Pindolol

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| _other_data=(RS)-1-(1H-indol-4-yloxy)-3-(isopropylamino)propan-2-ol

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Pindolol, sold under the brand name Visken among others, is a nonselective beta blocker which is used in the treatment of hypertension.<ref name="Drugs.com">Drugs.com International brand names for pindolol Template:Webarchive Page accessed Sept 4, 2015</ref><ref name="Cochrane">Template:Cite journal</ref> It is also an antagonist of the serotonin 5-HT_1A receptor, preferentially blocking inhibitory 5-HT_1A 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<ref name="pmid9635544" /><ref name="pmid23757185" /><ref name="pmid25689398" /> and obsessive-compulsive disorder.<ref>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.</ref><ref>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.</ref>

Medical uses

Pindolol is used for hypertension in the United States, Canada, and Europe, and also for angina pectoris outside the United States.<ref name="Cochrane" /> 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.<ref name=Cochrane/> In some countries, pindolol is also used for arrhythmias and prophylaxis of acute stress reactions.Template:Medical citation needed

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.<ref name=rx>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pindolol has intrinsic sympathomimetic activity and is therefore used with caution in angina pectoris.<ref name=rx/>

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref>
Site	Ki (nM)	Species	Ref
5-HT1A	15–81	Human	<ref name="pmid2078271">Template:Cite journal</ref><ref name="pmid1565658">Template:Cite journal</ref><ref name="pmid17804228">Template:Cite journal</ref>
5-HT1B	4,100 34–151	Human Rodent	<ref name="pmid1565658" /> <ref name="PDSP" /><ref name="pmid7984267">Template:Cite journal</ref><ref>Template:Cite journal</ref>
5-HT1D	4,900	Human	<ref name="pmid1565658" />
5-HT1E	>10,000	Human	<ref name="pmid1513320">Template:Cite journal</ref>
5-HT1F	>10,000	Human	<ref name="pmid8380639">Template:Cite journal</ref>
5-HT2A	9,333	Human	<ref name="pmid15322733">Template:Cite journal</ref>
5-HT2B	2,188	Human	<ref name="pmid15322733" />
5-HT2C	>10,000	Human	<ref name="pmid15322733" />
5-HT3	≥6,610	Multiple	<ref name="pmid9163561">Template:Cite journal</ref><ref name="pmid3412489">Template:Cite journal</ref><ref name="pmid3352595">Template:Cite journal</ref>
5-HT4	>10,000 ?	Rat	<ref>Template:Cite journal</ref>
5-HT5B	>1,000	Rat	<ref name="pmid8224165">Template:Cite journal</ref>
5-HT6	>10,000 (Template:Abbr)	Mouse	<ref name="pmid8394987">Template:Cite journal</ref>
5-HT7	>10,000	Human	<ref name="pmid8226867">Template:Cite journal</ref><ref name="pmid9298538">Template:Cite journal</ref>
α1	7,585	Pigeon	<ref name="pmid9163561"/>
α2	Template:Abbr	Template:Abbr	Template:Abbr
β1	0.52–2.6	Human	<ref name="pmid17804228" /><ref name="pmid14730417">Template:Cite journal</ref>
β2	0.40–4.8	Human	<ref name="pmid17804228" /><ref name="pmid14730417" />
β3	44	Human	<ref name="pmid14730417" /><ref>Template:Cite journal</ref>
D2-like	>10,000	Rat	<ref name="pmid11044891">Template:Cite journal</ref>
D2	>10,000	Pigeon	<ref name="pmid9163561" />
D3	>10,000	Pigeon	<ref name="pmid9163561" />
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,<ref>Template:Cite journal</ref> 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-HT_1A receptor partial agonist (intrinsic activity = 20–25%) or functional antagonist.<ref name="pmid16475955">Template:Cite journal</ref>

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.<ref>"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. Template:ISBN p 185</ref> 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.<ref>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. </ref><ref name="pmid25689398" /> The rationale behind this strategy has its basis in the fact that pindolol is an antagonist of the serotonin 5-HT_1A receptor.<ref name="pmid23757185">Template:Cite journal</ref> Presynaptic and somatodendritic 5-HT_1A receptors act as inhibitory autoreceptors, inhibit serotonin release, and are pro-depressive in their action.<ref name="pmid23757185" /> This is in contrast to postsynaptic 5-HT_1A receptors, which mediate antidepressant effects.<ref name="pmid23757185" /> By blocking 5-HT_1A autoreceptors at doses that are selective for them over postsynaptic 5-HT_1A receptors, pindolol may be able to disinhibit serotonin release and thereby improve the antidepressant effects of SSRIs and clomipramine.<ref name="pmid23757185" /> The results of augmentation therapy with pindolol have been encouraging in early studies of low quality.<ref name="pmid9635544">Template:Cite journal</ref> 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".<ref name="pmid25689398">Template:Cite journal</ref> On the other hand, a 2017 systematic review indicated that pindolol's efficacy has been demonstrated in high evidence studies.<ref name="Kleeblatt">Template:Cite journal</ref> Initiating pharmacotherapy with an SSRI plus pindolol might accelerate the SSRI's therapeutic impact.<ref name="pmid23757185" /><ref name="Kleeblatt" /> Pindolol's antidepressive efficacy may predominantly result from its ability to desensitize 5-HT_1A autoreceptors.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

See also

• Bopindolol