SEROTONIN RECEPTOR AGONISTS (TRIPTANS)
Serotonin Receptor Agonists (Triptans)
The triptans are a group of serotonin receptor agonists that are useful in the therapy of vascular headaches and migraine. The triptans are generally used in low doses for a limited period of time and have not been associated with serum enzyme elevations, but some have been implicated in rare instances of clinically apparent, acute cholestatic hepatitis.
The triptans (trip' tans) are synthetic serotonin receptor agonists that are used in the therapy of migraine and vascular headache. Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine that has multiple actions, acting as a neurotransmitter and bioactive amine. The diversity of actions of serotonin is partially due to the multitude of different serotonin receptors and their tissue location. There are at least 15 classes of serotonin receptors which have overlapping actions, but variable distribution and intracellular pathways of response to stimulation and inhibition. The triptans are serotonin agonists with high affinity for the 5-HT1B and 5-HT1D receptors which are found on smooth-muscle cells of blood vessels. Simulation of the 5-HT1D receptor results in constriction of intracranial blood vessels. The triptans may also block the release of vasoactive peptides from perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on nerve terminals. Regardless, the triptans have been found to be effective in preventing or aborting migraine headaches with shortening of the period of pain and symptoms. The triptans are considered “first line” agents for patients whose vascular headaches do not reliably respond to conventional analgesics. They generally have a more rapid onset of action and fewer side effects than the ergot alkaloids. Seven triptans are approved for use in the United States including almotriptan (al" moe trip' tan), eletriptan (el" e), forvatriptan (froe" va), naratriptan (nar"' a), rizatriptan (rye" za, sumatriptan (soo" ma) and zolmitriptan (zole" ma). Generic formulations are becoming available for some of the initially approved agents. Brand names, year approved, tablet or wafer size, usual dose and maximum daily recommended doses are shown in the Table.
** Also available in orally disintegrading tablets and as nasal spray.
Early therapy is recommended in patients with recurrent migraine, and typically the dose is repeated in 2 to 4 hours if relief has not occurred. However, the total dosage should be limited to 2 to 3 doses per 24 hour period. Parenteral and intranasal administration is helpful in patients with nausea and vomiting. Chronic, long term use of triptans to prevent migraines has been studied, but is not currently approved. The seven triptans have similar side effect profiles which include “triptan sensations” characterized by tightening of the throat, chest, neck and limbs with paresthesias and hot or cold sensations. Triptans may also cause flushing, headache, somnolence and fatigue.
In large prospective controlled trials, the different triptans have not been associated with serum enzyme elevations or hepatotoxicity; however, the frequency of monitoring in most studies was limited and rates of ALT elevations not reported. There have been rare individual reports of cholestatic hepatitis after the use of triptans, largely associated with zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a protracted and severe migraine attack. Recurrent jaundice with intermittent therapy has also been reported (Case 1). The pattern of serum enzyme elevations was mixed or cholestatic, and recovery was complete within 1 to 2 months. Allergic manifestations (rash, fever, eosinophilia) were not present and autoantibodies did not develop.
Likelihood score, zolmitriptan: E* (unlikely but suspected rare cause of liver injury).
Likelihood score, other triptans: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of idiosyncratic liver injury after triptan use is not known, but is likely due to a toxic metabolite causing an acute, cholestatic hepatitis-like injury. An intriguing hypothesis is that the serotonin agonist activity causes biliary dyskinesis and functional obstruction.
Outcome and Management
Reported cases of hepatotoxicity from the triptans have been mild-to-moderate in severity, accompanied by symptoms and jaundice, but without acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There have been too few cases reported to know whether there is cross sensitivity to hepatotoxicity among the various triptans. Rechallenge should be avoided and switching to another triptan should be done with caution.
|Medication:||Zolmitriptan (5 mg 3-4 times weekly)|
|Severity:||3+ (jaundice, hospitalization)|
|Time After Starting||Time After Stopping||ALT* (U/L)||Alk P* (U/L)||Bilirubin* (mg/dL)||Other|
|Zolmitriptan started for migraine headaches|
|6 months||0||40||210||1.6||Abdominal pain|
|13 months||1 month||50||105||1.1|
|14 months||2 months||25||90||1.0|
|18 months||6 months||25||70||1.0|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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