Pharmacology of Headache/Migraine

Question 1

What is serotonin synthesized from?
What are the steps of synthesis and which is the rate limiting step (RLS)?
How is serotonin’s action terminated?

Answer 1

Synthesized from Tryptophan

First step, tryptophan hydroxylase is RLS
Second step is L-aromatic amino acid decarboxylase: 5-HO-Tryptophan to 5-HT

Reuptake by SERT then converted 5-hydroxyindoleacetic acid via MAO and aldehyde DH
Conversion to melatonin in pineal gland

Question 2

What is the location of serotonin in the body?

In the CNS specifically where is it?

Answer 2

90% - GI system
8% - Platelets (No synthesis)
2% - CNS

Cell bodies in midbrain raphe nuclei
Projection: Hypothalamus, neostriatum, limbic forebrain, neocortex, medulla, spinal cord

Question 3

What are the serotonin receptors?

Answer 3

5-HT_1(A-E) – Inhibition of adenylate cyclase
5-HT_1A – K+ channel opens
5-HT_2(A-C) – PI hydrolysis
5-HT₃ – Ligand-gated cation channels
5-HT_4-7 – Activation of adenylate cyclase or unknown
Auto-receptors – Decreased serotonin release (1A and 1D like)

Question 4

What is the cardiovascular role of serotonin?

Answer 4

Potent vasoconstriction of large arteries and veins; cranial (5-HT1D) blood vessels
Vasodilation in coronary, skeletal muscle and cutaneous blood vessels
Bezold-Jarisch reflex – Coronary chemoreceptors; Bradycardia, hypotension, and hypoventilation
Platelet aggregation – Active uptake of serotonin from circulation

Question 5

What is the CNS role of 5-HT

Answer 5

Sensory Perception
Sleep
Temperature regulation
Neuroendocrine regulation
Learning and memory, particularly short-term
Pain perception – spinal and brain sites of action
Drug abuse
Emesis – 5-HT3 receptors

Question 6

What is the role of 5-HT in mental illness?

Answer 6

Affective disorders – SSRIs and SNRIs
Schizophrenia – Atypical antipsychotics
OCD – SSRIs
Anxiety – 5-HT1A receptors
Aggressive behavior

Question 7

Lysergic Acid Diethylamide (MoA, Indication)

Answer 7

Nonspecific – 5-HT2 receptors
Potent hacllucinogen

Question 8

Buspirone (MoA, Indication)

Answer 8

5-HT1A Partial Agonist – Antianxiety

Question 9

Sumatriptan (Delivery, MoA, Indication)

Answer 9

Delivery: Oral, nasal spray, SC
Combination with naproxen

5-HT1B/D receptors on cerebral blood vessels (Vasoconstriction promoting)
CGRP – Inhibition of vasoactive peptides
NT inhibits of the trigeminal and cortical nerves
Block brainstem pain pathways

Treatment of migraine headaches, stop existing ones – Major abortive

Question 10

Sumatriptan (Side Effects, Contraindications)

Answer 10

Peripheral vasoconstriction
Nausea and vomiting
Angina
Dizziness
Flushing

Stroke/MI
Uncontrolled HTN, IHD

Question 11

Sumatripitan (Drugs in same class, and any details in delivery)

Answer 11

Almotriptan, eletriptan, frovatriptan (long half-life), naratriptan (long half-life), rizatriptan, zolmitripitan (oral, nasal spray)

Question 12

What are some other abortives?

Answer 12

Ergots – DHE
Many routes
Ergotamine – Oral

NSAIDS w/ caffeine (Excedrin)

Steroids

Butalbital/Caffeine/APAP (Fioricet)
Butalbital – Mild barbiturate
Bad choice

Question 13

What are some prophylactic drugs for headache?

Answer 13

Tricyclic Antidepressents: Amitryptyline, Nortriptyline
Sedating
Anti-ACh
Effective for variety of sources

Antiseizure agents
Divalproex sodium/valproic acid
Topiramate
Others – Gabapentin, pregabalin, lamotrigine

Vasoactive Agents
Beta blockers – Propranolol, atenolol
Calcium channel blockers – Verapamil, diltiazem
Variable efficacy – Side effects