CASE 25
A 40-year-old woman presents for evaluation of her chronic migraine headaches. She reports that approximately once a month she has a severe, unilateral headache associated with nausea and extreme photophobia. The headache will last for a full day if not treated. She has had success in reducing the severity of the headaches with opioid pain medications, but usually she is too nauseous to take them. When she is able to tolerate them, she will have to sleep for several hours afterward. She is missing about a day of work a month because of the headaches. She has no other significant medical history and takes no medications on a regular basis. Her examination today is normal. You decide to prescribe sumatriptan for her to try with her next migraine headache.
Which receptor is the site of action of sumatriptan?
What is the mechanism of action of sumatriptan?
ANSWERS TO CASE 25:
Serotonin Receptor Agonists and Antagonists
Summary: A 40-year-old woman with migraine headaches is treated with sumatriptan.
Receptor site of action of sumatriptan: Serotonin 5-HT1D and 5-HT1B receptors.
Mechanism of action of sumatriptan: Receptor activation inhibits the activity of adenylyl cyclase and decreases cAMP accumulation that results in contraction of arterial smooth muscle, especially in carotid and cranial circulation.
CLINICAL CORRELATION
Migraine headaches are common causes of severe symptoms among patients and a leading cause of absenteeism from work and school. Sumatriptan was the first of a class of serotonin (5-HT) agonist medications for the treatment of migraines. Multiple subtypes of 5-HT receptors have been identified. Sumatriptan specifically acts at the 5-HT1D and 5-HT1B receptor subtypes that are coupled to an inhibition of cAMP. Stimulation of these receptors results in vasoconstriction in the carotid circulation that may directly oppose the vasodilation and the release of vasodilating peptides thought to be involved in migraine.
At prejunctional sites, activation of these receptors results in decreased transmission of nociceptive signals in the trigeminal nerve. While being fairly specific for the carotid circulation, there can be activity at other vascular sites. Cerebrovascular, peripheral vascular, mesenteric arterial, or coronary artery diseases are all contraindications to its use. Vasospastic coronary disease is a contraindication as well.
APPROACH TO:
Pharmacology of Serotonin Receptor Agonists and Antagonists
OBJECTIVES
1. Describe the activity of the different classes of serotonin receptors.
2. List the agents that act as serotonin agonists and describe their mechanisms of action and uses.
3. List the agents that act as serotonin antagonists and describe their mechanisms of action and therapeutic uses.
DEFINITIONS
Partial agonist: A drug that at full receptor occupancy produces less of a response than a full agonist. Partial agonists can competitively inhibit the response to a full agonist, including the physiologic response to endogenously released hormones and neurotransmitters.
DISCUSSION
Class
Other than the triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan), which are the drugs of choice to treat acute, severe migraine headache, there are a few clinically important agents that are direct-acting serotonin receptor agonists. The ergot alkaloids (ergotamine [the prototype], dihydroergotamine, ergonovine, methylergonovine) act through the same mechanisms as the triptans and are effective clinically during the prodrome of a migraine attack. Diarrhea, nausea and vomiting, and drowsiness are their most common adverse effects. Prolonged vasospasm resulting from smooth muscle stimulation is a serious consequence of overdose that may result in gangrene and amputation of arms, legs, or digits. Bowel infarction has also been reported. They are contraindicated for patients with obstructive vascular disease.
Cisapride, a 5-HT4 receptor agonist was voluntarily removed from the US market because of potential serious cardiac arrhythmias; however, it is still available for compassionate use. It promotes release of acetylcholine from the myenteric plexus and may be used to treat gastroesophageal reflux and motility disease.
The major clinical use of selective serotonin receptor antagonists is as first-line drugs for treatment of nausea and vomiting, resulting from vagal stimulation that is associated with surgery and cancer chemotherapy. These agents, the prototype being ondansetron (also granisetron, palonosetron, and dolasetron), act on 5-HT3 receptors. Their most common adverse effects are headache and constipation. Dolasetron prolongs the QT interval and, therefore, should not be administered to patients with this condition or with other similarly acting drugs.
Alosetron is a 5-HT3 receptor antagonist that is used to treat IBS with diarrhea. It is only approved for treatment of women because efficacy has not been documented for men. Its major adverse effects are constipation that may be severe and require discontinuation of therapy. Ischemic colitis (adverse incidence about 0.3%) may be fatal and therefore precludes the use of alosetron except for patients who have not responded to other therapies.
Mechanism of Action
The ergot alkaloids (dihydroergotamine, ergonovine, the prototype ergotamine, and methylergonovine) have agonist and partial agonist activity at serotonin (5-HT1D receptors and 5-HT1A receptors) that, like the triptans (see above), are responsible for their therapeutic action. Their antagonist and agonist and partial agonist activity at α-adrenergic receptors and dopamine receptors is responsible for some adverse actions. Cisapride and tegaserod activation of 5-HT4 receptors on enteric neurons promotes release of acetylcholine that results in increased lower esophageal sphincter pressure. Ondansetron and other selective serotonin antagonists act to inhibit nausea and vomiting through peripheral blockade of serotonin 5-HT3 receptors on intestinal vagal afferent nerves, and through central blockade of serotonin 5-HT3 receptors in the vomiting center and chemoreceptor trigger zone.
Alosetron and palonosetron are highly selective serotonin receptor 5-HT3 antagonists that act peripherally on enteric afferent and cholinergic neurons to reduce intestinal activity and visceral afferent pain. It also acts centrally on the same receptors to inhibit afferent nerve activation of the CNS.
Administration
Sumatriptan may be administered orally, as a subcutaneous injection, or as a nasal spray, making it particularly valuable for migraine patients with nausea and vomiting as symptoms. Ergotamines are available for oral, sublingual rectal, parenteral, and inhaler administration.
Selective serotonin receptor antagonists can be administered orally or IV. They are most effective against nausea and vomiting when administered IV prior to the administration of chemotherapeutic agents.
Pharmacokinetics
Tegaserod is poorly absorbed and should be taken before meals. Severe hepatic or renal disease may significantly reduce its clearance. Ergotamine tartrate may be administered combined with caffeine, which facilitates its absorption.
COMPREHENSION QUESTIONS
25.1 A 35-year-old woman is diagnosed with migraine headaches. She is prescribed sumatriptan. Which of the following is an effect of sumatriptan?
A. Causes vasoconstriction in the carotid and cranial circulation
B. Increases transmission of nociceptive signals in the trigeminal nerve
C. Increases adenylyl cyclase activity
D. Is an antagonist at the 5-HT1D receptor subtype
25.2 The major clinical use of ondansetron is which of the following?
A. Compassionate treatment of gastroesophageal reflux and motility disease
B. Major depression
C. Migraine headache
D. Nausea and vomiting that is associated with surgery and cancer chemotherapy
25.3 Prolonged vasospasm is a serious consequence of which of the following?
A. Alosetron
B. Cisapride
C. Ergotamine
D. Ondansetron
ANSWERS
25.1 A. Sumatriptan, a 5-HT1D receptor agonist, inhibits the activity of adenylyl cyclase and decreases cAMP accumulation that results in contraction of arterial smooth muscle, especially in carotid and cranial circulation.
25.2 D. The major clinical use of ondansetron, a 5-HT3 receptor antagonist, is for treatment of nausea and vomiting that is associated with surgery and cancer chemotherapy. Migraine is treated with triptans and ergot alkaloids. Cisapride, a 5-HT4 receptor agonist, is used only compassionately to treat gastroesophageal reflux and motility disease.
Selective serotonin reuptake inhibitors (SSRIs) act to block serotonin transporters and are used to treat major depression.
25.3 C. Prolonged vasospasm caused by smooth muscle stimulation is a serious consequence of overdose with ergotamine. The most common adverse effects of ondansetron are headache and constipation. Serious cardiac arrhythmia is a serious adverse effect of cisapride. The major adverse effect of alosetron, a 5-HT3 receptor antagonist, is constipation.
PHARMACOLOGY PEARLS
Because the vasoconstrictor activity of ergotamine is long-lasting, its dose and frequency of administration must be limited.
Ergot alkaloid agents can cause vasoconstriction and should not be used in patients with occlusive vascular disease.
The effects of selective serotonin receptor antagonists like ondansetron seem to be enhanced with concomitant administration of dexamethasone.
REFERENCES
Tepper SJ, Stillman MJ. What is the best drug-delivery approach for the acute treatment of migraine? Expert Rev Neurother 2012, 12(3):253–5.
Shugart C. Management of migraine headache: an overview of current practice. JAAPA 2012;25:48–52.
Ramadan NM. Current trends in migraine prophylaxis. Headache 2007;47(suppl 1):S52–7.