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Neurology > Ergots, Ergot Alkyloids, D2 Receptor Agonist > Flashcards

Ergots, Ergot Alkyloids, D2 Receptor Agonist Flashcards

1
Q

Ergot

A
  • French word ergot/argot (a spur) represents the dark brown, horn-shaped pegs that project from ripening ears of rye in place of rye grains
  • Comes from the fungus
  • Contains ergotoxine
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2
Q

Gangrenous Ergotism

A
  • Due primarily to effects of ergotoxine
  • Produces vigorous and prolonged occlusion of the arterioles
  • Severe symptoms take 2-3 weeks to manifest
  • Foot/leg becomes inflamed (St. Anthony’s Fire)
  • Numbness and dry gangrene
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3
Q

What are the 3 classes of ergot alkyloids?

A
  • Clavines
  • Ergoamides
  • Ergopeptides
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4
Q

What are the 3 sources of modern day ergot?

A
  • Parasitic source - infected fields
  • Saprophytic source - fungal cultures
  • Synthesis from lysergic acid
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5
Q

5-HT1 receptors

A
  • Strong affinity for serotonin
  • Present in both periphery and in CNS
  • In CNS, mediate synaptic inhibition via Gi/o, inhibition of adenylate cyclase, increased K+ conductance
  • Ex: some 5-HT1B and 5-HT1D agonist drugs
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6
Q

5-HT2 Receptors

A
  • Weaker affinity for serotonin than 5-HT1 receptors
  • Present in both brain and peripheral tissues
  • Produces synaptic excitation in the CNS via Gq/11, activation of PI, production of PIP3 and DAG, release of intracellular Ca++ stores
  • Stimulates smooth muscle contraction
  • Ex: Ergonovine - 5-HT2A and 5-HT2C agonist
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7
Q

5-HT3 receptors

A
  • Present in CNS (medullary chemoreceptor trigger zone) and in periphery (sensory and enteric neurons)
  • Receptors mediate excitation via a 5-HT-gated cation (sodium) channel
  • Ergot agonist activity at 5-HT3 will cause nausea
  • Ex: Ondansetron
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8
Q

How does Ergot affect the blood vessels?

A
  • Ergots produce alpha1-adrenoreceptor-mediated vasoconstriction that is both significant and prolonged
  • Ischemia and gangrene may result
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9
Q

How does Ergot affect the uterus?

A
  • Ergots produce direct uterine smooth muscle stimulation (alpha-adrenergic and 5-HT receptors)
  • A gravid (pregnant) uterus that is near term will undergo powerful contractions, potentially resulting in abortion or miscarriage
  • Administration of these drugs after the delivery of the placenta can be useful in preventing hemorrhage/blood loss
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10
Q

How does Ergot affect the CNS?

A
  • Ergots can produce hallucinations
  • Dopamine receptor agonism at the D2 receptors in the anterior pituitary inhibits prolactin secretion, enabling the use of ergots in treating hyperprolactinemia
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11
Q

What is the bioactivity of ergots?

A

Agonists to
* Alpha-adrenoreceptor
* 5-HT1B, 5HT1D, 5HT2A, and 5HT2C receptors
* D2 dopamine receptor
* Uterine smooth muscle

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12
Q

What ergots are oxytocics?

A

Ergonovine and Methylergonovine

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13
Q

Ergonovine and Methylergonovine

A
  • Ergoamides (e.g., nonpeptide alkaloids)
  • Colorless
  • Water soluble as a tertiary amine (free base) – Note that this is highly unusual
  • Light sensitive
  • Marketed as the water-soluble maleate salt
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14
Q

What are the indications of Oxytocics?

A

Following delivery of the placenta. For the management of:
* Uterine atony
* Uterine hemorrhage
* Subinvolution (turning inward of the edges) of the uterus
* Administered only after placental expulsion because prior administration may result in entrapment of the placenta

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15
Q

What are the contraindications of Ergonovine and Methylergonovine?

A
  • Ergonovine is metabolized is metabolized by CYP3A4. Therefore will be affected by CYP3A4 inhibitors & inducers (Inhibitors: grapefruit juice, tacrolimus, cyclosporine, macrolide antibiotics [e.g., clarithromycin, erythromycin], specific Ca2+ channel blockers [e.g., diltiazem, verapamil], antifungals [e.g., itraconazole, ketoconazole], ritonavir, specific antidepressants, goldenseal)
  • Pregnancy – Risk Factor Category X – potential risk of spontaneous abortion
  • Induction of labor – increased chance of stillbirth
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16
Q

What is a migraine headache?

A
  • Pulsatile quality of headache
  • One-day duration (4-72 hours)
  • Unilateral location (hemiorbital)
  • Nausea or vomiting OR photophobia or phonophobia
  • Disabling intensity
17
Q

Depolarization theory

Contemporary Migraine Pathogenesis Theory

A
  1. Wave of neuronal and glial cell activity
  2. trigeminovascular system activated
  3. release of CGRP by trigeminal afferents
  4. inflammatory mediators released
  5. meningeal inflammation
  6. cortical sensitization
18
Q

What ergots treat migraine?

A

Ergotamine and dihydroergotamine

19
Q

Ergotamine & Dihydroergotamine

A
  • Peptide alkaloids
    • Alanine-Proline-Phenylalanine
  • Colorless
  • Very low water solubility
  • Marketed as water soluble tartrate salt (ergotamine) or mesylate salt (DHE)
20
Q

What are the indications for Ergotamine and DHE?

A
  • Effective for ACUTE therapy of vascular headaches
    • Migraine and migraine variants
    • Cluster (histamine cephalgia)
  • NOT RECOMMENDED for chronic prophylaxis
21
Q

What is the MOA of Ergotamine & Dihydroergotamine?

A
  • Agonist at 5-HT1B and 5-HT1D receptors, similar to triptans
  • Also partial agonist at:
  • 5-HT2 receptors
  • Alpha-adrenergic receptors
  • Dopamine D2 receptors
  • Causes vasoconstriction peripheral and cranial blood vessels
22
Q

What are some other effects of Ergotamine & Dihydroergotamine?

A
  • Central vasomotor centers are depressed
  • Potent emetic effect via stimulation of the medullary chemoreceptor trigger zone (CTZ)
  • Very active uterine stimulant – direct (like ergonovine/ergometrine)
23
Q

Cafergot

A
  • Oral ergotamine tartrate + caffeine
  • Work together to reduce dilation of cranial blood vessels
  • Is less effective than triptans in acute migraine therapy
24
Q

What is the bioactivity of triptans?

A

Triptans are more specific 5-HT1 receptor agonist. They are active at:
* 5-HT1B
* 5-HT1D
* Some at 5-HT1F

25
Q

What are the adverse effects of Ergotamine and DHE?

A
  • Nausea, vomiting
  • weakness
  • paresthesia/myalgias of extremities
26
Q

What is the overdosage of Ergotamine and DHE?

A

> 15 mg/24 hours or 40 mg in 2-3 days

27
Q

What are the symptoms of overdosage of Ergotamine and DHE?

A
  • Severe vasoconstriction; peripheral ischemia
  • Fingers/toes
    • Numbness/tingling; cold; pale
  • Endarteritis (inflammation of the inner lining of an artery)
  • Acute arterial occlusion
  • Gangrene of the extremities
28
Q

How do you treat overdose of Ergotamine and DHE?

A

Treat with an ACE inhibitor such as captopril (50 mg TID PO for several days) [produces systemic arteriolar dilation]

29
Q

What are some warnings of Ergotamine and DHE?

A
  • Pregnancy category X
  • FDA Box Warning – Concomitant use with strong inhibitors of CYP3A4 may produce acute argot toxicity that may be serious and life-threatening
  • Avoid prolonged administration or excessive dosage
  • Rebound headache
30
Q

Bromocriptine

A
  • prepared via bromination of the peptide alkaloid ergocriptine
  • Colorless; water insoluble as a base
  • Marketed as its water soluble mesylate salt
  • Potent D2 receptor agonist
31
Q

What are the indications of bromocriptine?

A
  • Hyperprolactinemia – associated dysfunctions
    • Amenorrhea
    • Prolactin-secreting adenomas
  • Acromegaly (overproduction of growth hormone by anterior pituitary)
  • Treatment of Type 2 DM (Cycloset® only)
32
Q

Cabergoline

A
  • An ergopeptine
  • Potent D2 receptor agonist
  • Approved for treatment of hyperprolactinemia, prolactin-secreting tumors, reduce breast milk production, etc…
33
Q

Ropinirole (Requip)

A
  • Dopamine D2 receptor agonist
  • Used to treat PD and restless leg syndrome
  • 50% is 1st pass metabolized in liver by CYP1A2
  • Dosing starts low and titrates up
  • Rapid withdrawal can produce serious side effects mimicking symptoms of NMS (insomnia, anxiety, apathy, depression, sweating, fatigue, and pain)
  • Symptoms do not respond to treatment with levodopa
34
Q

Pramipexole (Mirapex)

A
  • Dopamine D2 and D3 receptor agonist
  • Used to treat PD and restless leg syndrome
  • Also has antidepressants effects in patients with PD
  • 90% recovered in urine
  • Rapidly absorbed
  • As with ropinirole, dosing starts low and titrates up. Rapid withdrawal can produce serious side effects
35
Q

Rasagiline (Azilect)

A
  • Irreversible MAOI-B inhibitor
  • Used alone in early stages of PD or as an adjunct therapy in later stages of PD
  • Potential for serotonin syndrome when used in combination with serotonin-enhancing medications
  • Potential interactions with sympathomimetic medications (potential for hypertensive crisis)
  • Potential for rapid withdrawal to produce serious side effects (depression, anxiety with panic attacks, dysphoria, and agitation)

Neurology (21 decks)

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