Triptans and Ergot Alkaloids

Triptans and ergot alkaloids are agents used mainly for the management of acute migraines. The therapeutic effect is induced by binding to serotonin receptors, which causes reduced vasoactive neuropeptide release, pain conduction, and intracranial vasoconstriction. Triptans are the preferred therapy, followed by ergot alkaloids, but both agents have good efficacy. Due to the vasoconstriction effect, the medications should not be used concurrently or be prescribed to patients with cardiovascular disease.

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Overview

Pathophysiology of migraine

  • The pathophysiology of migraines is not completely understood.
  • Involves:
    • The trigeminovascular system:
      • Neurons originate from trigeminal ganglion
      • Innervate cerebral, pial, and dura vessels
    • Vasoactive neuropeptide release
    • Vasodilation
    • Plasma protein extravasation
  • Serotonin plays a role through 5-hydroxytryptamine (5-HT) 1B and 1D receptors in: 
    • Trigeminal neurons 
    • Cerebral and meningeal vessels

The role of triptans and ergot alkaloids

  • Both medication classes: 
    • Work on 5-HT 1B and 1D receptors
    • Have similar mechanisms of action
    • Are effective migraine-specific therapies
  • Migraine use:
    • Unresponsive to analgesics
    • For moderate-to-severe attacks
  • Triptans are preferred over ergot alkaloids because:
    • 5-HT 1B and 1D receptor specificity (ergots interact with multiple receptors)
    • Better tolerated:
      • Milder side effects
      • Less incidence of coronary vasospasm and vasospasm is less prolonged.
  • Disadvantages of triptans:
    • Expensive
    • Potential for rebound headaches

Triptans

Chemistry

Triptans and serotonin share a similar core molecule (tryptamine).

Chemical structure of tryptamine

Chemical structure of tryptamine:
the core molecule for both serotonin and triptans

Image: “Tryptamine” by Harbin. License: Public Domain

Pharmacodynamics

  • Mechanism of action: Triptans are agonists of 5-HT 1B and 1D receptors.
  • Physiologic effects:
    • Not completely understood
    • Neuron effects: 
      • Inhibited vasoactive neuropeptide release
      • Inhibited pain conduction
    • Vascular smooth muscle effect: promotes vasoconstriction of intracranial arteries

Pharmacokinetics

Pharmacokinetic variability exists among the triptan medications.

Absorption:

  • Fast GI absorption
  • Time to achieve peak plasma concentration depends on the route of administration:
    • Subcutaneous: 12 minutes
    • Intranasal: 15 minutes
    • Oral: 1–2 hours

Distribution: 

  • Half-life: 2–6 hours for most triptans
  • Sumatriptan does not easily cross the blood-brain barrier.
  • Zolmitriptan and frovatriptan penetrate the blood-brain barrier more easily.

Metabolism: 

  • Cytochrome P450 (CYP) system 
  • Monoamine oxidase (MAO) system

Excretion:

  • Renal (primary)
  • Feces
Table: Comparison of the pharmacokinetics of triptan medications
MedicationOnset of action and formulationElimination half-lifeMetabolism and excretion
Sumatriptan
  • Oral: 30–60 minutes
  • Nasal: 15–30 minutes
  • Subcutaneous: 10 minutes
2 hours
  • Metabolism: MAO system
  • Excretion: Renal
Zolmitriptan
  • Oral: 30–60 minutes
  • Nasal: 10–15 minutes
2–3 hours
  • Metabolism: CYP system, MAO system
  • Excretion: Renal, feces
NaratriptanOral: 1–2 hours6 hours
  • Metabolism: CYP system
  • Excretion: Renal
RizatriptanOral: 30–60 minutes2–3 hours
  • Metabolism: MAO system
  • Excretion: Renal, feces
AlmotriptanOral: 30–60 minutes3–4 hours
  • Metabolism: MAO system, CYP system
  • Excretion: Renal, feces
EletriptanOral: 30–60 minutes3–4 hours
  • Metabolism: CYP system
  • Excretion: Renal
FrovatriptanOral: 2 hoursApproximately 25 hours
  • Metabolism: CYP system, MAO system
  • Excretion: Feces, renal
CYP: cytochrome P450
MAO: monoamine oxidase

Indications

  • Migraine with or without aura (1st-line):
    • Sumatriptan is the most commonly used agent:
      • Cheapest
      • Can be used subcutaneously (a benefit in patients with nausea)
    • Capacity to decrease associated nausea and vomiting
    • Not for prophylaxis
  • Cluster headaches

Adverse effects and contraindications

Adverse effects:

  • Nausea
  • Dizziness
  • “Triptan sensations”:
    • Paresthesia
    • Flushing
    • Tingling
    • Neck pain
    • Chest tightness
  • Cardiovascular effects:
    • Coronary vasoconstriction
    • Rare: atrial and ventricular arrhythmias, myocardial infarction, stroke 
  • Serotonin syndrome
  • “Triptan-overuse headache” (rebound headache)

Drug interactions:

  • Ergot alkaloids: enhanced vasoconstriction
  • MAO inhibitors: ↑ serotonin effects, serotonin syndrome 
  • CYP3A4 inhibitors (with eletriptan):
    • Azoles
    • Macrolides
    • Protease inhibitors

Contraindications:

  • History of coronary artery disease, myocardial infarction, or stroke 
  • Hemiplegic migraines
  • Untreated or uncontrolled hypertension
  • Ischemic or vasoocclusive cerebrovascular disease
  • Bowel ischemia
  • Peripheral vascular disease
  • Severe hepatic or renal failure (naratriptan and eletriptan)

Ergot Alkaloids

Chemistry

  • Ergot alkaloids are derived from lysergic acid (from tryptophan) and contain a tetracyclic “ergoline” structure.
  • 2 families: 
    • Amine alkaloids
    • Peptide alkaloids: ergotamine, dihydroergotamine (DHE), bromocriptine

Pharmacodynamics

  • Mechanism of action: 
    • Ergotamine and DHE:
      • 5-HT 1B and 1D agonists, and other serotonin receptors
      • Alpha-adrenergic receptor agonists
    • Bromocriptine: dopaminergic receptor agonist
  • Physiologic effects:
    • Neuron effects: 
      • Inhibited vasoactive neuropeptide release
      • Inhibited pain conduction
    • Vascular smooth muscle: vasoconstriction
    • Uterine smooth muscle: 
      • Stimulates contraction
      • The effect increases dramatically during pregnancy
    • Suppression of prolactin secretion (bromocriptine)

Pharmacokinetics

Absorption:

  • Variable absorption in the GI tract
  • Improved absorption with coadministration of caffeine

Metabolism: 

  • Hepatic
  • 1st-pass
  • CYP3A4

Excretion: 

  • Feces (primary)
  • Renal (minor)

Indications

  • Ergotamine and DHE: migraine
  • Bromocriptine: 
    • Hyperprolactinemia
    • Parkinsonism
    • Neuroleptic malignant syndrome (off-label)

Adverse effects and contraindications

Adverse effects:

  • Nausea and vomiting
  • Diarrhea
  • Prolonged vasospasm, resulting in:
    • Gangrene
    • Bowel infarction
  • Valvular sclerosis (with long-term use)
  • Arrhythmia

Drug interactions:

  • Triptans: Combined use is contraindicated due to vasoconstriction.
  • Do not combine with other vasoconstrictors.
  • CYP3A4 inhibitors:
    • Azoles
    • Macrolides 
    • Protease inhibitors

Contraindications:

  • Cardiovascular and peripheral vascular disease
  • Hypertension
  • Severe hepatic or renal impairment
  • Hemiplegic migraine
  • Breastfeeding and pregnancy

Ergotism

Etiology:

  • Accidental or intentional medication overdose
  • Prolonged ergot use
  • Accidental ingestion of grain contaminated by Claviceps purpurea, a rye fungus that synthesizes natural ergot alkaloids

Clinical presentation:

  • Initial symptoms:
    • Flu-like
    • Headache
    • Nausea and vomiting
  • Neurologic:
    • Drowsiness
    • Involuntary, spastic movements
    • Hallucinations
    • Altered mental status
    • Seizures
  • Ischemic:
    • Claudication
    • Burning sensation of the limbs
    • Diminished distal pulses
    • Peripheral dry gangrene
    • Bowel ischemia and infarction 

Management:

  • Discontinue ergot alkaloid medications.
  • Vasospasm is resistant to most vasodilators, but may be responsive to large doses of nitrates (e.g., nitroprusside, nitroglycerin).
  • Gangrene may require amputation.

References

  1. Katzung, B.G. (2021). Histamine, serotonin, & the ergot alkaloids. In Katzung, B.G., & Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15e. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2988&sectionid=250596392
  2. Sibley, D.R., Hazelwood, L.A., & Amara, S.G. (2017). 5-hydroxytryptamine (serotonin) and dopamine. In Brunton, L.L., Hilal-Dandan, R., & Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170105881
  3. Aronson, J.K. (2016). Triptans. In Aronson, J.K. (Ed.), Meyler’s Side Effects of Drugs. pp. 205–210. https://doi.org/http://dx.doi.org/10.1016/B978-0-444-53717-1.01601-2 
  4. Nicolas, S., & Nicolas, D. (2021). Triptans. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved June 16, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK554507/
  5. Armstrong, S.C., & Cozza, K.L. (2002). Triptans. Psychosomatics. 43(6), 502–504. https://pubmed.ncbi.nlm.nih.gov/12444236/
  6. Waller, D.G., & Sampson, A.P. (2018). 26 – migraine and other headaches. In Waller, D. G., & Sampson, A. P. (Eds.), Medical pharmacology and therapeutics (fifth edition). pp. 341–347. https://www.sciencedirect.com/science/article/pii/B9780702071676000269 
  7. Bardal, S.K., Waechter, J.E., & Martin, D.S. (2011). Chapter 21 – neurology and the neuromuscular system. In Bardal, S. K., Waechter, J. E., & Martin, D. S. (Eds.), Applied pharmacology. pp. 325–365. Philadelphia: W.B. Saunders. https://www.sciencedirect.com/science/article/pii/B978143770310800021X 
  8. Parisi, P., et al. (2014). Chapter 23 – obesity and migraine in children. In Watson, R.R., et al. (Eds.), Omega-3 fatty acids in brain and neurological health. pp. 277–286. Boston: Academic Press. doi:https://doi.org/10.1016/B978-0-12-410527-0.00023-5 Retrieved from https://www.sciencedirect.com/science/article/pii/B9780124105270000235 
  9. Smith, J.H., Schwedt, T.J., and Garza, I. (2021). Acute treatment of migraine in adults. In Goddeau, Jr., R.P. (Ed.), UpToDate. Retrieved June 21, 2021, from https://www.uptodate.com/contents/acute-treatment-of-migraine-in-adults

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