Neuro/Psych Final - Lecture 3 Ergots, Ergot Alkaloids & D2 Receptor Agonists

Dr. Gibbs: Slide Sledge Hammer Approach

Ergot is derived from which organism?

Claviceps purpurea

Gangrenous ergotism is primarily caused by which component of ergot?

Ergotoxine

Which of the following correctly names the three classes of ergot alkaloids?

Clavines, ergoamides, ergopeptines

The basic ring structure shared by all ergot alkaloids is called:

Ergoline

Activation of 5-HT3 receptors by ergot alkaloids produces which effect?

Nausea

5-HT2 receptors mediate smooth muscle contraction primarily through which second messenger pathway?

Gq/11 → phosphoinositide → IP3/DAG → Ca2+ release

Ergonovine and methylergonovine are correctly classified as which type of alkaloid?

Ergoamides

Why must ergonovine be administered ONLY after placental expulsion?

Prior administration may result in entrapment of the placenta

Ergonovine is metabolized primarily by which enzyme, making it susceptible to drug interactions with macrolide antibiotics?

CYP3A4

The migraine diagnostic mnemonic POUND stands for Pulsatile quality, One-day duration, Unilateral location, Nausea/Vomiting, and:

Disabling intensity

The primary mechanism by which ergotamine and DHE relieve migraines is:

Agonism at 5-HT1B/1D receptors causing constriction of cranial blood vessels

Which of the following is the onset of action for dihydroergotamine (DHE)?

15–30 minutes

Cafergot® contains which combination of drugs?

Ergotamine tartrate + caffeine

A patient overdoses on ergotamine and develops arterial occlusion and gangrene. Which agent is most appropriate for treatment?

Captopril (ACE inhibitor)

Triptans differ from ergotamine primarily because they:

Selectively act at 5-HT1B/1D receptors with fewer off-target effects

The D2 receptor agonist activity of ergot alkaloids in the anterior pituitary is therapeutically useful for treating:

Hyperprolactinemia

Bromocriptine (Cycloset®) is approved as an adjunct to diet and exercise for which condition?

Type 2 diabetes

Pergolide (Permax®) was withdrawn from the market in 2007 primarily due to:

Valvulopathies (cardiac valve abnormalities)

Ropinirole and pramipexole are both used to treat Parkinson's disease and restless leg syndrome. Which of the following distinguishes pramipexole from ropinirole?

Pramipexole also agonizes dopamine D3 receptors and has antidepressant effects

Rasagiline carries a risk of serotonin syndrome when combined with serotonin-enhancing drugs because it is:

An irreversible MAO-B inhibitor

Ergot is the dried sclerotium of which fungus?

Claviceps purpurea

Ergot most commonly grows on which grain?

Rye

The early history of ergot dates back to approximately what time and location?

600 BC in Assyria

The word "ergot" derives from a French word meaning:

Spur

Ergot appears physically as:

Dark brown, horn-shaped pegs projecting from ripening rye

Ergot contains which toxic substance responsible for gangrenous ergotism?

Ergotoxine

How many distinct types of ergotism are recognized?

Two

The two types of ergotism are:

Gangrenous and convulsive/spasmodic

Gangrenous ergotism is caused by:

Ergotoxine

Convulsive/spasmodic ergotism is:

NOT caused by ergotoxine

Gangrenous ergotism epidemics were historically concentrated in which country between 800–1300 AD?

France

The mechanism of gangrenous ergotism involves:

Vigorous and prolonged occlusion of the arterioles

Severe symptoms of gangrenous ergotism take approximately how long to manifest?

2–3 weeks

Which symptom complex is characteristic of gangrenous ergotism, historically called "St. Anthony's Fire"?

Foot/leg inflammation feeling hot, alternating with cold sensations

Which of the following is NOT a sign or symptom of gangrenous ergotism?

Bilateral tinnitus and vertigo

Which religious order historically cared for sufferers of gangrenous ergotism, lending its name to the disease?

Order of St. Anthony

Ergotism epidemics historically followed which conditions?

Bad seasons with poor harvests, scarcity of food, extreme poverty

Although the source of ergotism has been known since the 17th century, outbreaks have continued in:

India (1958–1975) and Ethiopia (1978, 2001)

Today, ergotism in developed countries is largely controlled by:

Modern grain cleaning techniques and standards

Ergotism remains a significant disease in which field today?

Veterinary medicine (sheep, cattle, pigs, chickens)

In 1582, ergot was first employed by midwives to:

Produce strong uterine contractions

Ergot was first used in official medicine in 1808 as a remedy for:

"Quickening childbirth"

In 1824, ergot's medicinal use was restricted to which indication due to increased stillbirths?

Treatment of postpartum hemorrhage

The basic ring structure of all ergot alkaloids is called:

Ergoline

The ergoline ring structure most closely resembles which compound?

Lysergic acid

Modern-day ergot is sourced from all of the following EXCEPT:

Recombinant bacterial fermentation

Ergot alkaloids are isolated and converted via hydrolysis to which key intermediate?

Lysergic acid

Lysergic acid is used to prepare which two ergot alkaloid derivatives?

Ergonovine (ergoamide) and ergotamine (ergopeptine)

The three classes of ergot alkaloids are:

Clavines, ergoamides, ergopeptines

Clavines are characterized as:

Simpler structures (R1: OH/acetoxy; R2: H/prenyl)

Ergoamides are best described as:

Nonpeptide alkaloids (lysergic acid amides)

Which is an example of an ergoamide?

Ergonovine

Ergopeptines are characterized as:

Peptide alkaloids

Which of the following is an ergopeptine?

Ergotamine

Bromocriptine and cabergoline are categorized as which class of ergot alkaloid?

Ergopeptines

Ergot alkaloids generally act as which type of ligand at their target receptors?

Partial agonists, with agonist vs. antagonist balance varying by alkaloid

Ergot alkaloids act at which of the following receptor types?

α-Adrenoceptors, multiple 5-HT subtypes, and dopamine D2 receptors

Which adrenergic receptor subtypes are activated by ergot alkaloids?

α1 and α2

Activation of α1-adrenoceptors by ergot alkaloids leads to:

Vasoconstriction → ischemia, gangrene

5-HT1A, 5-HT1B, and 5-HT1D receptors mediate synaptic inhibition through which mechanism?

Gi/o → ↓ adenylate cyclase, ↑ K+ conductance

5-HT1 receptors are characterized by:

Strong affinity for serotonin, present in CNS and periphery

5-HT2A and 5-HT2C receptors mediate synaptic excitation through which signaling pathway?

Gq/11 → phosphoinositide → IP3/DAG → Ca²⁺ release

5-HT2 receptors stimulate smooth muscle contraction in which tissues?

Blood vessels, uterus, bronchi, gut

5-HT2 receptor affinity for serotonin compared to 5-HT1 receptors is:

Weaker

5-HT3 receptors are unique among serotonin receptors because they:

Are 5-HT-gated cation (Na⁺) channels

Where are 5-HT3 receptors located?

CNS (medullary chemoreceptor trigger zone) and periphery (sensory and enteric neurons)

Ergot agonist activity at 5-HT3 receptors produces what clinical effect?

Nausea (via CTZ stimulation)

Which class of drugs are 5-HT3 antagonists used as antiemetics?

The "-setron" drugs (ondansetron, granisetron, dolasetron)

Examples of 5-HT1B/1D agonist drugs (other than ergotamine) include:

Sumatriptan and zolmitriptan

Ergot agonism at dopamine D2 receptors in the anterior pituitary produces what effect?

Inhibits prolactin secretion

Some D2 agonism by ergot alkaloids in the CNS may also cause:

Nausea/vomiting

In blood vessels, ergot alkaloids produce vasoconstriction primarily through:

α1-adrenoceptor-mediated mechanisms (significant and prolonged)

The vascular effects of ergots are responsible for which classic clinical syndrome?

Ischemia and gangrene (St. Anthony's Fire)

Ergot alkaloid uterine effects are mediated by:

α-adrenergic and 5-HT receptors causing direct smooth muscle stimulation

When ergots are administered to a near-term gravid uterus, the most likely outcome is:

Powerful contractions, with risk of abortion or miscarriage

A nongravid uterus or early-term pregnancy typically requires what to produce contractions with ergots?

A high dose of ergot

Administration of ergots AFTER placental delivery is useful for:

Preventing hemorrhage/blood loss

Within the CNS, ergot alkaloids can produce:

Hallucinations (severity varies by alkaloid)

D2 agonism in the anterior pituitary by ergot alkaloids enables their use in treating:

Hyperprolactinemia

Ergonovine and methylergonovine are which class of ergot alkaloid?

Ergoamides (nonpeptide alkaloids)

Alternative names (AKA) for ergonovine include all of the following EXCEPT:

Ergotamine

Ergonovine is unusual among alkaloids because it is:

Water soluble as a tertiary amine (free base)

Ergonovine is:

Light-sensitive

Ergonovine and methylergonovine are marketed commercially as which salt form?

Maleate (water-soluble)

The mechanism by which ergonovine/methylergonovine stimulate the uterus involves:

Direct uterine stimulation via α-adrenergic and 5-HT2A/2C agonism

Which oxytocic agent is the preferred FIRST-LINE therapy, with ergonovine/methylergonovine reserved for second-line use?

Oxytocin

Indications for ergonovine/methylergonovine include all of the following EXCEPT:

Induction of labor

Why must ergonovine be administered ONLY after placental expulsion?

Prior administration may result in entrapment of the placenta

The brand name for ergonovine is:

Ergotrate®

The standard oral dosing of ergonovine (Ergotrate®) is:

0.2 mg PO every 6–12 hours for up to 48 hours

The brand name for methylergonovine is:

Methergine®

Methylergonovine is available in which routes of administration?

Oral tablets, IM, and IV

Standard oral methylergonovine dosing is:

0.2 mg TID/QID for 2–7 days

Standard parenteral (IM/IV) methylergonovine dosing is:

0.2 mg every 2–4 hours up to 5 doses

Ergonovine is metabolized primarily by which enzyme?

CYP3A4

Which of the following is a known CYP3A4 inhibitor that can affect ergonovine metabolism?

All of the above

Which of the following is a CYP3A4 inhibitor relevant to ergonovine drug interactions?

All of the above

What is the FDA pregnancy risk category for ergonovine and methylergonovine?

Category X

A major contraindication for ergonovine/methylergonovine is:

Pregnancy (Category X — risk of spontaneous abortion)

Using ergonovine for induction of labor is contraindicated because of:

Increased chance of stillbirth