Ergots, Ergot Alkyloids, D2 Receptor Agonist Flashcards
Ergot
- 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
Gangrenous Ergotism
- 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
What are the 3 classes of ergot alkyloids?
- Clavines
- Ergoamides
- Ergopeptides
What are the 3 sources of modern day ergot?
- Parasitic source - infected fields
- Saprophytic source - fungal cultures
- Synthesis from lysergic acid
5-HT1 receptors
- 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
5-HT2 Receptors
- 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
5-HT3 receptors
- 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
How does Ergot affect the blood vessels?
- Ergots produce alpha1-adrenoreceptor-mediated vasoconstriction that is both significant and prolonged
- Ischemia and gangrene may result
How does Ergot affect the uterus?
- 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
How does Ergot affect the CNS?
- 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
What is the bioactivity of ergots?
Agonists to
* Alpha-adrenoreceptor
* 5-HT1B, 5HT1D, 5HT2A, and 5HT2C receptors
* D2 dopamine receptor
* Uterine smooth muscle
What ergots are oxytocics?
Ergonovine and Methylergonovine
Ergonovine and Methylergonovine
- 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
What are the indications of Oxytocics?
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
What are the contraindications of Ergonovine and Methylergonovine?
- 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
What is a migraine headache?
- Pulsatile quality of headache
- One-day duration (4-72 hours)
- Unilateral location (hemiorbital)
- Nausea or vomiting OR photophobia or phonophobia
- Disabling intensity
Depolarization theory
Contemporary Migraine Pathogenesis Theory
- Wave of neuronal and glial cell activity
- trigeminovascular system activated
- release of CGRP by trigeminal afferents
- inflammatory mediators released
- meningeal inflammation
- cortical sensitization
What ergots treat migraine?
Ergotamine and dihydroergotamine
Ergotamine & Dihydroergotamine
- Peptide alkaloids
- Alanine-Proline-Phenylalanine
- Colorless
- Very low water solubility
- Marketed as water soluble tartrate salt (ergotamine) or mesylate salt (DHE)
What are the indications for Ergotamine and DHE?
- Effective for ACUTE therapy of vascular headaches
- Migraine and migraine variants
- Cluster (histamine cephalgia)
- NOT RECOMMENDED for chronic prophylaxis
What is the MOA of Ergotamine & Dihydroergotamine?
- 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
What are some other effects of Ergotamine & Dihydroergotamine?
- 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)
Cafergot
- Oral ergotamine tartrate + caffeine
- Work together to reduce dilation of cranial blood vessels
- Is less effective than triptans in acute migraine therapy
What is the bioactivity of triptans?
Triptans are more specific 5-HT1 receptor agonist. They are active at:
* 5-HT1B
* 5-HT1D
* Some at 5-HT1F
What are the adverse effects of Ergotamine and DHE?
- Nausea, vomiting
- weakness
- paresthesia/myalgias of extremities
What is the overdosage of Ergotamine and DHE?
> 15 mg/24 hours or 40 mg in 2-3 days
What are the symptoms of overdosage of Ergotamine and DHE?
- 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
How do you treat overdose of Ergotamine and DHE?
Treat with an ACE inhibitor such as captopril (50 mg TID PO for several days) [produces systemic arteriolar dilation]
What are some warnings of Ergotamine and DHE?
- 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
Bromocriptine
- 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
What are the indications of bromocriptine?
- Hyperprolactinemia – associated dysfunctions
- Amenorrhea
- Prolactin-secreting adenomas
- Acromegaly (overproduction of growth hormone by anterior pituitary)
- Treatment of Type 2 DM (Cycloset® only)
Cabergoline
- An ergopeptine
- Potent D2 receptor agonist
- Approved for treatment of hyperprolactinemia, prolactin-secreting tumors, reduce breast milk production, etc…
Ropinirole (Requip)
- 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
Pramipexole (Mirapex)
- 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
Rasagiline (Azilect)
- 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)
