5-HYDROXYTRYPTAMINE

Hawler Medical UniversityCollege of Medicine

Department of Pharmacology Prepared by:

Zanyar Sabah Aram Majeed

Ibrahim Hussein

Contents• Definition• Biosynthesis• Storage• Destruction• Central effects• Peripheral effects• 5-hydroxytryptamine receptors• 5-hydroxytryptamine receptor agonists• 5-hydroxytryptamine receptor antagonists

5-HYDROXYTRYPTAMINE• Serotonin was the name given to the vasoconstrictor substance which

appeared in the serum when blood clotted and Enteramine to the smooth muscle contracting substance present in enterochromaffin cells of gut mucosa.

• In early 1950s both were shown to be 5-Hydroxytryptamine ( 5-HT ) . About %90 of body’s content of 5-HT is localized in the intestines, most of the rest in the platelets and brain.

• It is also found in wasp and scorpion sting , and is widely distributed in invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle,cowage).

Biosynthesis, Storage and Destruction 5-HT occurs in the highest concentrations in three situation in the body.• In the wall of intestine about %90 of the total amount in the body is

present in enterochromaffin cells, which are cells derived from neural crest .

• Similar to those of the adrenal medulla , that are interspersed with mucosal cells , mainly in the stomach and small intestine . Some of 5-HT also occurs in nerve cells of myenteric plexus , where it functions as an excitatory neurotransmitter

Biosynthesis, Storage and Destruction • In blood 5-HT is present in high concentration in platelets which

accumulate it from the plasma by an active transport system and release it when they aggregate at sites of tissue damage.

• In the CNS 5-HT is a transmitter in the CNS and is present in high concentrations in localised region of the midbrain . Though 5-HT is present in diet , most of this is metabolized before entering the blood stream.

Biosynthesis, Storage and Destruction • Endogenous 5-HT arises by biosynthesis , which follows a pathway

similar to that of noradrenaline , except the precursor amino acid is tryptophan instead of tyrosine .

• Tryptophan is converted to 5-Hydroxy tryptamine ( in chromaffin cells and neurons, but not in platelets ) by the action of tryptophan hydroxylase ( an enzyme confined to 5-HT producing cells ) .

Biosynthesis, Storage and Destruction • The 5-hydroxytreptophan is then decarboxylated to 5-HT , by a

ubiquitous amino –acid decarboxylase that also participates in the synthesis of cathecholamines and histamine .

• Platelets (and neurons) possess a high affinity 5-HT uptake mechanism , and platelets become loaded with 5-HT as they pass through the intestinal circulation , where the local concentration is relatively high .

Biosynthesis, Storage and Destruction • 5-HT is often stored in neurons and chromaffin cells as a co-

transmitter together with various peptide hormones , such as somatostatin.

• Substance P or vasoactive intestinal polypeptide (VIP). Degradation of 5-HT occurs mainly through oxidative deamination , catalysed by monoamine oxidase , followed by oxidation to 5-hydroxyindoleacetic acid ( 5-HIAA ) .

Biosynthesis, Storage and Destruction • The pathway being the same as that of noradrenaline catabolism . 5-

HIAA is excreted in the urine and serves as an indicator of 5-HT production in the body , this is used for example , in the diagnosis of carcinoid syndrome .

Pharmacological effects1- Central effects

Hallucinatory effectsMany hallucinogenic drugs (e.g. LSD) are agonists at5-HT2A receptors and depress the firing of brain-stem 5-HTneurons, these neurons exert an inhibitory influence on corticalneurons

Sleep, wakefulness and mood

There is evidence that 5-HT may be involved in the control of mood and the

use of tryptophan to enhance 5-HT synthesis has been tried in depression,

with equivocal results

Feeding and appetite

Antagonists acting on 5-HT2 receptors, including several antipsychotic drugs

used clinically, also increase appetite and cause weight gain. On the other

hand, antidepressant drugs that inhibit 5-HT uptake cause loss of appetite.

Sensory transmissionAfter lesion of the raphe nuclei or administration of para-chlorophenylalanine animals show exaggerated responses to many forms of sensory stimulus.5-HT also exerts an inhibitory effect on transmission in the pain pathway.

Other possible rolesOther putative role of 5-HT include various autonomic and endocrine functions such as the regulation of body temperature, blood pressure, vomiting and sexual function.

Pharmacological effects2- Peripheral effectsGastrointestinal Tract Stimulates motilityNausea and vomiting

Smooth muscle Contraction, to a minor extent in humans

Blood vesselsSize, species, prevailing sympathetic activityArteries and veins constrictedArterioles dilate while venules constrictIf 5-HT is injected IV, BP first then

Platelet Platelet aggregation via 5-HT2A receptors and they release more 5-HT.

Nerve endingsStimulates nociceptive sensory nerve endings via 5-HT3 receptors.

GlandsInhibits gastric secretions but increases mucus secretion.

5-Hydroxytryptamine Receptors

Seven families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3,5-HT4, 5-HT5, 5-HT6, 5-HT7 )

All 5-HT receptors are G protein coupled receptors, except 5-HT3 which is a Ligand gated ion channel, its activation elicits fast depolarization.

Function through: 5-HT1 : decreasing cAMP production5-HT2 : produce IP3/DAG5-HT4,7 : increasing cAMP production

5-HT1 receptors

Occur mainly in the brainThe 5-HT1A subtype is particularly important in the brain, in relation tomood and behaviour.The 5-HT1D subtype, which is expressed in cerebral blood vessels, is important in migraine and is the target for Sumatriptan.

5-HT2 receptors

Particularly important in the peripheryStimulate IP3 /DAG formationThe 5-HT2A subtype is functionally the most important, mediates smooth muscle contraction and platelet aggregation.

5-HT3 receptors

Occur mainly in the PNS, particularly on nociceptive sensory neurons and autonomic and enteric neurons,5-HT3 receptors also occur in the brain, particularly in thearea postrema, a region of the medulla involved in the vomiting reflex.

5-HT4 receptors

Occur in the brain, as well as in peripheral organs such as the GIT, bladder and heart. Their main physiological role appears to be in the GIT where they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis.

5-Hydroxytryptamine Receptor AgonistsSelective 5-HT1A agonists :8-hydroxy-2-(di-npropylamino) tetralin (8-OH DPAT) highly selective agonist but not used clinically

Buspirone, Gepirone, Ipasapirone : potent 5-HT1A agonists used in treating anxiety.Given orally at a dosage of 15 mg/daythe drug is rapidly absorbedhalf-life of about 2.5 hoursThe mean peak plasma concentration (Cmax) is approximately 2.5 μg/L, and the time to reach the peak is under 1 hour, however it takes days or weeks to produce its effect.The absolute bioavailability of buspirone is approximately 4%.

Side effects: Mainly nausea, dizziness, headache, restlessness but no sedation or loss of coordination.

5-HT1D receptor agonists Sumatriptan, used for treating migrainePharmacokinetics:Administered subcutaneously, orally, and intranasally.Orally, single dose of 25, 50, or 100 mg, if patient has a partial response to the initial dose, a single additional dose may be taken after 2 h up to a max of 200 mg/daySubcutaneous 6 mg initially. May repeat once after 1 h (max, 6 mg per single dose or 12 mg/day).Intranasal Administer a single dose of 5, 10, or 20 mg in one nostril. The dose may be repeated once after 2 h (max, 40 mg/day).

Total plasma clearance is rapid, with an elimination half-life of around 2 hours.Bioavailability for subcutaneous, oral, and intranasal administration is 97%, 15%, and 15.8%, respectively.Metabolized by MAO-AContraindicated in patients with severe hepatic impairment, patients with history or symptoms of ischemic heart disease, cerebrovascular syndromes (strokes) or peripheral vascular syndromes (ischemic bowel disease).

5-HT4 receptor agonistsMetoclopramidewhich stimulate coordinated peristaltic activity (prokinetic action), are used for treating gastrointestinal disorders, increase motilityPharmacokinetics:Given orally at a dose of 5-10 mg, is rapidly and well absorbed, bioavailability is 80% ± 15.5%, plasma half life or 4-5 h and peak plasma concentrations occur at about 1 to 2 h.85% eliminated in the urine.

Side effects :Fatigue, motor restlessness, spasmodic torticollis, occulogyric crisis, also can cause galactorrhoea and disorders of menstruation. Contraindications : Metoclopramide should not be used whenever stimulation of gastrointestinal motility might be dangerous, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation.patients with pheochromocytoma, should not be used in epileptics or patients receiving other drugs, which are likely to cause extrapyramidal reactions

• Tegaserod is more selective and is used to treat irritable bowel syndrome.

Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. It is rapidly absorbed following oral administration, peak plasma concentrations are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions, food reduces the bioavailability of tegaserod by 40 to 65%.Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein

• Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine,

5-Hydroxytryptamine Receptor Antagonists5-HT2 receptor antagonists :Cyproheptadine: primarily blocks 5-HT2A receptor, used in controlling the symptoms of carcinoid tumors. Methysergide & Dihydroergotamine: used mainly for migraine prophylaxis. Ketanserin: 5HT2 (blockade of 5HT2A is stronger than of 5HT2C) and α1 antagonist, used as antihypertensive.Clozapine: partial antagonist at 5-HT2A/2C receptor, Risperidone: is a combined 5-HT2A + dopamine D2 antagonist,

Clozapine and Risperidone are both used in treatment of schizophrenia. Are recent (atypical) antipsychoticsThey can be given orally or IM injection, They take days or weeks to show their effectsThe absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70%.The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces.

Side effects : Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis.Common side effects include extreme constipation, night-time drooling, muscle stiffness, sedation, tremors, hyperglycemia, and weight gain. The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of typical antipsychotics.

5-HT3 receptor antagonists :Ondansetron, Granisetron, Tropisetron: These agents have an important place in treating emesis linked with chemotherapy.Long duration of action.Can be administered as a single dose prior to chemotherapy.Are extensively metabolized in the liver.Elimination is through the urine.Common side effect is headache.

5-HT mixed agonist and antagonist : Lysergic acid diethylamide (LSD) Is a potent hallucinogen, activates 5-HT1A, 5-HT2A/2C, 5-HT5-7, also antagonizes 5-HT2A receptors in the ileum.

• Other related drugs :SSRI : specifically inhibit serotonin reuptake, have 300-3000 fold selectivity, drug of choice in treating depression.Example : Fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline,Indication : Depression, obsessive compulsive disorder, panic disorder, generalized anxiety and bulimia nervosa.

Mechanism of action of SSRIs

• Pharmacokinetics : All the SSRIs are well absorbed after oral administration.All have large volume of distribution.Plasma half lives range between 16-36 h but Fluoxetine have a half life of 50 h.Fluoxetine and paroxetine are inhibitors of enzyme CYP2D6.Excretion is primarily through the kidneys, except Paroxetine and Sertraline undergo 35% fecal excretion, 50% renal excretion.Dosage should be adjusted downward in hepatic impairment.

Adverse effects : Nausea, vomiting, diarrhea, Headache, restlessness, fatigue, sleep disturbances.Should be used cautiously in children and teenagers, 1 out of 50 children become suicidal as a result of SSRI treatment,

SummaryReceptor Location Effect1A CNS Neuronal inhibition, behavioural effects: sleep, feeding, thermoregulation, anxiety.1B CNS, Presynaptic inhibition, Vascular smooth muscle Pulmonary vasoconstriction1D CNS, Cerebral vasoconstriction Blood vessels Behavioural effects: locomotion2A CNS, PNS, Neuronal excitation Smooth muscle Smooth muscle contraction platelets Platelet aggregation2B Gastric fundus Contraction

SummaryReceptor Location Effect2C CNS, Cerebrospinal fluid secretion Choroid plexus3 PNS Neuronal excitation (autonomic, nociceptive n) CNS, Emesis, anxiety4 CNS, PNS (GIT) Neuronal excitation, Gl motility5 CNS Not known6 CNS Not known7 CNS, GIT Not known Blood vessels

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