Serotonin (5-Hydroxytryptamine)

• Serotonin is one of autacoids

• In human:

• 90% of serotonin presents in the enterocromaffin cells in the intestine,

• 8% presents in platelets,

• 2% in CNS.

• Also, it is founds in plants.

Biosynthesis:

L-tryptophan hydroxylase L-tryptophan 5-hydroxytryptophan

Aromatic L-amino acid decarboxylase

5-hydroxytryptamine (serotonin)

Physiological function of serotonin:

serotonin involve in:

• Sleep

Appetite

Temperature regulation

Perception of pain

Regulation of blood pressure

Depression

Anxiety

Migraine

Serotonin (5HT) receptors

Mechanism of

action

Distribution Receptor subtype

Decrease cAMP Raphe

nuclei,hippocampus 5-HT1A

Decrease cAMP Substansia nigra,

basal ganglia 5-HT1B

Decrease cAMP Cortex, putamin 5-HT1D

Decrease cAMP Cortex,

hyppocampus 5-HT1E

Decrease cAMP Enteric nervous

system 5-HT1F

Mechanism of action Distribution Receptor subtype

Increase IP3 Platelets, smooth

muscle, cerebral

cortex, skeletal muscle

5-HT2A

Increase IP3 Stomach 5-HT2B

Increase IP3 Hippocampus,

substansia nigra 5-HT2C

Na+, K+ ion

channel

Enteric system 5-HT3

Increase cAMP CNS, smooth muscle 5-HT4

Decrease cAMP Brain 5-HT5

Increase cAMP Brain 5-HT6,7

• Pharmacological actions

• Nervous system:

• 5-HT3 receptors in the GIT and in vomiting center in the medulla play a role in vomiting center.

• Activation of 5-HT3 receptor on vagal nerve ending causes bradycardia and hypotension.

• Serotonin, like histamine, is a potent stimulant of pain and itch sensory ending.

2- Airways:

• has small direct stimulant effect on bronchiolar smooth muscle.

3-Cardiovascular system

• Serotonin causes contraction of vascular smooth muscle, through 5-HT2 receptors.

• Serotonin is a powerful vesoconstrictor except in skeletal muscle and heart where it dilate blood vessels.

• It can also, causes reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings.

• A triphasic blood pressure response is seen following injection of serotonin in experimental animals:

• Initially, there is a decrease in heart rate, cardiac output, and blood pressure caused by the chemoreceptor response.

• After this decrease, blood pressure increases as a result of vasoconstriction.

• The third phase is again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle.

• has small direct positive chronotropic and inotropic effects on the heart.

4- Gastrointestinal tract

• is a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. This action is caused by the direct action of serotonin on 5-HT 2 smooth muscle receptors..

•Over production of serotonin in carcinoid tumor is associated with severe diarrhea.

5. Skeletal muscle

• 5 -HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood.

Serotonin syndrome :

• It is a condition associated with restlessness, hyperthermia and skeletal muscle contractions. It is precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class.

• 6- The eye

• 5-HT 2A agonists reduce intraocular pressure in animal model of gluacoma.

Serotonin Agonists Serotonin has no clinical applications as a drug. Buspirone: a 5-HT1A agonist, is a

nonbenzodiazepine anxiolytic. Triptans Triptans ( eg, sumatriptan ), 5-HT ?? agonists,

are used for migraine headache.

Cisapride, a 5-HT 4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders.

Tegaserod, a 5-HT 4 partial agonist, is used for irritable bowel syndrome with constipation.

Fluoxetine and other selective serotonin reuptake inhibitors (SSRIs), block reuptake of serotonin. It is used for treatment of depression.

SEROTONIN-RECEPTOR ANTAGONISTS Phenoxybenzamine blocks 5-HT 2 receptors. Ergot alkaloids are partial agonists at serotonin

receptors. Cyproheptadine blocks H 1 –receptor and 5-HT 2

actions. The actions of cyproheptadine:

• antimuscarinic effects • sedation. • treatment of carcinoid tumor • urticaria. • appetite stimulant.

Ketanserin blocks:

• 5-HT 2 receptors on smooth muscle and platelets

• vascular α 1 adrenoceptors.

• The drug:

• inhibits platelet aggregation promoted by serotonin.

• decreases blood pressure

Ritanserin, another 5-HT 2 antagonist, has little or no α-blocking

Ondansetron:

• It is 5-HT 3 antagonist.

• It is very important in the prevention and treatment of nausea and vomiting associated with surgery and cancer therapy.

Ergot alkaloids

• Ergot alkaloids are produced by Claviceps purpurea , a fungus that infects grasses and grains—especially rye—under damp growing or storage conditions.

• This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to ergot alkaloids.

• These alkaloids affect α adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps other receptor types

Organ System Effects

1-Central nervous system

Lysergic acid diethylamide (LSD) is a synthetic, 5-HT 2 antagonis, powerful hallucinogens.

• It has no clinical value.

• Abuse of this drug is widespread.

Bromocriptine suppresses prolactin secretion from pituitary cells by activating dopamine receptors.

•

2- Vascular smooth muscle

• Ergotamine and similar compounds constrict most vessels.

3- Uterine smooth muscle

• In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus.

• At higher concentrations, these drugs induce powerful and prolonged contracture.

4- Other smooth muscle organs

• Ergot alkaloids have little or no significant effect on bronchiolar or urinary smooth muscle.

• Ergot s cause nausea, vomiting, and diarrhea even by low doses in some patients.

Clinical Uses

A. Migraine:

Ergot derivatives are specific for migraine pain. Such as:

Ergotamine tartrate It is often combined with caffeine.

Dihydroergotamine .

B. Hyperprolactinemia: Bromocriptine is used to r treatment of hyperprolactinemia.

C. Postpartum Hemorrhage: • Oxytocin is the preferred agent for control of

postpartum hemorrhage, but if this agent is ineffective, ergonovine maleate given intramuscularly.

• Ergot derivatives should be used only for control of postpartum uterine bleeding and should never be given before delivery.

DRUGS USED TO TREAT MIGRAINE HEADACHE

• Types of headaches:

• Migraine: pulsatile, throbbing pain

• Cluster headache: sever, sharp, steady pain

•Tension-type headache: dull pain, with a persistent, tightening feeling in the head.

• Types of migraine headaches:

• migraine without aura ( called common migraine)

• migraine with aura ( called classic migraine), the headache is preceded by visual, sensory, and/or cause speech or motor disturbances.

• Migraine may be due to extracranial and intracranial arterial dilation. This stretching leads to release of neuroactive molecules, such as substance P.

Symptomatic (nonspecific) treatment of acute migraine

• Nonsteroidal anti-inflammatory drugs such as aspirin, indomethacine

• antiemetics, such as metoclopromide, prochlorperazine, to control vomiting.

• Opioids

• β-adrenoceptor blockers : such as Propranolol

• calcium channel blockers : such as verapamil

• tricyclic antidepressants: such as amitriptyline

• several antiseizure agents.

Specific treatment of migraine

1- Triptans:

This class of drugs includes:

sumatriptan ,

naratriptan ,

rizatriptan,

eletriptan ,

almotriptan ,

frovatriptan

zolmitriptan

• The triptans are serotonin agonists( type of receptor ?? ), acting at serotonin receptors found on peripheral nerves that innervate the intracranial vasculature.

• Triptans causes less nausea than dihydroergotamine .

• Adverse effects are elevation of blood pressure. Therefore, triptans should not be used in coronary artery disease .

2- Dihydroergotamine:

Dihydroergotamine , a derivative of ergotamine, is administered intravenously and has an efficacy similar to that of sumatriptan, but nausea is a common adverse effect.