Medical uses

Pindolol is used for hypertension in the United States , Canada , and Europe, and also for angina pectoris outside the United States.[2] When used alone for hypertension, pindolol can significantly lower blood pressure and heart rate, but the evidence base for its use is weak as the number of subjects in published studies is small.[2] In some countries, pindolol is also used for arrhythmias and prophylaxis of acute stress reactions.

Contraindications

Similar to propranolol with an extra contraindication for hyperthyroidism. In patients with thyrotoxicosis, possible deleterious effects from long-term use of pindolol have not been adequately appraised. Beta-blockade may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of pindolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.[8]

Pindolol has intrinsic sympathomimetic activity and is therefore used with caution in angina pectoris.[8]

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
5-HT1A 15–81 Human [9][10][11]
5-HT1B 4,100
34–151		 Human
Rodent		 [10]
[12][13][14]
5-HT1D 4,900 Human [10]
5-HT1E >10,000 Human [15]
5-HT1F >10,000 Human [16]
5-HT2A 9,333 Human [17]
5-HT2B 2,188 Human [17]
5-HT2C >10,000 Human [17]
5-HT3 ≥6,610 Multiple [18][19][20]
5-HT4 >10,000 ? Rat [21]
5-HT5B >1,000 Rat [22]
5-HT6 >10,000 (–) Mouse [23]
α1 7,585 Pigeon [18]
α2 ND ND ND
β1 0.52–2.6 Human [11][24]
β2 0.40–4.8 Human [11][24]
β3 44 Human [24][25]
D2-like >10,000 Rat [26]
  D2 >10,000 Pigeon [18]
  D3 >10,000 Pigeon [18]
M1 ? ?
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Pindolol is a first generation,[27] non-selective beta blocker in the class of β-adrenergic receptor antagonists. On the receptor level it is a competitive partial agonist. It possesses intrinsic sympathomimetic activity, meaning it has some degree of agonist effects in the absence of competing ligands. Pindolol shows membrane-stabilizing effects like quinidine, possibly accounting for its antiarrhythmic effects. It also acts as a serotonin 5-HT1A receptor partial agonist (intrinsic activity = 20–25%) or functional antagonist.[28]

Pharmacokinetics

Pindolol is rapidly and well absorbed from the GI tract. It undergoes some first-pass-metabolization leading to an oral bioavailability of 50-95%. Patients with uremia may have a reduced bioavailability. Food does not alter the bioavailability, but may increase the resorption. Following an oral single dose of 20 mg peak plasma concentrations are reached within 1–2 hours. The effect of pindolol on pulse rate (lowering) is evident after 3 hours. Despite the rather short halflife of 3–4 hours, hemodynamic effects persist for 24 hours after administration. Plasma halflives are increased to 3–11.5 hours in patients with renal impairment, to 7–15 hours in elderly patients, and from 2.5 to 30 hours in patients with liver cirrhosis. Approximately 2/3 of pindolol is metabolized in the liver giving hydroxylates, which are found in the urine as gluconurides and ethereal sulfates. The remaining 1/3 of pindolol is excreted in urine in unchanged form.

History

Pindolol was patented by Sandoz in 1969 and was launched in the US in 1977.[29] Towards end of February 2020 FDA added this product to their "DRUG SHORTAGE" list stating this is due to "Shortage of an active ingredient" and this is likely to be related to Coronavirus outbreak and related supply chain impacts.

Research

Depression

Pindolol has been investigated as an add-on drug to antidepressant therapy with SSRIs like fluoxetine in the treatment of depression since 1994.[30][5] The rationale behind this strategy has its basis in the fact that pindolol is an antagonist of the serotonin 5-HT1A receptor.[4] Presynaptic and somatodendritic 5-HT1A receptors act as inhibitory autoreceptors, inhibit serotonin release, and are pro-depressive in their action.[4] This is in contrast to postsynaptic 5-HT1A receptors, which mediate antidepressant effects.[4] By blocking 5-HT1A autoreceptors at doses that are selective for them over postsynaptic 5-HT1A receptors, pindolol may be able to disinhibit serotonin release and thereby improve the antidepressant effects of SSRIs.[4] The results of augmentation therapy with pindolol have been encouraging in early studies of low quality.[3] A 2015 systematic review and meta-analysis of five randomized controlled trials found no overall significant benefit at 2.5 mg although, with regard to patients with SSRI-resistant depression, "once-daily high-dose pindolol (7.5 mg qd) appears to show a promising benefit in these patients".[5] On the other hand, a 2017 systematic review indicated that pindolol's efficacy has been demonstrated in high evidence studies.[31] Initiating pharmacotherapy with an SSRI plus pindolol might accelerate the SSRI's therapeutic impact.[4][31] Pindolol's antidepressive efficacy may predominantly result from its ability to desensitize 5-HT1A autoreceptors.[32]

Others

  • Pindolol is a potent scavenger of nitric oxide. This effect is potentiated by sodium bicarbonate. Inhibition of nitric oxide synthesis has an anxiolytic effect in animals.[33]
  • Augmentation therapy of premature ejaculation: According to a recent study, pindolol can be effectively added to a standard anti-premature-ejaculation therapy, which usually consists of daily doses of an SSRI antidepressant such as fluoxetine or paroxetine. Augmentation of pindolol results in substantial increase of ejaculatory latency, even in those who previously did not experience in an improvement with the SSRI monotherapy.[34]

See also

References

  1. ↑ 1.0 1.1 Drugs.com International brand names for pindolol Page accessed Sept 4, 2015
  2. ↑ 2.0 2.1 2.2 "Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension". The Cochrane Database of Systematic Reviews 2014 (11): CD007450. November 2014. doi:10.1002/14651858.CD007450.pub2. PMID 25427719. 
  3. ↑ 3.0 3.1 "The use of pindolol to potentiate antidepressant medication". The Journal of Clinical Psychiatry 59 (Suppl 5): 16–23; discussion 24–5. 1998. PMID 9635544. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research". CNS Drugs 27 (9): 703–716. September 2013. doi:10.1007/s40263-013-0071-0. PMID 23757185. 
  5. ↑ 5.0 5.1 5.2 "Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis". Human Psychopharmacology 30 (3): 132–142. May 2015. doi:10.1002/hup.2465. PMID 25689398. 
  6. ↑ Mundo, Emanuela, Emanuela Guglielmo, and Laura Bellodi. "Effect of adjuvant pindolol on the antiobsessional response to fluvoxamine: a double blind, placedo-controlled study." International clinical psychopharmacology 13, no. 5 (1998): 219-224.
  7. ↑ Sassano-Higgins, S.A. and Pato, M.T., 2015. Pindolol augmentation of selective serotonin reuptake inhibitors and clomipramine for the treatment of obsessive-compulsive disorder: A meta-analysis. Journal of Pharmacology and Pharmacotherapeutics, 6(1), pp.36-38.
  8. ↑ 8.0 8.1 "RxMed: Pharmaceutical Information - VISKEN". http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20V%29/VISKEN.html. 
  9. ↑ "The main features of central 5-HT1 receptors". Neuropsychopharmacology 3 (5–6): 349–360. 1990. PMID 2078271. 
  10. ↑ 10.0 10.1 10.2 "Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta". Proceedings of the National Academy of Sciences of the United States of America 89 (8): 3630–3634. April 1992. doi:10.1073/pnas.89.8.3630. PMID 1565658. Bibcode: 1992PNAS...89.3630W. 
  11. ↑ 11.0 11.1 11.2 "Indoloxypropanolamine analogues as 5-HT(1A) receptor antagonists". Bioorganic & Medicinal Chemistry Letters 17 (20): 5600–5604. October 2007. doi:10.1016/j.bmcl.2007.07.086. PMID 17804228. 
  12. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  13. ↑ "Molecular biology of 5-HT receptors". Neuropharmacology 33 (3–4): 275–317. 1994. doi:10.1016/0028-3908(94)90059-0. PMID 7984267. 
  14. ↑ Rojas-Corrales, Olga M.; Ortega-Alvaro, Antonio; Gibert-Rahola, Juan; Roca-Vinardell, Aranzazu; Micó, Juan A. (November 2000). "Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol". Pain 88 (2): 119–124. doi:10.1016/S0304-3959(00)00299-2. ISSN 0304-3959. PMID 11050366. https://pubmed.ncbi.nlm.nih.gov/11050366/. 
  15. ↑ "Human gene S31 encodes the pharmacologically defined serotonin 5-hydroxytryptamine1E receptor". Molecular Pharmacology 42 (2): 180–185. August 1992. PMID 1513320. 
  16. ↑ "Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase". Proceedings of the National Academy of Sciences of the United States of America 90 (2): 408–412. January 1993. doi:10.1073/pnas.90.2.408. PMID 8380639. Bibcode: 1993PNAS...90..408A. 
  17. ↑ 17.0 17.1 17.2 "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 370 (2): 114–123. August 2004. doi:10.1007/s00210-004-0951-4. PMID 15322733. 
  18. ↑ 18.0 18.1 18.2 18.3 "The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons". European Journal of Pharmacology 325 (2–3): 145–153. May 1997. doi:10.1016/s0014-2999(97)00131-3. PMID 9163561. 
  19. ↑ "Characterisation of 5-HT3 recognition sites in membranes of NG 108-15 neuroblastoma-glioma cells with [3H]ICS 205-930". Naunyn-Schmiedeberg's Archives of Pharmacology 337 (5): 493–499. May 1988. doi:10.1007/bf00182721. PMID 3412489. 
  20. ↑ "Identification of serotonin 5-HT3 recognition sites in membranes of N1E-115 neuroblastoma cells by radioligand binding". Molecular Pharmacology 33 (3): 303–309. March 1988. PMID 3352595. 
  21. ↑ Ge, J.; Barnes, N. M. (April 1996). "5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo". British Journal of Pharmacology 117 (7): 1475–1480. doi:10.1111/j.1476-5381.1996.tb15309.x. ISSN 0007-1188. PMID 8730742. PMC 1909436. https://pubmed.ncbi.nlm.nih.gov/8730742/. 
  22. ↑ "Cloning and characterization of the rat 5-HT5B receptor. Evidence that the 5-HT5B receptor couples to a G protein in mammalian cell membranes". FEBS Letters 333 (1–2): 25–31. October 1993. doi:10.1016/0014-5793(93)80368-5. PMID 8224165. 
  23. ↑ "Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase". Molecular Pharmacology 44 (2): 229–236. August 1993. PMID 8394987. 
  24. ↑ 24.0 24.1 24.2 "Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells". Naunyn-Schmiedeberg's Archives of Pharmacology 369 (2): 151–159. February 2004. doi:10.1007/s00210-003-0860-y. PMID 14730417. 
  25. ↑ Horinouchi, Takahiro; Koike, Katsuo (2001-01-01). "(±)-Pindolol Acts as a Partial Agonist at Atypical β -Adrenoceptors in the Guinea Pig Duodenum". Japanese Journal of Pharmacology 85 (1): 35–40. doi:10.1254/jjp.85.35. ISSN 0021-5198. https://www.sciencedirect.com/science/article/pii/S0021519819304688. 
  26. ↑ "Characterization of (125)I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors". Synapse 38 (4): 438–449. December 2000. doi:10.1002/1098-2396(20001215)38:4<438::AID-SYN9>3.0.CO;2-5. PMID 11044891. 
  27. ↑ "Beta-blockers and the treatment of hypertension: it is time to move on". Cardiovascular Journal of Africa 18 (6): 351–352. 2007. PMID 18092107. 
  28. ↑ "Pindolol augmentation of antidepressant response". Current Drug Targets 7 (2): 139–147. February 2006. doi:10.2174/138945006775515446. PMID 16475955. 
  29. ↑ "Discovery and Development of Major Drugs. Chapter 2 in Pharmaceutical Innovation: Revolutionizing Human Health. Volume 2 of Chemical Heritage Foundation series in innovation and entrepreneurship. Eds Ralph Landau, Basil Achilladelis, Alexander Scriabine. Chemical Heritage Foundation, 1999. ISBN:9780941901215 p 185
  30. ↑ Pérez, V., Gilaberte, I., Faries, D., Alvarez, E. and Artigas, F., 1997. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. The Lancet, 349(9065), pp.1594-1597.
  31. ↑ 31.0 31.1 "Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence". European Neuropsychopharmacology 27 (5): 423–441. May 2017. doi:10.1016/j.euroneuro.2017.03.003. PMID 28318897. 
  32. ↑ "Effects of sustained (+/-)pindolol administration on serotonin neurotransmission in rats". Journal of Psychiatry & Neuroscience 25 (4): 378–388. September 2000. PMID 11022403. 
  33. ↑ "Pindolol is a potent scavenger of reactive nitrogen species". Life Sciences 77 (16): 1983–1992. September 2005. doi:10.1016/j.lfs.2005.02.018. PMID 15916777. 
  34. ↑ "Once-daily high-dose pindolol for paroxetine-refractory premature ejaculation: a double-blind, placebo-controlled and randomized study". Journal of Clinical Psychopharmacology 28 (1): 39–44. February 2008. doi:10.1097/jcp.0b013e31816073a5. PMID 18204339. 



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