Pindolol

Medical uses

Pindolol is used for hypertension in the United States, Canada, and Europe, and also for angina pectoris outside the United States. 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.

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.

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

Pharmacology

Pharmacodynamics

Pindolol is a first generation, 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. The drug additionally shows affinity for the serotonin 5-HT1B receptor.

Pharmacokinetics

Pindolol is rapidly and well-absorbed from the gastrointestinal tract. It undergoes some first-pass metabolism leading to an oral bioavailability of 50 to 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 20mg peak plasma concentrations are reached within 1 to 2hours. The effect of pindolol on pulse rate (lowering) is evident after 3hours.

The drug's volume of distribution is 1.2 to 2L/kg. The plasma protein binding is 40 to 60%. It crosses the blood–brain barrier and can produce centrally mediated side effects. Despite being moderately lipophilic, pindolol showed greater electroencephalogram (EEG) changes than the highly lipophilic propranolol. As a result, lipophilicity does not appear to be the sole determinant of blood–b rain barrier permeability of beta blockers.

Approximately two-thirds of pindolol is metabolized in the liver giving hydroxylates, which are found in the urine as gluconurides and ethereal sulfates. The remaining one-third of pindolol is excreted in urine in unchanged form.

Despite the rather short elimination half-life of 3 to 4hours, hemodynamic effects persist for 24hours after administration. The half-life is increased to 3 to 11.5hours in patients with renal impairment, to 7 to 15hours in elderly patients, and from 2.5 to 30hours in patients with liver cirrhosis.

Chemistry

The experimental log P of pindolol is 1.75 to 1.9. It is a moderately lipophilic beta blocker.

History

Pindolol was patented by Sandoz in 1969 and was launched in the US in 1977. 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.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. The rationale behind this strategy has its basis in the fact that pindolol is an antagonist of the serotonin 5-HT1A receptor. Presynaptic and somatodendritic 5-HT1A receptors act as inhibitory autoreceptors, inhibit serotonin release, and are pro-depressive in their action. This is in contrast to postsynaptic 5-HT1A receptors, which mediate antidepressant effects. 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 and clomipramine. The results of augmentation therapy with pindolol have been encouraging in early studies of low quality. 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". On the other hand, a 2017 systematic review indicated that pindolol's efficacy has been demonstrated in high evidence studies. Initiating pharmacotherapy with an SSRI plus pindolol might accelerate the SSRI's therapeutic impact. Pindolol's antidepressive efficacy may predominantly result from its ability to desensitize 5-HT1A autoreceptors.

References

References

1. Drugs.com [https://www.drugs.com/international/pindolol.html International brand names for pindolol] {{webarchive. link. (2017-10-01 Page accessed Sept 4, 2015)
2. (November 2014). "Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension". The Cochrane Database of Systematic Reviews.
3. 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.
4. 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.
5. (September 2015}} It has been used to treat [[anxiety]] as well.{{cite journal). "The Use of β-Adrenergic Receptor Antagonists in Psychiatry: A Review". J Acad Consult Liaison Psychiatry.
6. (January 2025). "Beta-blockers for the treatment of anxiety disorders: A systematic review and meta-analysis". J Affect Disord.
7. "RxMed: Pharmaceutical Information - VISKEN".
8. "PDSP K_i Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.
9. (1990). "The main features of central 5-HT1 receptors". Neuropsychopharmacology.
10. (April 1992). "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.
11. (October 2007). "Indoloxypropanolamine analogues as 5-HT(1A) receptor antagonists". Bioorganic & Medicinal Chemistry Letters.
12. (1994). "Molecular biology of 5-HT receptors". Neuropharmacology.
13. (November 2000). "Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol". Pain.
14. (August 1992). "Human gene S31 encodes the pharmacologically defined serotonin 5-hydroxytryptamine1E receptor". Molecular Pharmacology.
15. (January 1993). "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.
16. (August 2004). "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.
17. (May 1997). "The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons". European Journal of Pharmacology.
18. (May 1988). "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.
19. (March 1988). "Identification of serotonin 5-HT3 recognition sites in membranes of N1E-115 neuroblastoma cells by radioligand binding". Molecular Pharmacology.
20. (April 1996). "5-HT4 receptor-mediated modulation of 5-HT release in the rat hippocampus in vivo". British Journal of Pharmacology.
21. (October 1993). "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.
22. (August 1993). "Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase". Molecular Pharmacology.
23. (November 1993). "Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase". The Journal of Biological Chemistry.
24. (September 1997). "Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b)". British Journal of Pharmacology.
25. (February 2004). "Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells". Naunyn-Schmiedeberg's Archives of Pharmacology.
26. (January 2001). "(+/-)-Pindolol acts as a partial agonist at atypical beta-adrenoceptors in the guinea pig duodenum". Japanese Journal of Pharmacology.
27. (December 2000). "Characterization of (125)I-IABN, a novel azabicyclononane benzamide selective for D2-like dopamine receptors". Synapse.
28. (2007). "Beta-blockers and the treatment of hypertension: it is time to move on". Cardiovascular Journal of Africa.
29. (February 2006). "Pindolol augmentation of antidepressant response". Current Drug Targets.
30. (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem.
31. (1987). "Lipophilicity, hydrophilicity, and the central nervous system side effects of beta blockers". Pharmacotherapy.
32. "Pindolol".
33. "Pindolol".
34. (1982). "Pindolol: a review of its pharmacology, pharmacokinetics, clinical uses, and adverse effects". Pharmacotherapy.
35. (February 2005). "The impact of lipophilicity in drug research: a case report on beta-blockers". Mini Rev Med Chem.
36. "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
37. (September 2013). "Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research". CNS Drugs.
38. (1998). "The use of pindolol to potentiate antidepressant medication". The Journal of Clinical Psychiatry.
39. (May 2015). "Is pindolol augmentation effective in depressed patients resistant to selective serotonin reuptake inhibitors? A systematic review and meta-analysis". Human Psychopharmacology.
40. (May 2017). "Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence". European Neuropsychopharmacology.
41. (September 2000). "Effects of sustained (+/-)pindolol administration on serotonin neurotransmission in rats". Journal of Psychiatry & Neuroscience.