5-HT, 5-HT ANTAGONISTSDRUG THERAPY OF MIGRAINE

Dr. Anil Kumar Saxena

5-Hydoxytryptamine (5-HT, Serotonin)

About 90% of the body’s content of 5-HT is localized in the intestines; most of the rest is in platelets & brain.

It is also found in wasp & scorpion sting & widely distributed in invertebrates & plants (banana, pear, pineapple, tomato).

SYNTHESIS, STORAGE & RELEASE

5-HT is synthesized from the amino acid tryptophan by the enzyme tryptophan hydroxylase which converts tryptophan to 5-hydroxytryptophan.

Aromatic L-amino acid decarboxylase then converts 5-hydroxytryptophan to 5-HT.

Both these enzymes are present in the cytoplasm of serotonergic neurons.

5-HT is concentrated & stored within vesicles located in axons, cell bodies, & dendrites.

5-HT is degraded mainly by MAO & to a small extent by a dehydrogenase.

There is a close parallelism between CAs & 5-HT.

The decarboxylase is non-specific, acts on DOPA as well as 5-HTP to produce NA & 5-HT.

Like NA, 5-HT is actively taken up by an amine pump at serotonergic nerve endings & platelets (therefore 5-HT does not circulate in free form in plasma) & is inhibited by tricyclic antidepressants.

Platelets do not synthesize but acquire 5-HT by uptake during passage through intestinal blood vessels.

Again like CAs, 5-HT is stored within storage granules & its uptake at the granular membrane is inhibited by reserpine – causes depletion of CAs as well as 5-HT.

The degrading enzyme MOA is also common for both.

SEROTONIN NEUROTRANSMISIION

5-HT RECEPTORS

Four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4-7) comprising of 14 receptor subtypes have so far being recognized.

However, only some of these have been functionally correlated or their agonists / antagonists are known.

All 5-HT receptors (except 5-HT3) are G protein-coupled receptors which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7) cAMP production or by generating IP3 / DAG (5-HT2) as second messengers.

5-HT3 is a ligand gated cation (Na+, K+) channel which on activation elicits fast depolarization.

ACTIONS OF 5-HT

1.CVS

Arteries are constricted as well as dilated depending on the vascular bed & basal tone.

Larger arteries & veins are constricted, arterioles dilated & venules constricted.

Capillary pressure rises & fluid escapes. The direct action to increase capillary permeability is feeble.

5-HT is not involved in physiological regulation of BP.

2. Smooth muscles

•5-HT is a potent stimulator of GIT. Peristalsis is increased & diarrhea may occur.

•It constricts bronchioles, but less potent than histamine.

•Action on other smooth muscles in man are feeble & inconsistent.

3. Glands

•5-HT inhibits gastric secretion of acid & pepsin, but increases mucus production. It thus has ulcer protective property.

•Effect on other glandular secretions is not significant.

4. Nerve endings & adrenal medulla

•Tingling & pricking sensation, pain due to afferent nerve endings activation.

•Nausea & vomiting.

•Less potent than histamine in releasing CAs from adrenal medulla.

5. Respiration

•A brief stimulation of respiration & hyperventilation are the usual response, but large doses can cause transient apnea.

6. Platelets

•5-HT causes changes in shape of platelets.

•It is a weak platelet aggregator through 5-HT2A receptors.

7. CNS

•No central effects on 5-HT i.v. inj. as it poorly crosses BBB.

•However, it serves as an inhibitory neurotransmitter.

•Direct inj in brain produces sleepiness, changes in body temperature, appetite & a variety of behavioural effects.

PATHOPHYSIOLOGICAL ROLES OF 5-HT

1.Neurotransmitter

•5-HT is a confirmed neurotransmitter in the brain.

•Cells containing 5-HT are present in the raphe nuclei of brainstem, substantia nigra, & few other sites – send axons rostrally to limbic system, cortex, neostriatum & caudally to spinal cord.

•5-HT is probably involved in sleep, temperature regulation, thought, cognitive function, behaviour & mood (imbalance may result in affective disorders & schizophrenia), vomiting & pain perception.

2. Precursor of melatonin In pineal gland

•It is believed to regulate biological clock & maintain circadian rhythm.

3. Neuroendocrine function

•The hypothalamic neurons that control release of anterior pituitary hormones are probably regulated by serotonergic mechanism.

4. Nausea & vomiting

•Specially that evoked by cytotoxic drugs or radiotherapy is mediated by release of 5-HT & its action on 5-HT3 receptors in the gut, area postrema & nucleus tractus solitarious.

5. Migraine

•5-HT initiates the vasoconstrictor phase of migraine & participates in neurogenic inflammation of the affected blood vessels.

•Methysergide (5-HT antagonist) is an effective prophylactic & sumatriptan (5-HT1B/1D agonist) can control an attack of migraine.

6. Hemostasis

•5-HT increases platelet aggregation & clot formation.

7. Intestinal motility

• Enterochromaffin cells & 5-HT containing neurons may regulate peristalsis & local reflexes in the gut.

8. Carcinoid syndrome

• The carcinoid tumors produce massive quantities of 5-HT.

• Bowel hypermotility & bronchoconstriction in carcinoid is due to 5-HT, but flushing & hypotension are probably due to other mediators.

5-HT agonists

5-HT has no clinical application as a drug.

Buspirone

•5-HT 1A agonist.

•Effective non-benzodiazepine anxiolytic.

Dexfenfluramine

•Another selective 5-HT agonist.

•Was widely used as an appetite suppressant.

Sumatriptan & its congeners are agonists effective in the treatment of acute migraine headache attacks.

5-HT ANTAGONISTS

Many different types of drugs can block some actions of 5-HT, eg, ergot derivatives (ergotamine, LSD, methysergide), adrenergic α-blockers (phenoxybenzamine), chlorpromazine, morphine etc.

Some 5-HT antagonists are:

Cyproheptadine: 5-HT2A blocker + H1 antihistaminic, anticholinergic with sedative properties. Used in allergies & has good antipruritic action. Increases appetite & has been recommended in children & poor eaters to promote weight gain.

Methysergide:

5-HT2A/2C antagonist.

Used for migraine prophylaxis, carcinoid & postgastrectomy dumping syndrome.

Ketanserin:

Selective 5-HT2 receptor antagonist.

Effective antihypertensive.

Clozapine:

5-HT 2A/2C blocker + weak dopaminergic antagonist.

It is atypical antipsychotic & used for resistant cases of schizophrenia.

Risperidone:

Recently developed atypical antipsychotic is a combination of 5-HT2A + dopamine D2 antagonist.

Ondansetron:

New selective 5-HT3 antagonist effective in controlling nausea & vomiting following anticancer drugs & radiotherapy.

DRUG THERAPY OF MIGRAINE

Migraine is a mysterious disorder characterized by pulsating headache, usually restricted to one side, which comes in attacks lasting 4-48 hours & is often associated with nausea, vomiting, sensitivity to light & sound, vertigo, loose motions & other symptoms.

Pathophysiology is not well understood.

Drug therapy is individualized : severity & frequency of attacks & response of individual patients to various drugs determine the choice.

Sumatriptan

5-HT1D/1B agonists (Triptans like Sumatriptan, Almotriptan,

Flovatriptan, Naratriptan, Zolmitriptan etc) are used almost exclusively in acute migraine headache.

These receptors are found in cerebral & meningeal vessels & mediate vasoconstriction.

The mechanisms of action of drugs used in migraine are poorly understood, in part because they include such a wide variety of drug groups & actions.

Drugs for acute attack of migraine

Ergot alkaloids: Ergotamine, dihydroergotamine, methysergide, Bromocryptine, LSD, etc

They are highly specific for migraine pain.

They are not analgesic for any other condition.

Although triptan drugs are preferred, traditional therapy with ergotamine can also be quite effective for acute attack of migraine.

It becomes progressively less effective if treatment is delayed.

It is often combined with caffeine (100 mg caffeine for 1 mg ergotamine) to facilitate absorption of ergot alkaloid.

Prophylaxis of Migraine

A.Propranolol

B.Amitriptyline

C.Calcium channel blockers: Flunarizine, Verapamil