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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache

  • 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 Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache-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

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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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain conduction
    • Vascular smooth muscle effect: promotes vasoconstriction of intracranial arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. 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
Medication Onset of action and formulation Elimination half-life Metabolism 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
Naratriptan Oral: 1–2 hours 6 hours
  • Metabolism: CYP system
  • Excretion: Renal
Rizatriptan Oral: 30–60 minutes 2–3 hours
  • Metabolism: MAO system
  • Excretion: Renal, feces
Almotriptan Oral: 30–60 minutes 3–4 hours
  • Metabolism: MAO system, CYP system
  • Excretion: Renal, feces
Eletriptan Oral: 30–60 minutes 3–4 hours
  • Metabolism: CYP system
  • Excretion: Renal
Frovatriptan Oral: 2 hours Approximately 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 Cluster headaches Cluster headache is a primary headache disorder characterized by moderate-to-severe unilateral headaches that occur in conjunction with autonomic symptoms. Cluster headache can last from weeks to months, during which the affected individual may experience attacks up to several times a day, followed by a pain-free remission period. Cluster Headaches

Adverse effects and contraindications

Adverse effects:

  • Nausea
  • Dizziness
  • “Triptan sensations”:
    • Paresthesia
    • Flushing
    • Tingling
    • Neck pain Neck Pain Neck pain is one of the most common complaints in the general population. Depending on symptom duration, it can be acute, subacute, or chronic. There are many causes of neck pain, including degenerative disease, trauma, rheumatologic disease, and infections. Neck Pain
    • Chest tightness
  • Cardiovascular effects:
    • Coronary vasoconstriction
    • Rare: atrial and ventricular arrhythmias, myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction, stroke 
  • Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome
  • “Triptan-overuse headache” (rebound headache)

Drug interactions:

  • Ergot alkaloids: enhanced vasoconstriction
  • MAO inhibitors: ↑ serotonin effects, serotonin syndrome 
  • CYP3A4 inhibitors (with eletriptan):
    • Azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles
    • Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides
    • Protease inhibitors

Contraindications:

  • History of coronary artery disease, myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction, or stroke 
  • Hemiplegic migraines
  • Untreated or uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain conduction
    • Vascular smooth muscle: vasoconstriction
    • Uterine smooth muscle: 
      • Stimulates contraction
      • The effect increases dramatically during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Suppression of prolactin secretion (bromocriptine)

Pharmacokinetics

Absorption:

  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache
  • Bromocriptine: 
    • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
    • Parkinsonism
    • Neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome (off-label)

Adverse effects and contraindications

Adverse effects:

  • Nausea and vomiting
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles
    • Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides 
    • Protease inhibitors

Contraindications:

  • Cardiovascular and peripheral vascular disease
  • Hypertension
  • Severe hepatic or renal impairment
  • Hemiplegic migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache
  • Breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding and pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates (e.g., nitroprusside, nitroglycerin).
  • Gangrene may require amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. 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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