AUTACOIDS (II)AUTACOIDS (II)5-Hydroxytryptamine5-Hydroxytryptamine

(5-HT) (5-HT)

SEROTONINSEROTONIN

• It is widely distributed in plants and animals. Highest concentration in mammals is found in the pineal gland, acting as a precursor for melatonin. It is synthesized from the amino acid tryptophan and acts on several types of receptors.

Sources:-

Platelets

Enterochromaffin cells (Intestines)

CNS:- Tryptaminergic Neurons

Physiological Functions

1. Neurotransmitter (CNS)

2. 5-HT released from platelets may account

for vasospasm that accompanies

certain diseases like Raynaud’s.

3. Regulation of intestinal activity.

4. Synthesis of Melatonin in Pineal body.

5-HT 5-HT EFFECTS ON BLOOD VESSELS AND EFFECTS ON BLOOD VESSELS AND

HAEMOSTASISHAEMOSTASIS

VASCULAR INJURY

Initial Platelet aggregation

Release of 5-HT

Heamostasis Vascular occlusion

5-HT15-HT2A

5-HT2A

Release of EDRF (Vasodilatation)Accelerated

Platelet Aggregation

VasoconstrictionThrombus

• 5-HT causes constriction of renal, splanchnic, meningeal, and pulmonary arteries and veins and venules, but dilatation of the blood vessels of skeletal musles, coronaries, and skin capillaries. It has weak direct ino-chronotropic effect on the myocardium. It also stimulates smooth muscles, especially of the intestines.

• Serotonin is widely distributed in the CNS, serving as a neurotransmitter. Altered functions may be responsible for disturbances in sleep, mood, sexual behavior, motor activity, pain perception, migraine, temperature regulation, endocrine control, psychiatric disorders and extra-pyramidal activity.

PHARMACOLOGICAL ACTIONS

I. CARDIOVASCULAR SYSTEM

1. Blood Pressure

i. Fall (Bezold Jarisch Reflex)

stimulation of sensory

receptors in heart.

ii. Pressor phase:- Due to

vasoconstriction (Peripheral

vessels) and release of

NE.

iii. Prolonged Fall, with in 1 to 2

minutes of I/V injection.

Dilatation of B.V. in skeletal

muscles.

FALL

FALL

RISE

2. Capillary Permeability:- Nil

3. Blood vessels and Hemostasis:- See Fig

4. Heart:- +ve Inotropic, +ve Chronotropic

II. SMOOTH MUSCLE

Bronchial and Intestinal smooth muscles

stimulated Bronchospasm and Increased

peristalsis

III. Sensory neurons

5-HT receptors located on sensory neurons

mediate a depolarizing response causing:-

pain, itching, respiratory stimulation,

Bezold Jarisch reflex.

CARCINOID TUMOURS

Tumours of Enterochromaffin cells in G.I.T.

produce large quantities of 5-HT Diarrhaea;

Bronchospasm; Edema; Vasodilatation &

Flushing; Release of Substance P; Formation of

Kinins.

Excessive utilization of Tryptophan

Tryptophan Deficiency PELLAGRA

I. 5-HT AGONISTSI. 5-HT AGONISTS

1. BUSPIRONE

Anxiolytic

2. TRIPTANS

i) Sumatriptan ii) Naratriptan

iii) Rizatriptan iv) Zolmitriptan

Treatment of Acute Migraine Headache

3. CISAPRIDE

Gastro Esophageal Reflux

Sumatriptan is a selective agonist of 5-HT1 receptors, highly effective in treating acute attacks of migraine. It relieves the nausea and vomiting, but the headache may recur, necessitating repeated administrations.

• Adverse effects include flushing and heat at the injection site, neck pain, dizziness, and tingling of the hands.

• The drug is contraindicated with symptomatic ischemic heart diseases, angina, and hypertension as it may cause coronary vasoconstriction.

II. 5-HT ANTAGONISTSII. 5-HT ANTAGONISTS

1. Ketanserin

Hypertension (1 blockade)

Vasospastic conditions

2. Methysergide (Sansert)

Prophylaxis of Migraine

3. CYPROHEPTADINE (Periactin); also

blocks H1

Stimulation of appetite; Smooth muscle

manifestations of carcinoid tumours.

Post-gastrectomy dumping syndrome; Cold

induced urticaria.

4. CLOZAPINE

Antipsychotic (Schizophrenia)

5. Risperidone (Blocks D2 also)

Schizophrenia

6. Ritanserin

Reduction of thromboxane formation

7. Ondansetron

Nausea and Vomiting associated with

cancer chemotherapy.

8. Granisetron

As above

9. Alosetron

Irritable bowel syndrome.

SELECTIVE SEROTONIN SELECTIVE SEROTONIN REUPTAKE INHIBITORSREUPTAKE INHIBITORS

CITALOPRAM

FLUOXETINE

FLUVOXAMINE

PAROXETINE

SERTRALINE

Very commonly used class of Antianxiety

and Antidepressant agents.

Like Tricyclic antidepressants, which

block NE uptake, the SSRIs block

neuronal transport of Serotonin.

Increased synaptic availability of Serotonin

stimulates a large number of Post-synaptic

5-HT receptor subtypes.

____________________________________

SIDE EFFECTSSIDE EFFECTS

•Nausea and VomitingNausea and Vomiting

•Risk of Agitation and RestlessnessRisk of Agitation and Restlessness

RELEASE

REUPTAKE

TRYPTAMINERGIC NEURON

Lysergic Acid Diethylamide (LSD)

Psychedelic

Fluoxetine

5-HT-retuptake Inhibitor

Antidepressant

Ondansetro

n

Antiemetic

Sumatripta

n

Antimigrain

e

Hallucinati

on5-

HT2A

5-

HT1D

5-HT3

QUESTIONS

1. A patient has been diagnosed with a rare metastatic carcinoid tumor. The neoplasm is releasing serotonin, bradykinin and several unknown peptides. The effects of serotonin in this patient are most likely to include which one of the following:

a) Constipation

b) Episodes of bronchospasm

c) Hypotension

d) Hypersecretion of gastric acid

e) Urinary retention

2. In recommending treatment for a patient suffering from metastatic carcinoid tumors the one least likely to be helpful is :

a) Cyproheptadine

b) Ketanserin

c) Phenoxybenzamine

d) Sumatriptan

e) Ondansetron

3. A patient undergoing cancer chemotherapy is vomiting frequently. A drug that might help in this situation is :

a) Bromocriptine

b) Cimetidine

c) Ketanserin

d) Loratidine

e) Ondansetron

4. Which of the following is a serotonin agonist useful for aborting an acute migraine headache and is not derived from a fungus :a) Bromocriptine

b) Cimetidine

c) Ergotamine

d) Ketanserin

e) Sumatriptan