Pharmacology

Autacoid (5-hydroxytryptamine (5-HT, serotonin))

5-hydroxytryptamine (5-HT, serotonin)

  • Serotonin and enteramine both are 5-hydroxytryptamine, a monoamine neurotransmitter, and are derived from tryptophan.
  • About 90% of the body contains 5-HT is localized in the intestine and the rest are in platelets and the brain.
  • It also found in other animals and plants;
  • Animals: invertebrates and mollusks, arthropods, snake and bee venom/sting.
  • Plants: plants: tomato, pear, banana & pineapple.

Synthesis storage and destruction

  • It is synthesized from the amino acid tryptophan.
  • Tryptophan converted to 5-hydroxytryptophan with the help of enzyme hydroxylase.
  • 5-HTP decarboxylase to produce 5-HT.
  • The decarboxylase is non-specific, acts on DOPA as well as 5-hydroxytryptophan (5-HTP) to produce DA and 5-HT respectively.
  • It is degraded primarily by MAO and to a small extent by dehydrogenase.
  • 5-HT is actively taken up by an amine pump serotonin transporter (SERT), with a Na+ dependent carrier, which operates at a membrane of platelet and serotonergic nerve ending s (therefore, 5-HT does not circulate in free form in plasma).
  • This pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).
  • Platelets do not synthesize 5-HT but acquire it by uptake during passage through intestinal blood vessels.
  • Again 5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2).
  • It is inhibited by reserpine.
  • The enzyme MAO (especially MAO-A) metabolized 5-HT.

5-HT receptors

  • Musculotropic (D type) and Neurotropic (M type) – blockade by Dibenzyline (phenoxybenzamine) and Morphine.
  • 4 Families and 14 subtypes.
  • The present system of classifying 5-HT receptors is based on molecular characterization and cloning of the receptor cDNAs.
  • 5-HT receptor subtype-selective agonists or antagonists.
  • All are GPCRs except 5-HT3.
    • Decrease cAMP production
    • 5-HT1 – Increase cAMP production 5-HT4, 5-HT6, 5-HT7 
    • Generating IP3/DAG – 5-HT2.
  • The 5-HT3 is a ligand-gated cation (Na+, K+) channel which on activation elicits fast depolarization.

5-HT1 receptors

  • All subtypes of the 5-HT1 receptor couple with Gi/Go protein and inhibit adenylyl cyclase.
  • 5-HT1A activates the K+ channel and inhibits the Ca2+ channel resulting in hyperpolarization.
  • These receptors primarily act as an autoreceptor in the brain and inhibit the firing of 5-HT neurons or the release of 5-HT from nerve endings.
  • Location of 5-HT1A receptor: Somadendritic synapse in Raphe nucleus, Brainstem, and hippocampus (antianxiety – Buspirone).
  • 5-HT1D – Basal ganglia and substantia nigra (dopaminergic).
  • 5-HT1D/1B – Cranial Blood Vessels (for constriction – sumatriptan – agonist).
  • Also inhibits 5-HT release in the forebrain and NA release in sympathetic nerve endings.

5-HT2 Receptors

  • Mainly 3 subtypes (5-HT2A, B, C).
  • All are coupled to Gq protein – activate Phospholipase C – IP3/DAG.
    • 5-HT2A – – also inhibits K+ channels.
    • Location: – vascular, visceral, platelets and cerebral neurones (prefrontal cortex).
    • Mediates direct effects of 5-HT (D-type).
      • Vasoconstriction, intestinal, uterine, and bronchial constrictions, platelet aggregation, and activation of cerebral neurons.
  • Ketanserin, Cyproheptadine, Methysergide are antagonists.
  • 5-HT2B: contraction of Rat gastric fundus.
  • Location of 5-HT2C receptor: Vascular endothelium – EDRF release (Vasodilatation) and CSF formation in choroid plexus.

5-HT3 receptor

  • Neuronal receptors – depolarizes rapidly by acting on Na+, K+ channel, and also the Ca2+ channel.
  • Somatic and autonomic nerve endings – pain, itch, and coronary chemoreflex (bradycardia, fall in BP, respiratory stimulation/apnoea depending on stimulation of receptors in coronary bed).
  • Nerve endings in myenteric plexus: increased peristalsis and emetic reflex.
  • Area postrema and nucleus tractus solitarious (NTS): vomiting and nausea.
  • Ondansetron is a specific antagonist which inhibits vomiting by blocking these receptors in the brainstem as well as in the gut wall.

5-HT4-7 Receptors

  • Gs: activates the adenylate cyclase.
  • Present in the mucosa, plexuses, and smooth muscle of the gut.
  • Increase Intestinal secretion and peristalsis.
  • In the Brain: the hippocampus area and the colliculi cause slow depolarization by decreasing K+ conductance.
  • Cisapride and renzapride are selective 5-HT4 agonists.
  • Clozapine (atypical antipsychotic) has a high affinity for 5-HT6 and 5-HT7 receptors.

Action of 5 – HT

  • 5-HT is a potent depolarizer of nerve endings. It thus exerts direct as well as reflex and indirect effects.
  • Tachyphylaxis is common with repeated doses of 5-HT.

CVS

  • Large arteries and veins are constricted but in microcirculation, arterioles are dilated.
  • Release of 5 – HT from adrenal medulla that evokes cardiovascular reflexes.
  • Also releases Adrenaline, which affects ganglionic transmission and reflex CVS action.
  • The net effect on CVS is complex
  • BP:
    • Early sharp fall: Coronary chemoreflex.
    • A brief rise in BP: vasoconstriction and increased cardiac output – also due to vasoconstriction.
    • Prolonged fall in BP: arteriolar dilatation and extravasation of fluid – skeletal muscle.

GIT

  • Potent stimulator of GIT
    • partly through enteric plexuses direct effect on the smooth muscle cells (5-HT2 receptor)
    • partly as a result of indirect excitatory effect on enteric neurons (5- HT3 & 4 receptors)
    • Diarrhoea
  • 5-HT inhibit gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property.
  • Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally) on 5-HT receptors.

Respiration

  • Brief stimulation of smooth muscles of Bronchi via reflex stimulation of bronchial afferents- hyperventilation.
  • Large doses can cause transient apnoea through coronary chemoreflex.

Platelets

  • Responsible physiologically for Haemostasis by promoting platelet aggregation and clot formation, thereby preventing leakage.
  • Works in conjunction with collagen and other mediators.
  • Exogenous 5-HT also changes shape of platelets in injury and promote aggregation (via 5-HT2A).

CNS

  • Does not produce CNS effects because poor penetration across BBB.

5-HT agonist  

Cisapride

  • Cisapride shows peripheral 5-HT4 agonist action.
  • Useful in GERD, diabetic gastroparesis.
  • Oral bioavailability ~ 30%
  • t ½ 10 hours.
  • Adverse effect: serious ventricular arrhythmias.

Sumatriptan

  • Selective agonist for 5-HT1B, 1D
  • Useful in acute migraine attack
  • Bioavailability ~ 15%
  • Half-life 2-3 hours
  • Administered as oral, nasal or s.c.
  • In case 5% of patients shows chest pain.
  • Zolmitriptan, naratriptan can be given orally, longer acting, and safer.

Buspirone

  • Partial agonist at presynaptic 5-HT1A receptors.
  • Weak D2 blocker.
  • Used as anxiolytic.
  • Rapid absorbed, undergoes extensive first pass metabolism.
  • t ½ 2-4 hours.
  • Excreted in urine and faeces.

5-HT antagonist

1. Cyproheptadine

  • It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties.
  • Used as antipruritic.
  • It increases appetite, so used in children for weight gain.
  • Adverse effects: drowsiness, dry mouth, confusion, ataxia, weight gain.

2. Methysergide

  • It is chemically related to ergot alkaloids.
  • Antagonizes action of 5-HT on smooth muscles including that of blood vessels.
  • It does not interact with α adrenergic or dopamine receptors.
  • It is a potent 5-HT2A/2C antagonist.
  • Used for migraine prophylaxis, carcinoid and post-gastrectomy dumping syndrome.

3. Ketanserin

  • It has selective 5-HT2 receptor blocking property with very less action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity.
  • Stronger blockade of 5-HT2A.
  • It has additional weak α1, H1 and dopaminergic blocking activities.
  • Ritanserin is a relatively more 5-HT2A selective congener of ketanserin.

4. Clozapine

  • This atypical antipsychotic is a 5-HT2A/2C blocker.
  • Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia.

5. Risperidone

  • This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to clozapine.

6. Ondansetron

  • It is the prototype of the new class of selective 5-HT3 antagonists.
  • It control nausea and vomiting against anticancer drugs and radiology therapy.

Ergot alkaloid

  • Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains.

Classification of ergot alkaloids

1. Natural – Derivatives of the tetra-cyclic compounds (lysergic acid)

  • Amine alkaloids – Ergometrine (ergonovine)
  • Amino acid alkaloids – Ergotamine, Ergotoxine (ergocristine, ergocornine, ergocryptine)

2. Semi-synthetic

  • Dihydro-ergotamine (DHE), Dihydroergotoxine, Bromocriptine (2-Bromoα-ergocryptine), Methysergide,

3. Synthetic – (non lysergic acid derivative)

  • Metergotine

Ergotamine

  • 5-HT1 and 5-HT2 antagonist.
  • α-adrenergic antagonist.
  • Partial agonist activity at both types of receptor.
  • Used in acute migraine.
  • Action:
    • Sustained vasoconstriction, visceral smooth muscle contraction and vasomotor center depression.
    • Antagonizes action of NA and 5-HT in smooth muscles.
    • Potent emetic via CTZ and potent oxytocic.
    • Prolonged use – vasoconstriction and damage endothelium – thrombosis, gangrene.

Ergometrine

  • Amine ergot alkaloid.
  • Partial agonist of 5-HT receptor in uterus, placenta and umbilical blood vessels – but antagonist of 5-HT2 in GIT.
  • Weak partial agonist but no antagonistic effect of α-receptor – less vasoconstriction.
  • Moderately potent antagonist of 5-HT2 in intestine.
  • Weak DA agonist in lactotropes and CTZ – low vomiting.
  • Uterine myometrium.

Dihydroergotamine (DHE)

  • Hydrogenated ergotamine
  • Less serotonergic action than ergotamine and α-adrenergic action
  • Better blocker of α-adrenergic receptor
  • Less potent vasoconstrictor and so less intimal damage
  • Lesser oxytocic and emetic.

Dihydroergotoxine and Bromocriptine

  • Dihydroergotoxine: Hydrogenated mixture of ergotoxine groups – potent α-blocker
    • Variety of agonist/antagonist action in Brain on 5- HT, metabolic, vascular effects and Ach release.
    • Used for treatment of dementia.
  • Bromocriptine: selective D2 agonist in pituitary lactotropes (inhibits prolactin release), in striatum and in CTZ (emetic)
    • Used in Galactorrhoea, Parkinsonism etc.

Drug Therapy of Migraine

  • Migraine derived from the Greek word hemicrania, meaning “one side of head”.
  • Severe, throbbing, pulsating headache usually unilateral headache (few hours to a few days in duration).
  • Associated with nausea, vomiting, sensitivity to light and sound, flashes of light, loose motion and others.
  • Types:
    • Classical with aura: preceded by visual or other neurological symptoms – Without aura (common).

Pharmacotherapy of Migraine

  • Three types: Mild, Moderate, and Severe
  • Mild: Less than one attack per month of throbbing but tolerable headache lasting up to 8 hours – no incapacitation
  • NSAIDS or combinations: codeine/diazepam/anhihistaminics/caffeine
    • Ibuprofen (400 mg 8 hourly)
    • Paracetamol (500 mg 8 hourly)
    • Naproxen (250 mg 8 hourly)
    • Mefenamic acid (500 mg 8 hourly)
    • Diclofenac (50 mg 8 hourly)
  • Useful in without aura – should be used till the attack only – no long term
  • Antiemetics: Gastric stasis
    • Metoclopramide (10 mg oral or IV)
    • Domperidone (10 mg oral)

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Presently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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