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					Migraine Headache
  Prof. Dr. Shah Murad




                         1
• A migraine headache is a form of
  vascular headache.



• Migraine headache is caused by
  vasodilatation (enlargement of blood
  vessels) that causes the release of
  chemicals from nerve fibers that coil
  around the large arteries of the brain.


                                            2
• Enlargement of these blood vessels
  stretches the nerves that coil around
  them and causes the nerves to
  release chemicals.

• The chemicals cause inflammation,
  pain, and further enlargement of the
  artery. The increasing enlargement
  of the arteries magnifies the pain.


                                          3
• Migraine attacks commonly activate the
  sympathetic nervous system in the body.
• The sympathetic nervous system is often
  thought of as the part of the nervous
  system that controls primitive responses
  to stress and pain, the so-called "fight
  or flight" response, and this activation
  causes many of the symptoms associated
  with migraine attacks; for example, the
  increased sympathetic nervous activity in
  the intestine causes nausea, vomiting,
  and diarrhea.

                                              4
• Sympathetic activity also delays emptying of the
  stomach into the small intestine and thereby
  prevents oral medications from entering the
  intestine and being absorbed.


• The impaired absorption of oral medications is a
  common reason for the ineffectiveness of
  medications taken to treat migraine headaches.




                                                     5
• The increased sympathetic activity also
  decreases the circulation of blood, and
  this leads to pallor of the skin as well as
  cold hands and feet.

• The increased sympathetic activity also
  contributes to the sensitivity to light
  and sound sensitivity as well as blurred
  vision.



                                                6
    Medical Treatment
• Treatment for migraine headaches
  can relieve the pain and symptoms of
  a migraine attack -- and prevent
  further migraine attacks.

• Migraines can be treated with two
  approaches: abortive and preventive.

                                         7
• Abortive: The goal of abortive therapy is to
  prevent a migraine attack or to stop it once it
  starts. The prescribed medications stop a
  headache during its prodrome stage or once it has
  begun and may be taken as needed. Some can be
• administered as a self-injection into the thigh;
  others, as a wafer that melts on the tongue.
  These forms of medication are especially useful
  for people who vomit during a migraine, and they
  work quickly.



                                                      8
• Abortive drugs include the triptans,
  which specifically target serotonin.

• They are all very similar in their action
  and chemical structure.
• The triptans are used only to treat
  headache pain and do not relieve pain
  from back problems, arthritis,
  menstruation, or other conditions.



                                              9
• Sumatriptan (Imitrex)

• Zolmitriptan (Zomig)

• Eletriptan (Relpax)

• Naratriptan (Amerge, Naramig)

• Rizatriptan (Maxalt)

• Frovatriptan (Frova)

• Almotrip



                                  10
• The following drugs are mainly used
  for nausea, but they sometimes have
  an abortive or preventive effect on
  headaches:
• Prochlorperazine (Compazine)

• Promethazine (Phenergan)


                                        11
• The next drugs are weak members of the
  narcotic class.
• They are not specific for migraines, but they
  can help relieve almost any kind of pain.
• Since they are habit forming, they are less
  desirable than the specific headache drugs
  listed above. These drugs should be used
  primarily as a "backup" for the occasions when
  a specific drug does not work.
• Butalbital compound (Fioricet, Fiorinal)
• Acetaminophen and codeine (Tylenol With
  Codeine)

                                                   12
            Preventive:
• This type of treatment is considered if a
  migraineur has more than one migraine per
  week. The goal is to lessen the frequency
  and severity of the migraine attacks.
  Medication to prevent a migraine can be
  taken daily.



                                          13
• Preventive treatment medications
  include the following:

• Medications used to treat high blood
  pressure -- Beta-blockers (propranolol
  [Inderal]), calcium channel blockers
  (verapamil [Covera])

• Antidepressants -- Amitriptyline (Elavil),
  nortriptyline (Pamelor)


                                               14
• Antiseizure medications -- Gabapentin
  (Neurontin), valproic acid (Depakote),
  topiramate (Topamax)

• Some antihistamines and anti-allergy
  drugs, including diphenhydramine
  (Benadryl) and cyproheptadine (Periactin)



                                              15
16
       ERGOT ALKALOIDS
• Ergot alkaloids -- produced by Claviceps purpurea,
  a grain (rye, especially) fungus
• This fungus synthesizes many biologically active
  agents including:
   –   acetylcholine
   –   histamine
   –   tyramine and
   –   many unique ergot alkaloids -- which effect:
        • alpha-adrenergic receptors
        • dopamine receptors
        • serotonin receptors




                                                       17
• Ergot poisoning (ergotism, St. Anthony's fire)--
  symptoms:
• dementia
• florid hallucinations
• persistent vasospasm (gangrene may develop)
• uterine muscle stimulation (may cause abortion in
  pregnancy)
• Ergot poisoning specific manifestations depend on
  the alkaloids mixture



                                                      18
• Chemistry and pharmacokinetics:
• Two Major Families:
   – Tetracyclic Ergoline Nucleus: Examples --
      •    lysergic acid diethylamide (LSD)
      •    ergonovine
      •    methysergide (Sansert)
      •   6-methylergoline
      •   lysergic acid
   – Peptide alkaloids: Examples --
      • ergotamine
      • alpha-ergocryptine
      • bromocriptine (Parlodel)




                                                 19
• Ergot alkaloids -variably absorbed from
  the GI tract
• Absorption following oral administration:
  improved by caffeine
• Bromocriptine (Parlodel): well absorbed
  from the GI tract
• Metabolism:
• extensively metabolized


                                              20
• Pharmacodynamics:
• Mechanism of Action:
  – Targets: several receptor types
    •   agonist effects
    •   partial agonist effects
    •   antagonist effects
    •   Pre- and post-synaptic sites



                                       21
• Ergot AlkaloidsAlpha-adrenergic
  receptorDopamine receptorSerotonin
  receptor(5 HT2)Uterine smooth muscle
  stimulationBromocryptine-+++-
  0Ergonovine++-(partial
  agonist)+++Ergonovine--(partial
  agonist)0+(partial agonist)+++LSD0+++--
  +Methysergide+/0+/0---(partial
  agonist)+/0


                                            22
•   Organ Systems:
•   CNS:
    –   hallucinogenic-- LSD:
        • peripheral (5 HT2) serotonin receptor peripheral antagonist
        • behavioral effects: agonist presynaptic or postsynaptic 5 HT2 effects.
    –   Dopamine Receptor Interactions:
        • Extrapyramidal system
        • Prolactin release regulation:
             –   bromocriptine (Parlodel) and pergolide (Permax)}specificity for pituitary dopamine
                 receptors
                    » suppression of pituitary prolactin secretion: by activating regulatory
                       dopamine receptors
                    » Bromocriptine (Parlodel) and pergolide (Permax) are competitive with
                       dopamine and other dopamine agonists (apomorphine) before the these
                       binding sites




                                                                                                      23
•   Vascular Smooth Muscle:
•   Ergotamine (unrelated compounds) are mainly vasoconstricting.
     –   Vasoconstriction: partially blocked by alpha adrenergic receptor blocking drugs--
           •   suggesting vasoconstriction by ergot alkaloids may be due to partial agonist effects at alpha adrenergic
               receptors
     –   Vasoconstriction: long-lasting--
           •   alpha adrenergic receptor effects
           •   5 HT receptor-mediated effects
     –   Vasoconstriction: differential vascular sensitivity to ergot alkaloids
           •   most sensitive: cerebral arteriovenous anastomotic vessels to:
                  –    ergotamine
                  –    dihydroergotamine
                  –    sumatriptan (Imitrex)
           •   Antimigraine specificity: mediated by neuronal or vascular serotonin receptors
     –   Most-common drugs used for migraine treatment:
           •   ergotamine
           •   ergonovine
           •    methysergide (Sansert)
     –    Overdosage (ergotamine and related agents)
           •   Severe, long-lasting vasospasm --
                  –   not reversible by alpha-antagonists
                  –   not reversible by serotonin antagonists




                                                                                                                          24
• Uterine Smooth Muscle
• Stimulant action: involves serotonergic, alpha-adrenergic,
  and other effects
• Uterine sensitivity changes during pregnancy (possibly due
  to progressively increasing numbers of alpha1 receptors
• Small doses: rhythmic uterine contraction and relaxation
• Larger doses: substantial, prolonged contractions
• Ergonovine: more uterine selective (agent of choice for
  obstetric uses)




                                                               25
• Other Smooth Muscle:
• Bronchiolar smooth muscle: no effect
• Gastrointestinal smooth muscle: variable
  sensitivity {nausea, diarrhea, and vomiting
  -- occurs with variability in required
  dosage probation impatient}
  – Mechanism of Action:
     • activation of gastrointestinal serotonin receptors
     • CNS emetic centers



                                                            26

				
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