Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

SEROTONIN AND DRUG THERAPY OF MIGRAINE

Serotonin or 5-hydroxytryptamine

• Serotonin is used throughout the body in multiple physiological roles.

• 90% of all serotonin in human body in the GI tract -enterochromaffin cells.

• 8% in blood platelets Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve terminals).

• 2% in CNS.• Neurons in brain make their own; does not cross

Blood Brain Barrier (BBB)• Cell storage in granules similar to catecholamines

N

C

N

C NH2

COOH COOH

NH2

OH

N

C NH2

OH H

Tryptophan 5-Hydroxytryptophan

5-Hydroxytryptamine

N

C COOH

5-OH Indole Acetaldehyde

5-Hydroxy Indole Acetic Acid- 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine

Tryptophan hydroxylase

5-OH Tryptophan decarboxylase

MAO

Aldehyde dehydrogenase

(Rate limiting)

In diet. ActiveCNS transport

Synthesis:

High serotonin levels within neuron do not inhibit enzyme synthesis-serotonin just builds upNo end-

product negative feedback Tryptophan hydroxylase (rate limiting step)

Rate of enzyme activity can be modulated by second messengers involving cAMP.Can be modulated by Oxygen levels in blood; more

oxygen, more synthesis of serotonin.

Serotonin Pathways in Brain

Pain perception Sleep/Wakefulness Central neurotransmitter 5HT synthesized by pineal glandPrecursor of

melatonin Various behaviors normal/abnormal: depression,

schizophrenia, obsessive compulsive behavior, etc. Neuroendocrine regulation – controls hypothalamic

cells involved in release of several anterior pituitary hormones.

Serotonin in the Central Nervous System

Endogenous Function

Central neurotransmitter 5HT synthesised by pineal glandPrecursor of

melatonin CVS- constriction of vascular smooth muscles Heart vasodilatation and bradycardiahypotnsn In carcinoid tumors: large amounts released leading

to diarrhea, broncho constriction and edema Platelets: 5-HT2 receptors → aggregation and

vasoconstriction Like histamine it can stimulate perception of pain

and itch

Serotonin ReceptorsReceptors Distribution Agonist Antagonist

5-HT1 +subtypes CNS & Cerebral Blood vessels

BUSPIRONE SUMATRIPTAN

SPIPIRONE ERGOTAMINE

5-HT2 + subtypes CNS, Smooth vessels, platelets

LSD(non-selective) KETANSERINMETHYSERGIDECLOZAPINECYPROHEPTADINE

5-HT3 CNS (area posterna), PNS, ENS

2-methyl- 5-HT ONDANSETRONGRANISETRON

5-HT4 CNS(Hippocampus)ENS

METACLOPRAMIDE, CISAPRIDE, MOSAPRIDETEGASEROD

GR-113808

Serotonin Receptors

At least 15 types and subtypesMultiple transduction mechanisms5HT-1A: role in anxiety/depression, affects mood and

behavior5HT-1D: role in migraine5HT-2: role in CNS various behaviors, and in

cardiovascular system5-HT3: role in nausea and vomiting esp. due to

Chemotherapy.5-HT4: GI tract: increase motility

Lysergic acid diethylamide (LSD)Objects appeared to gain in relief; they assumed unusual dimensions; and colours became more glowing. Even self-perception and the sense of time were changed. When the eyes were closed, there surged upon me an uninterrupted stream of fantastic images of extraordinary plasticity and vividness and accompanied by an intense, kaleidoscope-like play of colours.” (Albert Hofmann, discoverer of LSD, 1943)

5-HT receptor antagonists

KETANSERIN -5-HT2A-on platelets antagonizes aggregation

α-adrenergic blocking property effective antihypertensive drug

- can be used in Raynaud’s disease RITANSERIN-5-HT2A-antagonist it reduces thromboxane formation and increases

bleeding time presumably by inhibiting platelet aggregation

Receptor Overview

Serotonin syndrome

Excess synaptic serotonin causes serious, potentially fatal syndrome, diagnosed on the basis of history of taking serotonergic drugs

Drugs causing –SSRIs, second gen antidepressants, MOIs, linezolid, tramadol, meperidine, fentanyl,ondansetron, sumatriptan, LSD

Clinical features- hypertension, hyperreflexia, tremor, clonus, hyperthermia, diarrhoea, mydriasis

Treatment-Sedation-benzodiazepines Intubation and ventilation, HT2 block –

cyproheptadine, chlorpromazine

Migraine

Possible Triggers of a Migraine Attack

Food and food additives Bright lights/glare Smells/odors Dieting/hunger Loud noises/sounds Changes in altitude/

air travel

Stress Weather changes Caffeine Alcoholic beverages Changes in sleep habits Hormonal fluctuations/ menstrual cycle

Premonitory/

Prodrome

Aura

Mild Moderate to Severe

Postdrome

Time

Mig

rain

e I

nte

nsit

y

Phases of a Migraine Attack

Migraine symptoms occurring

hours/days prior

to headache

Migraine when

headache is mild

Migraine when headache is moderate to

severe

Migraine symptoms occurring

hours/days after

headache resolution

Focal neurological symptoms preceding headache (<1 hour)

Symptoms :• Food cravings• Mood changes• Yawning• Fatigue

Symptoms:• Tiredness• Confusion• Lowered appetite• Stiff or sore muscles

Symptoms:• Same as mild but

more intense

Symptoms:• Flashing lights or wavy lines• Numbness• Tingling in face• Disturbed senses

Symptoms:• Sensitivity to light• Sensitivity to sound• Nausea• Pain in the back of

the head and neck

Pre-HA Post-HA

Headache

Treatment Phase

Migraine Pathophysiology:

Vasomotor mechanism -- inferred from: increased temporal artery pulsation magnitude pain relief (by ergotamine) occurs with decreased

artery pulsations Migraine attack associated with (based on histological

studies): sterile neurogenic perivascular edema inflammation (clinically effective antimigraine

medication reduce perivascular inflammation)5-HT-urinary excretion of 5-HIAA5-HT antagonists effective in treatment

Migraine treatment

Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses ▪ Blocks trigeminal nerve transmission▪ combined with caffeine: better absorption ▪ potentially severe long-lasting Vasoconstriction.▪ poor oral bioavailabilityS/E-vomiting, uterine contractionsC/I- CAD, PVD

Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine

Migraine treatment

Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspirin, paracetamol, Naproxen, Diclofenac -inhibits prostaglandin and kinin release due to neurogenic

inflammation Used for migraine without aura S/E-GIT disturbances and bleeding

β-adrenoceptor blockers-Propranolol, Metoprolol, NadololUsed orally, very effectiveMost common for continuous prophylaxis, best established drug

for migraine attack prevention.S/E- bronchoconstriction, fatigue,C/I- asthmatics

Migraine treatment

Cyproheptadine –low efficacyFlunarizine- cerebroselective Ca+ channel blocker,

reduces intracellular ca+ overload due to hypoxia S/E-sedation, constipation, dry mouthClonidine –α2-adrenoceptor agonist, reduces cerebral blood flow given orallyTricyclic antidepressnts-5-HT blocking property

-orally at bed time S/E- dry mouth, blurred vision, constipation, urinary

retension, postural hypotension weight gain

Migraine treatment

Sumatriptan: 5HT1D-1B agonist, blocks trigeminal nerve transmission, constricts dilated extracranial blood vessels, suppresses inflammation▪ formulations: subcutaneous injection, oral, nasal

spray▪ Lesser oral dose, cross BBB▪ probably more effective than ergotamine for

management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray) ▪ not recommended for patients with coronary

vascular disease risk.

Migraine: Prophylaxis METHYSERGIDE▪ effective in about 60% of patients ▪ Not effective in treating an active migraine attack or even

preventing an impending attack. ▪ Methysergide toxicity: retroperitoneal fibroplasia,

subendocardial fibrosis. Recommend 3-4 week drug holiday every six months

PROPRANOLOL. AMITRIPTYLINE (TCA) ▪ most frequently used among the tricyclic

antidepressants VALPROIC ACID (ANTIEPILEPTIC) ▪ effective in decreasing migraine frequency.

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) ▪ used for attack prevention and aborting acute attack

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