Upload
raghu-prasada
View
159
Download
0
Embed Size (px)
DESCRIPTION
brief summary of serotonin receptors, treatment of migraine serotonin syndrome
Citation preview
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
THANK YOU & download –slideshare, author stream