Documenti di Didattica
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Dr Manukumar
Post graduate
Dept of Pharmacology
VMMC & Safdarjung hospital
• Outline
• Migraine
• Pathophysiology
Theories
Vascular theory
Neurogenic theory
Neurovascular theory
• Acute treatment of migraine
Non-specific treatment
Specific treatment
• Preventive treatment of migraine
• Newer targets and drugs
Migraine headache
26% 12%
• Triptan-Sumatriptan, naratriptan,
rizatriptan, eletriptan, zolmitriptan,
almotriptan & frovatriptan
• Selective activity on 5-HT1B/1D agonist.
• Mechanisms of action
Cranial vasoconstriction
Modulating neurotransmitter release from
neuronal terminals.
• The triptans -preventing the peripheral release of
vasoactive peptides (CGRP), reduce PPE.
• Also inhibit the abnormal activation of peripheral
nociceptors.
• The 5-HT1D receptor-selective agonist PNU-
142633 showed greater potency than
sumatriptan in blocking electrically induced PPE,
and had little to no detectable vascular activity in
carotid, meningeal arteries
Adverse Effects and Contraindications
• coronary artery vasospasm, transient myocardial
ischemia, atrial and ventricular arrhythmias, MI
• Irritation at the site of injection. The most
common side effect of sumatriptan nasal spray is
a bitter taste.
• Contraindicated- coronary artery disease ,
history of stroke or transient ischemic attacks,
cerebrovascular or peripheral vascular disease,
• J Manag Care Pharm. 2005;11(5):394-402
Ergot alkaloids
• The pharmacological effects of the ergot
alkaloids are varied and complex; partial
agonists or antagonists at serotonergic,
dopaminergic, and adrenergic receptors
• Ergot alkaloids at 5-HT1B/1D receptors likely
mediate their acute anti-migraine effects
Selection of patients – ergot
• Which patients?
Patients requiring migraine-specific therapy
Patients established on ergotamine
• Special cases
Patients with very long attacks
Patients with frequent headache recurrence
Adverse Effects and Contraindications
of Ergot Alkaloids
• Nausea and vomiting, due to a direct effect on
CNS emetic center.
• contraindicated in pregnant, peripheral vascular
disease, coronary artery disease, hypertension,
impaired hepatic or renal function
• In contrast to triptans, the contractile effect of
ergotamine in the human isolated coronary
artery is long- lasting and persists even after
repeated washings
• Comparison of vasoconstriction action of
ergotamine and triptan
Jackson, JE., et al. (2010). Tricyclic antidepressants and headaches: systematic review and
meta-analysis. Bmj, 341(oct20 1)
• SSRI- In a recent review, SSRIs resulted as
efficacious as placebo for preventing migraine
and less effective than TCA.
• In a randomized controlled study fluoxetine,
venlafaxine, duloxetine versus placebo,
reduced frequency of migraine attacks, but
not significant.
Beta blocker
• Clinical findings support the efficacy of
propranolol, timolol, atenolol, nadolol and
metoprolol in migraine preventive treatment.
• Exhibit high affinity for 5-HT receptor( 1a,
1b/d,2a)
• propranolol blocked CSD in rats, without
altering regional cerebral blood flow and
systemic arterial blood pressure
Cont…
• 53 studies including meta-analysis involving
2403 patients who are treated with either
propranolol and/or placebo , propranolol
yielded 44% reduction in migraine attack.
• Two clinical trials valproic acid compared with
propranolol, in both trials efficacy is identical.
Anti-epileptics
• An unbalanced activity b/w excitatory
glutamatergic transmission and GABAnergic
inhibition, abnormal activation of voltage-
operated ionic channels; Na , Ca channels ,
has been postulated in these two pathological
condition.
• “Valproate, topiramate”, gabapentin,
lamotrigine are best for prophylaxis.
Cont..
• VPA, TPM, Effect on voltage gated Na channels
modify the neuronal excitability(CSD), role of
Na channels are proved in FHM.
• VPA reduces the neurogenic inflammation,
plasma extravasation (Cutrer et al., 1997),
possibly through a GABA-mediated
mechanism
Calcium channel blockers
• In an experimental model of neurogenic
inflammation, blockade of L-type channels
attenuates dural vasodilatation.
• flunarizine could exert its antimigraine effect
by reducing neural NO synthase (NOS) activity
• In a double- blind study, flunarizine 5 mg/day
was as effective as propranolol 160 mg/day in
reducing the attack frequency.
Newer targets and drugs
• Non-triptan 5-HT1 agonist,
5-HT1D agonists (PNU-109291 and PNU- 142633)
are potent inhibitors of dural plasma protein
extravasation (PPE)