Sunday, 9 June 2013

Yohimbine

Yohimbine (chemical structure is given in figure 1) is the name of a fascinating drug found within Yohimbe and plants. It is sold, in herbal and herbal extract form, usually (although pure forms are available but generally require a prescription), as an over-the-counter treatment for sexual dysfunction, especially in men (and as such it can cause priapisma dangerously and painfully long-lasting erection). It is sometimes also used as a treatment for type II diabetes mellitus.1

Figure 1: Yohimbine

It works, or so we believe by antagonising (blocking) the α2 adrenergic receptor2. α2 adrenoceptors (adrenergic receptors) are auto- and hetero- receptors that regulate the release of norepinephrine,3,4 serotonin (5-HT),5 dopamine,5 GABA,5 acetylcholine6 and other neurotransmitters. α2 adrenergic receptors also regulate vaso- constriction6 and dilation in certain parts of the body. It also, as part of its actions that lead to side effects, antagonises (blocks) the α1 adrenoceptors which regulate heart rate, blood pressure and blood vessel diameter (e.g. α1 adrenoceptor agonists produce vasoconstriction and this fact allows them to relieve nasal congestion). It also serves as a partial agonist (i.e. activates the receptor less strongly than serotonin) at the 5-HT1A serotonin receptor and antagonises the 5-HT1B5-HT1D and 5-HT2B receptors with moderate (and thus clinically significant) affinity. It also appears to inhibit monoamine reuptake. Additionally it blocks the D2 dopamine receptor, the significance of which is unknown but this action might, in theory, exacerbate the extrapyramidal (Parkinson's disease-like) side effects of antipsychotics.7,8

5-HT1B and 5-HT1D receptors regulate the release of serotonin (i.e. they serve as serotonin autoreceptors) and hence 5-HT1B and 5-HT1D antagonists catalyse the release of serotonin, as does the α2 antagonism, however, 5-HT1A partial agonism may do the reverse since 5-HT1A receptors are also autoreceptors.4,9 5-HT1A partial agonism also means that it might have some antidepressant and anxiolytic (anti-anxiety) effects10 and its α2 antagonist effects do likewise.11 One placebo-controlled clinical trial demonstrated that yohimbine, when given in combination with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, both increased response rates and decreased therapeutic lag times.11 α2 antagonists, like yohimbine, also elicit stimulant effects increasing wakefulness due to its regulatory effects on norepinephrine and dopamine release. It might also cause weight-loss due to these stimulant effects, which thing a few placebo-controlled clinical trials have confirmed.12,13 This can be especially helpful when used in conjunction with SSRIs to treat depression since a few SSRIs are known to cause statistically significant weight gain, on average.14 It may also treat diabetes mellitus type II by stimulating insulin release by the beta cells of the pancreas.15

In the treatment of sexual dysfunction it appears to work by increasing the activity in brain regions to do with sexual arousal.16 Randomised, double-blind, placebo-controlled clinical trials support its efficacy in the treatment of erectile dysfunction.17 One randomised, crossover placebo-controlled trial demonstrated that it is efficacious in the treatment of xerostomia (dry mouth).18



Glossary

Autoreceptor: Presynaptic receptors that regulate the release of their endogenous ligand.
Clinical Trial Designs:
  • Crossover: a trial in of which patients originally given placebo are then started on the active partway through the trial and vice versa.
  • Double-blind: neither the doctor nor the patient knows which drug the patient is receiving.
  • Placebo-controlled: a trial in of which there is a group of patients receiving a placebo instead of the active treatment.
Randomised: patients are randomly assigned either a placebo or the active treatment.
Endogenous: Body-synthesised.
Heteroreceptor: Presynaptic receptors that regulate the release of endogenous ligands other than their own.
Ligand: Compound that binds to the receptor in question.
Neuron: Electrically signalling brain, nerve and spinal cord cells. They have the structure depicted in figure 2.

Figure 2: The Neuron19

Postsynaptic: Pertaining to the neuron whose dendrite makes up the synapse in question.
Presynaptic: Things pertaining to the neuron that’s axon terminal makes up the synapse in question.
Synapse: A structure made up of an axon terminal, dendrite and a space known as the synaptic cleft. See figure 3 for a visual representation.

Figure 3: The Synapse19



References (Vancouver Style)
  1. MedlinePlus. Yohimbe; 2011 [cited 2013 June 10]; Online.
  2. DailyMed. YOBINE (yohimbine hydrochloride) injection [LLOYD Inc. of Iowa]; 2011 [cited 2013 June 10]; Online.
  3. Bremner JD, Innis RB, Ng CK et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Archives of General Psychiatry 1997[cited 2013 June 10]; 54(3): 246-254; Online.
  4. Brunton LL, Chabner BA, Knollmann BC. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. 12th ed. China: McGraw-Hill; 2012. Chapter 12. Adrenergic Agonists and Antagonists; p. 308-309, 399.
  5. Gilsbach R, Hein L. Are the pharmacology and physiology of a2-adrenoceptors determined by a2-heteroreceptors and autoreceptors respectively? British Journal of Pharmacology 2012[cited 2013 June 10]; 161(1): 90-102; Online.
  6. Scheibner J, Trendelenburg AU, Hein L. a2-Adrenoceptors in the enteric nervous system: a study in a2A-adrenoceptor-deficient mice. British Journal of Pharmacology 2002[cited 2013 June 10]; 135(3): 697-704; Online.
  7. Millan MJ, Newman-Tancredi A, Audinot V. Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Synapse 2000[cited 2013 June 10]; 35(2): 79-95; Online.
  8. University of North Carolina. PDSP Database; [cited 2013 June 10]; Online.
  9. Malagié I, Trillat AC, Bourin M et al. 5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex. Journal of Neurochemistry 2008[cited 2013 June 10]; 76(3): 865-871; Online.
  10. Robinson DS, Rickels K, Feighner J. Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. Journal of Clinical Psychopharmacology 1990[cited 2013 June 10]; 10(3 Suppl): 67S-76S; Online.
  11. Sanacora G, Berman RM, Cappiello A. Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response. Neuropsychopharmacology 2004[cited 2013 June 10]; 29(6): 1166-1171; Online.
  12. Kucio C, Jonderko K, Piskorska D. Does yohimbine act as a slimming drug? Israel Journal of Medical Sciences 1991[cited 2013 June 10]; 27(10): 550-556; Online.
  13. Ostojic SM. Yohimbine: the effects on body composition and exercise performance in soccer players. Research in Sports Medicine 2006[cited 2013 June 10]; 14(4): 289-299; Online.
  14. Fava M, Judge R, Hoog SL. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. Journal of Clinical Psychiatry 2000[cited 2013 June 10]; 61(11): 863-867; Online.
  15. Niddam R, Angel I, Bidet S et al. Pharmacological characterization of alpha-2 adrenergic receptor subtype involved in the release of insulin from isolated rat pancreatic islets. The Journal of Pharmacology and Experimental Therapeutics 1990[cited 2013 June 10]; 254(3): 883-887; Online.
  16. Guay AT, Spark RF, Jacobson J. Yohimbine treatment of organic erectile dysfunction in a dose-escalation trial. International Journal of Impotence Research 2002[cited 2013 June 10]; 14(1): 25-31; Online.
  17. Carey MP, Johnson BT. Effectiveness of yohimbine in the treatment of erectile disorder: four meta-analytic integrations. Archive of Sexual Behavior 1996; 25(4): 341-360. Online.
  18. Bagheri H, Schmitt L, Berlan M, Montastruc JL. A comparative study of the effects of yohimbine and anetholtrithione on salivary secretion in depressed patients treated with psychotropic drugs. European Journal of Clinical Pharmacology 1997[cited 2013 June 10]; 52(5): 339-342. Online.
  19. General Psychology. The Neuron; 2009 [cited 2013 June 10]; Online.

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