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serotonin_ph

serotonin receptors and pharmacology

5-HT1 receptor:

  • 6 sub-types: A-F;

5-HT1A:

  • found in Raphe nuclei & hippocampus, medullary neurons ⇒ decr. BP;
    • ⇒ decr. cAMP ⇒ veno/arteriolodil. without EDRF;
  • social cognitive component modulated by frontal & temporal cortices in conjunction with the hippocampus & mediated by 5HT1A and noradrenaline neurotransmission
    • drugs that influence 5HT1A function (buspirone) selectively affect performance on neuropsychological tests of memory and learning without affecting executive functions
  • urapidil: agonist + alpha1-adrenergic blocker ⇒ anti-HT;
  • buspirone:
    • partial agonist ⇒ slow-acting anxiolytic & antidepressant;
    • also pre-synaptic dopamine antagonist;
  • flibanserin: agonist and antagonist at 5-HT2a ⇒ supposedly increases female libido

5-HT1B:

  • found in substantia nigra, globus pallidus, & basal ganglia
  • ? decr. adenylate cyclase & ? activates K channel (musc.like) ⇒ decr. NA release

5-HT1C:

  • found in choroid, hippocampus & substantia nigra
  • similar to H1 in that causes:
    • vasodilatation via incr. Plipase C ⇒ incr. EDRF from vasc. endoth.
    • but:
      • no capill.perm. effect in humans;
      • doesn't constrict arteries/veins;

5-HT1D:

  • cerebral & middle menigeal Art vasoconstriction; CNS;
  • decr. release of peptides from trigeminal N terminals;
    • selective agonist 5-HT1Dz used to Rx migraine

5-HT1E:

  • cortex & putamen, causes decr. cAMP

5-HT1F:

  • cortex & hippocampus, causes decr. cAMP

5-HT2 receptors:

  • coupled to Plipase C → incr. [Ca]i;
  • contracts veins, arteries, venules, but not arterioles (which are dilated by 5-HT1);
  • stimulates platelet aggregation; incr. capill. permeability;
  • ? involved in PRL release; neuroendocrine functions;

5-HT2A:

  • found in platelets, smooth muscle, cerebral cortex
  • prefrontal cortex role in cognitive processes such as behavioural inhibition, feelings of hopelessness?
  • flibanserin: antagonist and agonist at 5-HT1a ⇒ supposedly increases female libido

5-HT2B:

  • agonism of these receptors on cardiac valvular interstitial cells appears to be involved in serotonin-associated cardiac valvulopathy as shown with the non-selective serotonergic diet medications such as fenfluramine and dexfenfluramine.
  • agonism at pulmonary smooth muscle cells may also be associated with pulmonary arterial hypertension

5-HT2C:

  • activation decreases food intake via the propiomelanocortin system of neurons
  • Lorcaserin:
    • selective 5-HT2C agonist with 15x more activity than on 5-HT2A receptors, and 100x more activity than on 5-HT2B receptors
    • under trial for obesity and weight management management in 20101) - appears to reduce weight by ~6kg in 1 year compared with 2kg for a placebo with almost 50% of patients losing at least 5% body weight compared with only 20% of those on placebo.

5-HT2F:

  • found in fundus of stomach.
  • Cyproheptadine:
    • prominent 5-HT2 block on various sm.muscles thus useful in pruritus, cold urticaria but as 5-HT not involved in allergic responses the only benefit are from anti-H1 & anticholin. activity;
  • Ketanserin:
    • Only 5-HT2 block (& alpha1, H1 & dopamine rec. block);
    • decr. 5-HT vasoconstriction (& alpha1 block decr. vasoc.)
    • incr.QT esp. if diuretics!
    • ⇒ decr. BP similar in degree to beta-block or diuretics;
    • ⇒ use as anti-HT & in vasospastic disorders but ? poor results;
  • Pizotifen: (Sandomigran)
    • selective antagonist 5-HT2 & affinity 5-HT1C used to prevent migraine
  • Mianserin:
    • 5-HT2 antagonist & actions @ H1, alpha1 receptors & pre-syn. alpha2 antag.;
  • Ritanserin:
    • 5-HT2 antagonist only ? ⇒ anxiolytic?;

5-HT3 receptor:

  • ? via activation of a cation channel;
  • found in area postrema, sensory & enteric nerves
  • depolarisation of sensory nerves ⇒ pain, itch & if GIT ⇒ N/V;
  • GIT myenteric plexus: antagonism ⇒ decr. bowel hypermotility & incr. gastric emptying;
  • CNS: antagonism ⇒ anxiolytic & neuroleptic & block CTZ/vomiting centre;
    • 5-HT3 antag. + 5-HT4 agonist + CNS dopamine antagonist;

selective 5-HT3 receptor antagonists

5-HT4 receptors:

  • found in CNS & myenteric neurons, smooth muscle;
  • ⇒ incr. cAMP.
  • GIT neuroexcitatory;
  • CNS effects
  • cardiac muscle stimulation
  • cisapride:
    • selective 5-HT4 agonist with M2 agonist & 5-HT3 antagonist actions
    • can cause diarrhoea and increased gastric emptying BUT also risk of arrhythmias due to prolongation of QTc and thus no longer used
  • prucalopride
    • a 5HT4 agonist introduced in Australia in 2011 (Resotrans) as a Rx for refractory constipation despite Rx over 6 months, however only 30% of patients will respond (vs ~10% responders to placebo)
    • usual dose 1-2mg once a day (no extra benefit at higher doses)
    • mainly excreted unchanged in urine
    • may cause headache, nausea, abdominal pain and diarrhoea, especially at the start of Rx
    • does not appear to affect QTc
    • C/I if ileus, obstruction, inflammatory bowel disease (IBD), or post-op bowel surgery
    • avoid pregnancy but beware diarrhoea may reduce effectiveness of OCP!!
    • cease if not effective after 4 weeks Rx

5-HT5 receptors:

  • found in brain; unknown mechanism;

5-HT6,7 receptors:

  • found in brain; ⇒ incr. cAMP.
  • clozapine:
    • partially selective 5HT7 antagonist.

Non-selective 5-HT Agonists-Antagonists:

Ergot alkaloids:

5-HT Re-uptake Blockers (SSRIs):

  • used as new antidepressants;
  • Fluoxetine:
    • long acting with active metabolite; elimination T« days-wks;
    • 20-40mg single dose/day as effective as 60-80mg/d;
    • dose-related side effects: N, nervousness, insomnia;
    • much less anticholinergic, wt. gain, sedation, cardiotoxic cf tricyclics;
    • as effective as & similar onset action to tricyclics & MAOI;
    • interactions with: cimetidine; tricyclics;

Other notes

  • tricyclics & cocaine inhibit neuronal amine uptake: ie. of both 5-HT & NA.
  • MAOI inhibit the metabolism of 5-HT.
  • reserpine releases & depletes 5-HT stores;
  • amphetamines incl. Ecstasy, release 5-HT & interfere with its synthesis;
1)
NEJM July 2010 363:3
serotonin_ph.txt · Last modified: 2020/12/26 10:47 by gary1