5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine

 Chapter -12 

5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine

5-HYDROXYTRYPTAMINE

(5-HT, Serotonin)

• Serotonin was the name given to the vasoconstrictor substance which appeared in the serum when blood clotted and Enter amine to the smooth muscle contracting substance present in enterochromaffin cells of gut mucosa. In the 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 is in 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).

SYNTHESIS, STORAGE AND DESTRUCTION

• 5-HT is β-aminoethyl-5-hydroxyindole. It is synthesized from the amino acid tryptophan and degraded primarily by MAO and to a small extent by a dehydrogenase

• There is close parallelism between CAs and 5-HT. The decarboxylase is non-specific, acts on DOPA as well as 5-hydroxytryptophan (5-HTP) to produce NA and 5-HT respectively. Like NA, 5-HT is actively taken up by an amine pump serotonin transporter (SERT), a Na+ dependent carrier, which operates at the membrane of platelets (therefore, 5-HT does not circulate in free form in plasma) and serotonergic nerve endings. This is inhibited by selective serotonin reuptake inhibitors (SSRIs) and 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 vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2) is inhibited by reserpine, which causes depletion of CAs as well as 5-HT. The degrading enzyme MAO is also common for both. The isoenzyme MAO-A preferentially metabolizes 5-HT.

SEROTONERGIC (5-HT) RECEPTORS

• Gaddum and Picarelli (1957) classified 5-HT receptors into Musculo tropic (D type) and neurotropic (M type) on the basis of pharmacological criteria. The classical 5-HT antagonists methergine and cyproheptadine blocked D type receptors. Subsequently 5-HT receptors were differentiated by their high or low affinity for [3 H] 5-HT in radioligand binding studies. The present system of classifying 5-HT receptors is based on molecular characterization and cloning of the receptor cDNAs.

• Four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5-HT4-7) comprising of 14 receptor subtypes have so far been recognized. However, only some of these have been functionally correlated or their selective agonists/antagonists defined. Knowledge of subtypes of 5-HT receptors has assumed importance because some newly developed therapeutically useful drugs can only be described as 5-HT receptor subtype selective agonists or antagonists.

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

• 5-HT1 Receptors Five subtypes (5-HT1A, B, D, E, F) have been identified. The 5-HT1C receptor is now designated 5HT2c. All subtypes of 5-HT1 receptor inhibit adenylyl cyclase; 5-HT1A in addition activates K+ channels (resulting in hyperpolarization) and inhibits Ca2+ channels. These receptors function primarily as auto receptors in brain— inhibit firing of 5-HT neurons or release of 5-HT from nerve endings.

• The most important location of 5-HT1A receptor are raphe nuclei of brainstem and hippocampus. The antianxiety drug buspirone acts as a partial agonist of 5-HT1A receptor. The 5-HT1D receptor has been shown to regulate dopaminergic tone in substantia nigra–basal ganglia, and 5-HT1B/1D to cause constriction of cranial blood vessels. The antimigraine drug sumatriptan is a selective 5-HT1B/1D agonist. Other functions subserved by 5-HT1D receptors are inhibition of NA release from sympathetic nerve endings and that of inflammatory neuropeptides from nerve endings in cranial blood vessels.

• 5-HT2 Receptors There are 3 subtypes of 5-HT2 receptor; all are coupled to phospholipase C and function through generation of IP3/DAG. 5-HT2A receptor also inhibits K+ channels resulting is slow depolarization of neurons. α-methyl 5-HT is a selective agonist for all 3 subtypes.

• 5-HT2A is the most widely expressed postjunctional 5-HT receptor (designated earlier as D type) located on vascular and visceral smooth muscle, platelets and cerebral neurons especially prefrontal cortex. It mediates most of the direct actions of 5-HT like vasoconstriction, intestinal, uterine and bronchial contraction, platelet aggregation and activation of cerebral neurons. Ketan Serin is a 5-HT2 antagonist more selective for 5-HT2A.

• Contraction of rat gastric fundus is mediated by 5-HT2B receptor.

• 5-HT2C receptor is located on vascular endothelium— elicits vasodilatation through EDRF release. Choroid plexus expresses large number of 5-HT2C receptors.

• 5-HT3 Receptor This is the neuronal 5-HT receptor which rapidly depolarizes nerve endings by opening the cation channel located within it and corresponds to the original M type receptor. It mediates the indirect and reflex effects of 5-HT at:

• Somatic and autonomic nerve endings → pain, itch, coronary chemoreflex (bradycardia, fall in BP due to withdrawal of sympathetic tone, respiratory stimulation or apnea elicited by stimulation of receptors in the coronary bed), other visceral reflexes

• Nerve endings in myenteric plexus → augmentation of peristalsis, emetic reflex.

• Area postrema and nucleus tractus solitaries in brainstem → nausea, vomiting    

• Ondansetron is a selective 5-HT3 antagonist which inhibits vomiting by blocking these receptors in brainstem as well as in gut wall. 2-Methyl 5-HT is a selective 5-HT3 agonist.

• 5-HT4–7 Receptors The 5-HT4 receptor has been demonstrated in the mucosa, plexuses and smooth muscle of the gut → probably involved in augmenting intestinal secretion and peristalsis. It is also located in brain, especially hippocampus and the colliculi where it causes slow depolarization by decreasing K+ conductance.

• Tiapride and renzapride are selective 5-HT4 agonists. The recently cloned 5-HT5, 5-HT6 and 5-HT7 receptors are closely related to the 5-HT4 receptor. These are mainly located in specific brain areas, but their functional role is not known. An interesting finding is that clozapine (atypical neuroleptic) has high affinity for 5-HT6 and 5-HT7 receptors in addition to being a 5-HT2A/2C antagonist.

ACTIONS

• 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. The overall effects therefore are often variable.

• CVS Arteries are constricted (by action on smooth muscle) as well as dilated (through EDRF release) by direct action of 5-HT, depending on the vascular bed and the basal tone. In addition, 5-HT releases Ard from adrenal medulla, affects ganglionic transmission and evokes cardiovascular reflexes. The net effect is complex. Larger arteries and veins are characteristically constricted. In the microcirculation 5-HT dilates arterioles and constricts venules: capillary pressure rises and fluid escapes. The direct action to increase capillary permeability is feeble.  

• Isolated heart is stimulated by 5-HT: both directly and by release of NA from nerve endings. In intact animals, bradycardia is mostly seen due to activation of coronary chemoreflex (Bezold Jarisch reflex) through action on vagal afferent nerve endings in the coronary bed, evoking bradycardia, hypotension and apnea. BP: a triphasic response is classically seen on i.e., injection of 5-HT in animals.

1. Early sharp fall in BP—due to coronary chemoreflex.
2. Brief rise in BP—due to vasoconstriction and increased cardiac output.
3. Prolonged fall in BP—due to arteriolar
4. dilatation and extravasation of fluid. However, 5-HT is not involved in the physiological regulation of BP

• Smooth muscles 5-HT is a potent stimulator of g.i.t., both by direct action as well as through enteric plexuses. Several subtypes of 5-HT receptors are present in the gut (See box). Peristalsis is increased and diarrhea can occur (also due to increased secretion). It constricts bronchi but is less potent than histamine. Action on other smooth muscles in man are feeble and inconsistent.

• Glands5-HT inhibits gastric secretion (both acid and pepsin) but increases mucus production. It thus has ulcer protective property. Effect on other glandular secretions is not significant.

• Nerve endings and adrenal medullaAfferent nerve endings are activated—tingling and prickling sensation, pain. Depolarization of visceral afferents elicits respiratory and cardiovascular reflexes, nausea and vomiting. 5-HT is less potent than histamine in releasing CAs from adrenal medulla

• Respiration A brief stimulation of respiration (mostly reflex from bronchial afferents) and hyperventilation are the usual response, but large doses can cause transient apnea through coronary chemoreflex.

• Platelets 5-HT causes changes in shape of platelets and is a weak aggregator through 5- HT2A receptors. However, it does not induce the release reaction. 

• CNS Injected i.e., 5-HT does not produce central effects because it poorly crosses blood brain barrier. However, it serves as a transmitter, primarily inhibitory. Direct injection in the brain produces sleepiness, changes in body temperature, hunger and a variety of behavior

PATHOPHYSIOLOGICAL ROLES

• Neurotransmitter5-HT is a confirmed neurotransmitter in the brain; brain 5-HT has a fast turnover rate. Cells containing 5-HT are present in the raphe nuclei of brainstem, substantia nigra and few other sites—send axons rostrally (to limbic system, cortex and neostriatum) as well as caudally to spinal cord. 5-HT is probably involved in sleep, temperature regulation, thought, cognitive function, behavior and mood (imbalance may result in affective disorders and schizophrenia), vomiting and pain perception. Some serotonergic fibers are present in intestines also.

• Precursor of melatonin in pineal gland. It is believed to regulate biological clock and maintain circadian rhythm.

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

• Nausea and vomitingEspecially that evoked by cytotoxic drugs or radiotherapy is mediated by release of 5-HT and its action on 5-HT3 receptors in the gut, area postrema and nucleus tractus Solitario us

• Migraine5-HT is said to initiate the vasoconstrictor phase of migraine and to participate in neurogenic inflammation of the affected blood vessels. Methergine (5-HT antagonist) is an effective prophylactic and sumatriptan (5-HT1B/1D agonist) can control an attack. However, the role of 5-HT in this condition is not precisely known

• Haemostasias Platelets release 5-HT during aggregation at the site of injury to blood vessel. Acting in concert with collagen and other mediators, this 5-HT accelerates platelet aggregation and clot formation. Thus, it serves to amplify the response. Its contractile action appears to promote retraction of the injured vessel. Both the above actions contribute to haemostasias.

• Raynaud’s phenomenon Release of 5-HT from platelets may trigger acute vasospastic episodes of larger arteries. Ketan Serin has prophylactic value in Raynaud’s

• Variant angina Along with thromboxane A2, 5-HT released from platelets has been implicated in causing coronary spasm and variant angina. However, the inefficacy of anti 5-HT drugs in this condition points to involvement of other mediators.

• Hypertension Increased responsiveness to 5-HT as well as its reduced uptake and clearance by platelets has been demonstrated in hypertensive patients. Ketan Serin has antihypertensive property. 5-HT has been held responsible for preeclamptic rise in BP

• Intestinal motility Enterochromaffin cells and 5-HT containing neurons may regulate peristalsis and local reflexes in the gut. This system appears to be activated by intestinal distension and vagal efferent activity

• Carcinoid syndrome The carcinoid tumor's produce massive quantities of 5-HT. Bowel hypermotility and bronchoconstriction in carcinoid is due to 5-HT but flushing and hypotension are probably due to other mediators. Pellagra may occur due to diversion of tryptophan for synthesizing 5-HT.

DRUGS AFFECTING 5-HT SYSTEM

• 5-HT precursor Tryptophan increases brain 5-HT and produces behavioral effects because tryptophan hydroxylase in brain is not saturated by the amount of tryptophan available physiologically.

• Synthesis inhibitor p-Chlorophenyl alanine (PCPA) selectively inhibits tryptophan hydroxylase (rate limiting step) and reduces 5-HT level in tissues. It is not used clinically due to high toxicity.

• Uptake inhibitor Tricyclic antidepressants inhibit 5-HT uptake along with that of NA. Some like fluoxetine, sertraline are selective serotonin reuptake inhibitors (SSRI).

• Storage inhibitor Reserpine blocks 5-HT (as well as NA) uptake into storage granules and causes depletion of all monoamines. Fenfluramine selectively releases 5-HT and has anorectic property.

• Degradation inhibitor Nonselective MAO inhibitor (tranylcypromine) and selective MAO-A inhibitor (cordyline) increase 5-HT content by preventing its degradation.

• Neuronal degeneration 5, 6 dihydroxytryptamine selectively destroys 5-HT neurons.

• 5-HT receptor agonists A diverse range of compounds producing a variety of actions have been found to activate one or more subtypes of 5-HT receptors. Notable among these are:

1. (D-Lysergic acid diethyl amide (LSD)—Synthesized as an ergot derivative LSD was found to be an extremely potent hallucinogen. It is a nonselective 5-HT agonist— activates many subtypes of 5-HT receptors including 5-HT1A on raphe cell bodies, 5-HT2A/2C (probably responsible for the hallucinogenic effect) and 5-HT5-7 in specific brain areas. However, it antagonizes 5-HT2A receptors in the ileum. A number of other hallucinogens also interact with brain 5-HT receptors.
2. Azapirones like buspirone, peperone and Ipsa Pirone are a new class of antianxiety drugs which do not produce sedation. They act as partial agonists of 5-HT1A receptors in the brain.
3. 8-Hydroxydipropylamino tetralone (8-OH DPAT) is a highly selective 5-HT1A agonist which is used only as an experimental tool.
4. Sumatriptan and other triptans are selective 5-HT1B/1D agonists, constrict cerebral blood vessels and have emerged as the most effective treatment of acute migraine attacks.
5. Tiapride This prokinetic drug which increases gastrointestinal motility is a selective 5-HT4 agonist. Renzapride is still more selective for 5-HT4 receptors.
6. m-chlorophenyl piperazine (MCPc) It is an active metabolite of the antidepressant drug trazodone; found to be an agonist of 5-HT1B as well as 5-HT2A/2C receptors in the brain. In human volunteers it induces anxiety and enhances release of prolactin, ACTH, and growth hormone.

• 5-HT receptor antagonists A variety of drugs block serotonergic receptors; many are nonselective, but some newer ones are highly subtype selective.

5-HT ANTAGONISTS

• The ability to antagonize at least some actions of 5-HT is found in many classes of drugs, e.g., ergot derivatives (ergotamine, LSD, 2-bromo LSD, methergine), adrenergic α blockers (phenoxybenzamine), antihistaminic (cyproheptadine, cinnarizine), chlorpromazine, morphine, etc., but these are nonselective and interact with several other receptors as well. Many are partial agonists or antagonize certain actions of 5-HT but mimic others. The salient features of drugs which have been used clinically as 5-HT antagonists and some newly developed selective antagonists are described below:

• The anti 5-HT activity of cyproheptadine has been utilized in controlling intestinal manifestations of carcinoid and post gastrectomy dumping syndromes as well as in antagonizing priapism/orgasmic delay caused by 5-HT uptake inhibitors like fluoxetine and trazodone.

• Side effects drowsiness, dry mouth, confusion, ataxia, weight gain.

• Methergine It is chemically related to ergot alkaloids; antagonizes action of 5-HT on smooth muscles including that of blood vessels, without producing other ergot like effects: does not interact with α adrenergic or dopamine receptors. Methergine is a potent 5-HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective—acts on 5-HT1 receptors also. It has been used for migraine prophylaxis, carcinoid and post gastrectomy dumping syndrome. Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of which it has gone into disrepute.

•  Ketan Serin It has selective 5-HT2 receptor blocking property with negligible action on 5-HT1, 5-HT3 and 5 HT4 receptors and no partial agonistic activity. Among 5-HT2 receptors, blockade of 5-HT2A is stronger than 5-HT2C blockade. 5-HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle are antagonized but not contraction of guinea pig ileum or rat stomach. It has additional weak α1, H1 and dopaminergic blocking activities.

• Ketan Serin is an effective antihypertensive, but α1 adrenergic blockade appears to be causative rather than 5-HT2A blockade.

• Trials of Ketan Serin in vasospastic conditions have shown symptomatic improvement only in Raynaud’s disease.

• Retendering is a relatively more 5-HT2A selective congener of Ketan Serin.

• Clozapine In addition to being a dopaminergic antagonist (weaker than the typical neuroleptics), this atypical antipsychotic is a 5-HT2A/2C blocker (see Ch. 32). Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia.

• Risperidone This atypical antipsychotic is a combined 5-HT2A + dopamine D2 antagonist, similar to clozapine. Like the latter, it especially ameliorates negative symptoms of schizophrenia, but produces extrapyramidal side effects at only slightly higher doses.

• Other atypical antipsychotics like olanzapine and quetiapine are also combined 5-HT and DA antagonists but interact with other neurotransmitter receptors as well.

• Ondansetron It is the prototype of the new class of selective 5-HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy. It is described in Ch. 47.

• Granstrom and Proposition are the other selective 5-HT3 antagonists.

ERGOT ALKALOIDS

• Ergot is a fungus Claviceps purpurea which grows on rye, millet and some other grains. The grain is replaced by a purple, hard, curved body called ‘sclerotium’. Epidemics of ergot poisoning (ergotism), due to consumption of contaminated grains, have been recorded from the beginning of history. It still occurs in epidemic and sporadic forms. Dry gangrene of hands and feet which become black (as if burnt) is the most prominent feature. Miscarriages occur in women and cattle. A convulsive type is also described.

• Ergot had been used by midwives to quicken lab our since the Middle Ages. This use received medical sanction in the 19th century, but its dangers were recognized by the beginning of the present century and then it was advocated only after delivery. Dale and Barger (1906 onwards) isolated the ergot alkaloids and studied their pharmacology. Ergometrine was isolated in 1935

• Ergot contains a host of pharmacologically active substances—alkaloids, LSD, histamine, Ach, tyramine and other amines, sterols, etc.

• Natural ergot alkaloids These are tetracyclic indole containing compounds which may be considered as derivatives of lysergic acid. They are divided into—

1. (a) Amine alkaloid Ergometrine (Ergonovine): which is oxytocic 
2. (b) Amino acid alkaloids Ergotamine, Ergotoxine (mixture of ergocriptine + ergocornine + ergocryptine): they are vasoconstrictor and α adrenergic blocker

Other semisynthetic derivatives

1. Dihydroergotamine (DHE), Dihydroergotamine (Categorize): are antiadrenergic, corroborative. 
2. 2-Bromo-α-ergocryptine (Bromocriptine): is a dopaminergic agonist (see Ch. 17). 
3. Methergine: it is mainly anti 5-HT.

• Synthetic non-lysergic acid derivatives which pharmacologically resemble ergot alkaloids are — Leisured, Pergolide, Lergotrile and Metergoline.

• The ergot alkaloid related compounds have diverse pharmacological properties. They act as agonists, partial agonists and antagonists on certain subtypes of α adrenergic, serotonergic and dopaminergic receptors in a tissue specific manner.

Actions

• Ergotamine It acts as a partial agonist and antagonist at α adrenergic and all subtypes of 5-HT1 and 5-HT2 receptors but does not interact with 5-HT3 or dopamine receptors: produces sustained vasoconstriction, visceral smooth muscle contraction, vasomotor center depression and antagonizes the action of NA and 5-HT on smooth muscles. The overall effect of oral/rectal doses of ergotamine on BP is insignificant. It is a potent emetic (through CTZ) and moderately potent oxytocic. At high doses CNS stimulation and paresthesia's may be experienced. On chronic exposure (ergot poisoning) vasoconstriction is accompanied by damage to capillary endothelium—thrombosis, vascular stasis and gangrene

• Dihydroergotamine (DHE) Hydrogenation of ergotamine reduces serotonergic and α-adrenergic agonistic actions but enhances α-receptor blocking property. Consequently, DHE is a less potent vasoconstrictor; primarily constricts capacitance vessels and causes less intimal damage. It is a weaker emetic and oxytocic but has some antidopaminergic action as well.

• Dihydroergotamine (Categorize) This hydrogenated mixture of ergotoxine group of alkaloids is a more potent α blocker and a very weak vasoconstrictor. In the brain, a variety of partial agonistic/ antagonistic actions on 5-HT receptors, metabolic and vascular effects and enhancement of Ach release in cerebral cortex have been demonstrated. It has been advocated for treatment of dementia (see Ch. 35).

• Bromocriptine The 2 bromo derivative of ergocryptine is a relatively selective dopamine D2 agonist on pituitary lactotrophs (inhibits prolactin release), in striatum (antiparkinsonian) and in CTZ (emetic—but less than ergotamine). In certain brain areas weak antidopaminergic action has also been shown. It has very weak anti 5-HT or α blocking actions and is not an oxytocic.

• Ergometrine (Ergonovine) This amine ergot alkaloid has very weak agonistic and practically no antagonistic action on α adrenergic receptors: vasoconstriction is not significant. Partial agonistic action on 5-HT receptors has been demonstrated in uterus, placental and umbilical blood vessels and in certain brain areas. It is a moderately potent 5-HT2 antagonist in gig smooth muscle and a weak dopaminergic agonist on the pituitary lactotrophs as well as CTZ; emetic potential is low. The most prominent action is contraction of myometrium; used exclusively in obstetrics (see Ch. 23).

• Pharmacokinetics Oral bioavailability of amino acid ergot alkaloids and their hydrogenated derivatives is poor (< 1%) due to slow and incomplete absorption as well as high FirstPass metabolism. Bioavailability is better after sublingual and rectal administration, but still often erratic. They are metabolized in liver and excreted primarily in bile. Ergotamine is sequestrated in tissues—produces longer lasting actions compared to its plasma t½ of 2 hours. Ergot alkaloids effectively cross blood-brain barrier.

• Adverse effects Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesia's, coronary and other vascular spasm, chest pain are the frequent side effects. These drugs are contraindicated in presence of sepsis, ischemic heart disease, peripheral vascular disease, hypertension, pregnancy, liver and kidney disease.

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 and is often associated with nausea, vomiting, sensitivity to light and sound, flashes of light, vertigo, loose motions and other symptoms. Two major types are—migraine with aura (classical migraine) in which headache is preceded by visual or other neurological symptoms, and migraine without aura (common migraine). Pulsatile dilatation of certain large cranial vessels is the immediate cause of pain. The pathogenic mechanisms are not well understood. The Vascular theory holds that initial vasoconstriction or shunting of blood through carotid arterio-venous anastomoses produces cerebral ischemia and starts the attack. The Neurogenic theory considers it to be a spreading depression of cortical electrical activity followed by vascular phenomena. Some triggering event appears to produce neurogenic inflammation of the affected blood vessel wall which is amplified by retrograde transmission in the afferent nerves and release of mediators like 5-HT, neurokinin, substance P, calcitonin gene related peptide (CGRP), nitric oxide, etc.

• Changes in blood/urinary levels of 5-HT and its metabolites during migraine attack, its precipitation by 5-HT releasers and efficacy of drugs having actions in the serotonergic system to prevent/abort/terminate migraine attacks suggest a pivotal role of 5-HT in this disorder.

• Drug therapy of migraine has to be individualized: severity and frequency of attacks and response of individual patients to drugs used earlier determine the choice. The strategy mostly adopted is summarized in the box.

• Mild migraine Cases having fewer than one attack per month of throbbing but tolerable headache lasting up to 8 hours which does not incapacitate the individual may be classified as mild migraine.

1. Simple analgesics like paracetamol (0.5– 1 g) or aspirin (300–600 mg) taken at the first indication of an attack and repeated 4–6 hourly abort and suppress most mild attacks
2. Nonsteroidal anti-inflammatory drugs (NSAIDs) and their combinations Drugs like ibuprofen (400–800 mg 8 hourly), naproxen (500 mg followed by 250 mg 8 hourly), diclofenac (50 mg 8 hourly), mathematic acid (500 mg 8 hourly), indomethacin (50 mg 6–8 hourly) either alone or combined with paracetamol/codeine/diazepam or another sedative/diphenhydramine or another antihistaminic/caffeine are found more satisfactory by some patients. These drugs are more effective in migraine without aura, but certain patients of migraine with aura also prefer them over ergot alkaloids. Drugs are taken only till the attack passes off. Taken in the prodromal stage they also have a prophylactic effect, but long-term treatment on a regular schedule to ward off migraine attacks is not advised.
3. Antiemetics Gastric stasis occurs during migraine which delays absorption of oral drugs. Metoclopramide (10 mg oral/a.m.) is frequently used: relieves nausea, vomiting and gastric stasis. Domperidone (10–20 mg oral) and prochlorperazine (10–25 mg oral/a.m.) are also effective. Diphenhydramine or promethazine exert sedative as well as antiemetic action.

• Moderate migraine Migraine may be labelled as moderate when the throbbing headache is more intense, lasts for 6–24 hours, nausea/vomiting and other features are more prominent, and the patient is functionally impaired. One or more attacks occur per month.

• Simple analgesics are usually not effective, but stronger NSAIDs or their combinations mentioned above are beneficial in many cases. The remaining are treated with an ergot preparation or sumatriptan. Antiemetics are almost regularly needed. Prophylactic therapy is advised only when attacks are more frequent than 2–3 per month.

• Severe migraine These patients suffer 2–3 or more attacks per month of severe throbbing headache lasting 12–48 hours, often accompanied by vertigo, vomiting and other symptoms; the subject is grossly incapacitated during the attack.

• Analgesics/NSAIDs and their combinations usually do not afford adequate relief—specific drugs like ergot alkaloids/sumatriptan have to be prescribed along with antiemetics. Prophylactic regimens lasting 6 months or more are recommended.

• Ergotamine It is the most effective ergot alkaloid for migraine. Given early in attack, relief is often dramatic and lower doses suffice, but when pain has become severe—larger doses are needed, and control may be achieved only after few hours. Oral/sublingual route is preferred, 1 mg is given at half hour intervals till relief is obtained or a total of 6 mg is given. Parenteral administration, though rapid in action is more hazardous.

• Ergotamine acts by constricting the dilated cranial vessels and/or by specific constriction of carotid A-V shunt channels. Ergotamine and DHE have also been shown to reduce neurogenic inflammation and leakage of plasma in durometer that occurs due to retrograde stimulation of perivascular afferent nerves. These actions appear to be mediated through partial agonism at 5-HT1B/1D receptors in and around cranial vessels.

• Dihydroergotamine (DHE) It is nearly as effective as ergotamine and preferred for parenteral administration because injected DHE is less hazardous.

• Because of erratic oral absorption, frequent side effects, especially nausea and vomiting, and availability of triptans, ergot preparations are not preferred now, except for considerations of cost. Ergot alkaloids have no prophylactic value: regular use is not justified—may itself produce a dull background headache and an attack may be precipitated on discontinuation. Caffeine 100 mg taken with ergotamine enhances its absorption from oral and rectal routes and adds to the cranial vasoconstricting action. Many combination preparations are available.

SELECTIVE 5-HT1B/1D AGONISTS

• These are a new class of antimigraine drugs that selectively activate 5-HT1B/1D receptors and are called ‘triptans’. Currently, they are the preferred drugs for patients who fail to respond to analgesics. Ergot alkaloids are now required only in few cases. Because these drugs have been designed to act on the same subtype of 5-HT receptor, pharmacodynamic differences among them are minor, but there are significant pharmacokinetic differences. All have higher oral bioavailability than sumatriptan. Fewer headache recurrences in an attack are reported with naratriptan and rizatriptan due to their longer t½ but may be slower in affording initial pain relief.

• Sumatriptan It is the first selective 5-HT1B/1D receptor agonist; activates other subtypes of 5- HT1 receptors only at very high concentrations, and does not interact with 5-HT2, 5-HT3, 5-HT4-7, α or β adrenergic, dopaminergic, cholinergic or GABA receptors. Administered at the onset of an attack of migraine, sumatriptan is as effective and better tolerated than ergotamine. About 3/4 patients obtain complete/significant relief within 2–3 hours. However, recurrence of headache within 24 hr. has been noted in 20–40% patients, probably due to short t½ of sumatriptan. It tends to suppress nausea and vomiting of migraine, while ergotamine accentuates these symptoms.

• The antimigraine activity of sumatriptan has been ascribed to 5-HT1B/1D receptor mediated constriction of dilated cranial extracerebral blood vessels, especially the arterio-venous shunts in the carotid artery, which express 5-HT1B/1D receptors. Dilatation of these shunt vessels during migraine attack is believed to divert blood flow away from brain parenchyma. In addition, it can reduce 5-HT and inflammatory neuropeptide release around the affected vessels as well as extravasation of plasma proteins across Dural vessels. Like ergotamine, the triptans have been found to suppress neurogenic inflammation of cranial vessels. Suppression of impulse transmission in the trigeminovascular system has also been implicated.    

• Pharmacokinetics: Sumatriptan is absorbed rapidly and completely after sic injection. Oral bioavailability averages 15%. It is rapidly metabolized by MAO-A isoenzyme and metabolites are excreted in urine; elimination t½ is ~2 hours.

• Side effects: to sumatriptan are usually mild. Tightness in head and chest, feeling of heat and other paresthesia in limbs, dizziness, weakness is short lasting, but dose related side effects.

• These are more common after sic injection, which is painful. Slight rise in BP occurs, but has little clinical relevance, because sumatriptan is not a drug for regular use. Bradycardia, coronary vasospasm and risk of myocardial infarction are the serious, but infrequent adverse effects. Few cases of sudden death have been ascribed to sumatriptan. Seizures and hypersensitivity reactions are rare.

• Contraindications: are in patients with ischemic heart disease, hypertension, epilepsy, hepatic or renal impairment and during pregnancy. Patients should be cautioned not to drive.

• Sumatriptan and ergotamine should not be administered within 24 hours of each other. Interaction with 5-HT uptake inhibitors, MAO inhibitors and lithium has been reported.

• Rizatriptan: This congener of sumatriptan is more potent, has higher oral bioavailability with slightly faster onset of action.

 Prophylaxis of migraine

• Regular medication to reduce the frequency and/or severity of attacks is recommended for moderate-to-severe migraine when 2–3 or more attacks occur per month. Diverse classes of drugs are used but none is effective in all cases, and none abolishes the attacks totally. It may be prudent to discontinue prophylaxis every 6 months to check whether its continuation is needed or not. It is important to avoid the precipitating factor(s).

• β-Adrenergic blockers Propranolol is the most commonly used drug reduces frequency as well as severity of attacks in up to 70% patients. Effect is generally seen in 4 weeks and is sustained during prolonged therapy. The starting dose is 40 mg BD, which may be increased up to 160 mg BD if required. The mechanism of action is not clear; that it is due to β adrenergic blockade has been questioned. Other nonselective (timolol) and β1 selective (metoprolol, atenolol) agents are also effective, but pindolol and others having intrinsic sympathomimetic action are not useful.

• Tricyclic antidepressants Many tricyclic compounds of which amitriptyline has been most extensively tried (25–50 mg at bedtime) reduces migraine attacks. It is effective in many patients but produces more side effects than propranolol. It is not known whether its 5-HT (and other monoamine) uptake blocking property is causally related to the prophylactic effect. The antimigraine effect is independent of antidepressant property, but this class of drugs are better suited for patients who also suffer from depression.

• round to reduce migraine attacks but was judged inferior to propranolol. Flunarizine is a relatively weak Ca2+ channel blocker that also inhibits Na+ channels. It is claimed to be as effective as propranolol, but convincing proof is lacking. Frequency of attacks is often reduced, but effect on intensity and duration of attacks is less well documented. It is claimed to be a Cerebro-selective Ca2+ channel blocker; may benefit migraine by reducing intracellular Ca2+ overload due to brain hypoxia and other causes. Side effects are sedation, constipation, dry mouth, hypotension, flushing, weight gain and rarely extrapyramidal symptoms.

• Anticonvulsants Valproic acid (400–1200 mg/day) and gabapentin (300–1200 mg/day) have some prophylactic effect in migraine. The newer drug topiramate has recently been approved for migraine prophylaxis. A 50% reduction in the number of attacks in half of the patients was noted in 2 randomized trials. Start with 25 mg OD and gradually increase to 50 mg OD or BD. Efficacy of anticonvulsants in migraine is lower than that of β blockers. They are indicated in patient's refractory to other drugs or when propranolol is contraindicated.

• 5-HT antagonists the prophylactic effect of methergines and cyproheptadine is less impressive than β blockers. They are seldom used now for migraine.