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SEROTONIN RECEPTOR AGONISTS (TRIPTANS)

OVERVIEW
Serotonin Receptor Agonists (Triptans)

 

Introduction

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.

 

Background

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.

    Generic (and Brand) Name Year Approved Tablet (or Wafer) Size Usual Initial Dose Maximum 24 Hour Dose
Almotriptan (Axert)20016.25 and 12.5 mg12.5 mg25 mg
Eletriptan (Relpax)200220 and 40 mg40 mg80 mg
Frovatriptan (Frova)20012.5 mg2.5 mg7.5 mg
Naratriptan (Amerge)19981 and 2.5 mg2.5 mg 5 mg
Rizatriptan (Maxalt)19985 and 10 mg10 mg30 mg
Sumatriptan (Imitrex) 1997 25, 50 and 100 mg* 50 mg 200 mg
Zolmitriptan (Zomig) 1997 2.5 mg and 5 mg**5 mg 10 mg
* Also available as nasal spray, transdermal patch and solution for injection.
** 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.

 

Hepatotoxicity

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.

Agents used specifically in management of migraines and vascular headaches include:  the ergot alkaloids, ergotamine and dihydroergotamine; and, the serotonin receptor agonists (triptans), including almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.

References regarding the safety and potential hepatotoxicity of the drugs used for migraine headache are provided together at the end of the Overview section on migraine headache agents.

 

Drug Class:  Migraine Headache Agents, Vasoconstrictor Agents


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CASE REPORT
Serotonin Receptor Agonists (Triptans)

 

Case 1.  Recurrent jaundice in a patient taking zolmitriptan for migraine headaches.
[Modified from: Deixler E, Helmke K. [Extrahepatic cholestasis during therapy with zolmitriptan (AscoTop)]. Z Gastroenterol 2005; 43: 1045-9. German. PubMed Citation]


A 62 year old man developed recurrent episodes of jaundice and abdominal pain approximately 6 months after starting zolmitriptan (5 mg, averaging 3-4 times weekly) for migraine headaches.  During an early attack, serum bilirubin was 6.6 mg/dL (4.5 mg/dL direct), ALT 230 U/L, Alk P 350 U/L, GGT 375 U/L (Table).  Tests for hepatitis A, B and C were negative as were routine autoantibodies.  Because of recurrent bouts of jaundice were suggestive of cholangitis, he underwent cholecystectomy.  Histologically, the gallbladder showed evidence of chronic inflammation, but was without stones and the extrahepatic biliary tree appeared normal.  Three months after cholecystectomy, jaundice recurred.  Endoscopic retrograde cholangiopancreatography again failed to show evidence of extrahepatic obstruction, but suggested dysfunction of the ampula of Vater.  At that point, total serum bilirubin was 7.8 mg/dL, ALT 680 U/L, and alkaline phosphatase 205 U/L.  Because zolmitriptan is a serotonin agonist and might affect gastrointestinal and biliary smooth muscle function, it was discontinued, whereupon liver test abnormalities rapidly improved.  During a year of follow up, he had no further attacks of jaundice or abdominal pain and liver tests were repeatedly normal.  His migraine headaches were managed with beta-blockers.

 

Key Points

Medication:Zolmitriptan (5 mg 3-4 times weekly)
Pattern: Mixed (R=2.7)
Severity: 3+ (jaundice, hospitalization)
Latency:Six months
Recovery:One month
Other medications:None

Laboratory Values

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
7 months 0 30 200 1.2
8 months 0 110 360 6.6 Cholecystectomy
9 months 0 90 200 1.2
12 months 0 690 218 7.8 ERCP
Zolmitriptan stopped
13 months 1 month 50 105 1.1
14 months 2 months 25 90 1.0
18 months 6 months 25 70 1.0
Normal Values <35 <130 <1.2

* Selected values estimated from Figure 1.

 

Comment

This patient had intermittent and fluctuating jaundice that suggested intermittent extrahepatic obstruction due to choledocholithiasis.  The possibility that zolmitriptan was the cause arose only after repeated evaluations failed to show frank extrahepatic obstruction, but indicated biliary akinesia or abnormalities in the function of the ampula of Vater.  The intermittency and variable doses of the migraine medication made it difficult to incriminate its use and perhaps explained the fluctuating course of liver injury.  The possibility that the triptans may affect biliary kinesis is intriguing (but unproven) explanation for occasional instances of cholestatic jaundice.

 

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PRODUCT INFORMATION
Serotonin Receptor Agonists (Triptans)

 

REPRESENTATIVE TRADE NAMES
Almotriptan – Generic, Almogran®, Axert®
Eletriptan – Relpax®
Frovatriptan – Frova®
Naratriptan – Generic, Amerge®
Rizatriptan – Maxalt®
Sumatriptan – Generic, Imitrex®
Zolmitriptan – Zomig®

 

DRUG CLASS
Migraine Headache Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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CHEMICAL FORMULAS AND STRUCTURES
Serotonin Receptor Agonists (Triptans)
DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Almotriptan 154323-57-6 C17-H25-N3-O2-S Almotriptan Chemical Structure
Eletriptan 177834-92-3 C22-H26-N2-O2-S.Br-H Eletriptan Chemical Structure
Frovatriptan 158930-17-7 C14-H17-N3-O.C4-H6-O4.H2-O Frovatriptan Chemical Structure
Naratriptan 121679-13-8 C17-H25-N3-O2-S Naratriptan Chemical Structure
Rizatriptan 144034-80-0 C15-H19-N5 Rizatriptan Chemical Structure
Sumatriptan 103628-46-2 C14-H21-N3-O2-S Sumatriptan Chemical Structure
Zolmitriptan 139264-17-8 C16-H21-N3-O2 Zolmitriptan Chemical Structure

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OTHER REFERENCE LINKS
Serotonin Receptor Agonists (Triptans)
  1. PubMed logoRecent References on Triptans

  2. Clinical Trials logoTrials on Triptans

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