5-HT/Migraine Flashcards
Serotonin
5-HT
-rapidly metabolized by monoamine oxidase (MAO)
Product of L-tryptophan
-90% of serotonin is found in ECL cells of GI tract, also stored in platelets and serotonergic nerve endings
5-HT3
in brainstem
Target of odansetron for anti-emesis
5-HT effects- CNS
CNS-affects sleep, sensory perception, motor, temp regulation, sexual behavior, hormone secretion
5-HT3 receptors in GI tract and medulla- vomiting
Local effects in periphery- pain and itch by sensory nerve endings (insect bites)
Coronary vascular beds have 5-HT3 receptors on vagal nerve endings- chemoreceptor reflex leading to bradycardia and hypotension
5-HT on pulmonary
stimualtion of bronchial smooth muscle
stimulates ACh release from bronchial vagal nerve endings
5-HT on CV
5-HT2- vasoconstriction (except in heart and skeletal muscle)
triphasic change in bp
platelet aggregation
GI tract 5-HT
stimulation of smooth muscle- facilitation of peristalsis
inc ach release from nervous system upon 5-ht4
Carcinoid tumors that overproduce serotonin–> diarrhea
Buspirone
5-HT1a partial agonist
non-benzodiazepine anxiolytic
Dexfenfluramine
5-HT2c agonist
appetite suppression
withdrawn due to toxicity
Sumatriptan
5-HT1b/1d agonist
Inhibition of release of vasodilating peptide calcitonin gene related peptide
constrict cerebral and meningeal vessels in tx of acute migraine headaches
AE: tingling, warmth sensations, dizziness, muscle weakness, neck pain, chest discomfort
5-HT4 agonists
Cisaperide- GERD and motility disorders
Tegaserod- partial agonist for IBS w/ constipation
5-HT receptor antagonists
Useful in treating carcinoid tumor
-inhibitors of synthesis and storage (reserpine) are too toxic
-dirty drugs- often have other targets
Phenoxybenzamine
-long acting 5-ht2 antagonist and alpha-adrenergic receptor antagonist
CYprohepatidine
5-HT2 antagonist and H1 receptor antagonist
-useful for smooth muscle effects of carcinoid tumors (serotonin syndrome tx)
Ketanserin
not approved in US
5-ht2 antagonist and alpha1 adrenergic antagonist
tx of htn and vasospastic conditions
Ondanestron, granisetron, dolasetron
5-HT3 receptor antagonist
tx of nausea and vomiting in cancer chemo
Serotonin Syndrome
- Overrelease of too much serotonin
- Htn, hyperreflexia, tremor, clonus, hyperthermia, hyperactive bowel sounds, diarrhea, mydriasis, agitation, coma
-preciptating drugs- SSRIs, second gen antidepressants, MAOIs, linezolid, tramadol, ondansetron, sumatriptan, st. john’s wort, ginseng
Ergot Alkaloids
- share properties of serotonin and catecholamines
- Produced by claviceps purpurea (fungus that infects stored grains under damp storage)
- hallucinations, convulsions, prolonged vasospasm (gangrene and fiery pain), uterine contractions resulting in abortion
some agonists and antagonists work at adrenergic receptors, 5-HT receptors, dopamine and uterine smooth muscle recepors
Ergotamine
-typically used for smooth muscle stimuatlion in uterus
-potent vasoconstrictor
ergot alkaloid
Dihydroergotamine (DHT)
ergot alkaloid
- tx of migraine
- vasoconstrictors of bv in dura
Bromocriptine, cabergoline
Ergot alkaloid
works on copamine receptor -suppress prolactin secretioon and useful in treating pituitary tumor
LSD
ergot alkaloid, power hallucinogen
Ergonavine
ergot alkaloid used for uterine smooth muscle contraction
utilized to limit post partum hemorrhage
Ergot Alkaloid toxicity
GI disturbance due to inc GI motility from activation of 5-HT receptors in CNS and GI
-prolonged vasospasm of arms and legs–> gangrene and amputation
Drowziness and hallicinations
Migraine
Two of following symptoms:
- unilateral pain
- pain ranging from moderate-severe
- throbbing (not rhythmic with heart beat)
- aggravating upon movement
one or more of following:
- nausea or vomiting
- photophobia or phonophobia
-triggered from stress, spikes in bp, skipping meals, exercise, rain, etc
Pathophys of migraines
-dural vasculature dilated- noxious stimulus from trigeminal system
Tx of migraine
Preventative therapy or tx of acute migraine attack (nonspecific- nsaids, aspirin) or specific migraine (ergotamine, DHT, triptans)
Preventative migraine therapy
Limited for those having >5 migraines per month
-beta blocker (propranolol, metoprolol), amitriptyline (antidepressant), anticonvulsants (valproate, topiramate), CCB (flunarizine), serotonin antagonist (methysergide- withdrawn)
Have adverse effects
all have drowziness, tiredness, some have weight gain,
other not as beneficial- verapamil (CCB) and fluoxetine (SSRI)
Tx of acute migraine attacks
non specific pain therapy
tx immediately
-co administer with anti emetic drug
-avoid overuse- limit drug tx to 2-3 days
risk of transforming migraine into severe, chronic condition
Opiate analgesics
for acute migraine attacks
- meperidine, butorphanol, oxycodone, hydromorphone
- relief for severe migraine
- risk of dependence nad tolerance
- AE: rebound headaches, dizziness, nausea, vomiting
Antiemetics
tx acute migraines
- metoclopramide, chlorpramazine, prochlorperazine
- combat nausea and vomiting due to migraine or ergot alkaloid tx
- metoclopramine is also weak 5-ht3 receptor antagonist which may also have direct effect
ergot derivatives
for migraine specific acute therapy
- vasoconstriction of cerebral and dural vessels
- but can have variable absorption and sustained vasoconstrictor effects (contra in CAD)
Triptans
sumatriptan
Selective 5-HT1D and 5-HT1B receptor agonist
-distinct advantage over ergot derivatives
-established efficacy and established safety record
-high cost
-MOA poorly defined
-inhibit activation of trigeminal afferent nociceptors
-cranial/dural vasoconstriction via 5-HT
-generally safe, but can mimic angina by constricting coronary arteries
-contra in ischemic heart disease, htn, cerebrovascular disease
-
can cause tingling, sensation of warmth, dizziness, flushing, neck pain, stiffness
