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Migraine & Serotonin
Dr M Rabbani Department of Pharmacology School of Pharmacy IUMS 93 آذر
History of Migraines
Have been with us for 7,000 years.
In ancient Greece, they attributed these painful headaches as “ascent of vapors” or humors from the liver to the brain.
In the 17th century, the idea of rising humors was replaced by increased blood flow.
In the 1980s, Harold G. Wolff said that migraine pain stems from the dilation and stretching of brain blood vessels, leading to the activation of pain-signaling neurons.
Thought that trigeminal nerves are the ones to blame.
Migraine is a severe painful headache that is often preceded or accompanied by sensory warning signs such as flashes of light, blind spots, tingling in the arms and legs, nausea, vomiting, and increased sensitivity to light and sound. The pain can last for hours or even days.
How Migraine develops
After brainstem activation the trigeminal system is activated, releasing neuropeptides in the brainstem and in the peripheral nerve endings at the meninges.
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Changes in nerve cell activity and blood flow may result in visual disturbance, numbness or tingling, and dizziness.
Chemicals in the brain cause blood vessel
dilation and inflammation of the surrounding tissue
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The inflammation irritates the trigeminal nerve, resulting in severe or throbbing pain
Electrical impulses spread to other regions of the brain.
1 Migraine originates deep within the brain
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Common triggers:
◦ ◦ ◦ ◦ ◦
Hormonal: Estrogen and Progesterone Foods: alcohol, chocolate, etc. Stress, physical activity, sleep Environmental stimulus: sight, smells Medications
1. Prodrome 2. Aura 3. Headache 4. Postdrome
Characterized by difficulty concentrating, yawning, fatigue and/or sensitivity to light and noise.
Duration: A few hours to a few days
2- Aura
Characterized by: visual illusions of sparks and lights, often followed by blind or dark spots in the same place as the bright hallucinations. Duration: 20-60 minutes
4- Postdrome
3- Headache
Characterized by excruciating or throbbing pain along with sensitivity to light and sound.
May be accompanied by nausea and vomiting
Sometimes only half of the head or part of the head is in pain.
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Duration: 4 – 72 hours
Characterized by: ◦ ◦ ◦ ◦
Sensitivity to light and movement Lethargy Fatigue Difficulty focusing
Also called a “zombie phase”
Duration: A few hours to a few days
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Avoiding Trigger Factors
Non-Drug Treatment
Pain Medications
Prophylactic Medications
Abortive Medications
Magnesium
For those patients who experience severe and complicated migraines more than 2 times a month.
Four categories ◦ ◦ ◦ ◦
Ergots: introduction Ergotamine Tartrate Dihydroergotamine (DHE) Cafergot Isomethaheptane
Triptans
• Sumatriptan
If thid doesn’t work then it is given in combination with the others.
Produced by a fungus that infects grain especially rye
• Naratriptan
Affect many kinds of receptors.
• Zolmitriptan
Ergot poisoning signs & symptoms (ergotism) :
• Rizatriptan
◦ Dementia with hallucinations
• Almotriptan
◦ Prolonged vasospasm, which mayLysergic resultacid in gangaeren diethylamide (LSD)
• Frovatriptan
◦ Stimulation of uterine smooth muscle, which in pregnancy may result in abortion
• Eletriptan
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Anticonvulsants (Topiramate) Antidepressants (Nortriptyline) Antihypertensives (Propranolol) Cacluium channel blocker (Verapamil)
Structurally similar to amines, serotonin, norepinephrine, and dopamine
interact with multiple receptors
cause constriction of the blood vessels
Problems: avoid if patient has coronary disease; safety margin is small; overdose
Best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses ◦ combined with caffeine: better absorption ◦ potentially severe long-lasting vasoconstriction موجود در فرم قرص در طرح ژنریک
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Seretonin System
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May be appropriate for intractable migraine
Introduction
Serotonin is a monoamine neurotransmitter.
Distribution & synthesis
An „indoleamine‟ – has an indole ring structure
Serotonin roles
Serotonin Receptors
IV administration mainly
Disorders associated with malfunctioned Serotonergic System.
Triptans
Serotonin was the name given to an unknown vasoconstrictor substance found in serum after blood clotted 1n 1948 was identified and named 5-HT which was shown to originate from platelet
This structure is also found in „hallucinogenic‟ or „psychedelic‟ drugs Serotonin identified as a key player in the generation of a migraine attack “migraine medicines of today”
Widely distributed amine (animals + plants) Extensively in GIT, 80-90%- enterochromaffin cells in the gut, where it regulate intestinal movements. The remainder is synthesized in serotonergic neurons in the CNS. Despite the abundance of peripheral serotonin, its inability to cross the BBB necessitates the synthesis of serotonin within the brain. Synthesized from the amino acid tryptophan, which is derived from the diet. Metabolised by MAO-A
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Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting.
Majority released from gut ◦ ◦ ◦ ◦
Responsible for smooth muscle contractions Release stimulated by food intake Inhibits release of gastric acid Softens stool
Cardiovascular system – vasoconstrictor Role as a growth factor for some types of cells, which may give it a role in wound healing. Bronchioconstriction Uterine contractions
Serotonin Receptors
Peripheral ◦ ◦ ◦ ◦ ◦
Peristalsis Vomiting Platelet aggregation and haemostasis Inflammatory mediator Sensitisation of nociceptors
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Control of appetite Sleep Mood Hallucinations Stereotyped behaviour Pain perception Vomiting
Central
Receptor 5-HT1A
Distribution
5-HT1D
Raphe nuclei, hippocampus Substantia nigra, globus pallidus, basal ganglia Brain
5-HT1E
Cortex, putamen
5-HT1F
Cortex, hippocampus
5-HT1P
5-HT2C
Enteric nervous system Platelets, smooth muscle, cerebral cortex Stomach fundus Choroid, hippocampus, substantia nigra
5-HT3
Area postrema, sensory and enteric nerves
5-HT4
CNS and myenteric neurons, smooth muscle
5-HT5A,B
Brain
5-HT6,7
Brain
5-HT1B
5-HT2A 5-HT2B
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At least 15 types and subtypes All GPCR except 5-HT3
Agonists
Antagonists
Buspirone Sumatriptan Sumatriptan
Granisetron, Ondansetron, Tropisetron Cisapride, Metoclopramide Clozapine (5-HT7)
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1.
Mood Disorders
2.
Anxiety Disorder
3.
Schizophrenia
4.
ADHD
5.
Sexual Disorders
6.
Impulse Control Disorder
7.
Personality disorders
8.
Carcinoid syndrome
The first selective serotonin agonist (5-HT1D agonist) approved for the treatment of migraine Alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk. Probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray)
A family of tryptamine-based drugs used as abortive medication in the treatment of migraines They were first introduced in the 1990s. Triptans include sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, and avitriptan
Acts on receptors at smooth muscle cells of brain vessels (also in peripheral blood vessels like coronary artery = side effects) Rapid relief
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Sumatriptan Side-effects
Relieves pain of migraine and associated symptoms
Side effects:
◦ Change in taste ◦ Discomfort in the jaw or mouth ◦ Dizziness
3 dosage forms: oral, nasal, & parenteral
◦ Severe chest pain ◦ Convulsions ◦ Swelling of the eyelids ◦ Shortness of breath and trouble breathing
◦ Drowsiness ◦ Lightheadedness ◦ muscle aches
فرم قرص درطرح ژنریک موجود است
Rare side effects:
◦ nausea or vomiting
•contraindicated in patients with angina
Oral bioavailability ~40%
half-life of 2.5 hours
shows the fastest time of onset!
rizatriptan Side-effects
Side effects: ◦ ◦ ◦ ◦ ◦ ◦
در شکل قرص موجود در طرح ژنریک
Dizziness Nausea Tiredness Hot flashes Chest pain Shortness of breath
Rare side effects: ◦ ◦ ◦ ◦ ◦ ◦ ◦
Agitation Anxiety Blurred vision Chills Confusion Insomnia Irregular heartbeat
Methysergide, 5-HT2 receptor antagonist/PA 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
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Cyproheptadine, 5-HT2 receptor antagonist also blocks histamine and Ca channels
Pizotifen, 5-HT2 receptor antagonist also mACh receptor antagonist
Side effects: Sedation and weight gain
Side effect: weight gain, antimuscarinic side effects
Rarely used
Propranolol and similar (metoprolol) most common for continuous prophylaxis
Amitriptyline (TCA) most frequently used among the tricyclic antidepressants
best established drug for migraine attack prevention.
Valproic acid effective in decreasing migraine frequency.
Mechanim not clear
NSAIDs used for attack prevention and aborting acute attack
