Serotonin & the Ergot Alkaloids - PowerPoint Presentation

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Serotonin& the Ergot Alkaloids

Assist. ProfessorDr. Haitham M. AlwaliPh.D. PharmacologyAl-Nahrain College of Pharmacy

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Serotonin& the Ergot Alkaloids

Serotonin (5-hydroxytryptamine; 5-HT) is endogenous autacoids molecules that do not fall into traditional autonomic groups. Serotonin( and Histamine) are the most important amine autacoids have

powerful pharmacologic effects on smooth muscle and other tissues.

The

ergot alkaloids

are a heterogeneous group of drugs (not autacoids) that interact with serotonin receptors, dopamine receptors, and α receptors.

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SEROTONIN (5-HYDROXYTRYPTAMINE;5-HT) & RELATED AGONISTS

Serotonin is produced from tryptophan and stored in vesicles in the enterochromaffin cells of the gut and neurons of the CNS and enteric nervous system.After release, it is metabolized by monoamine oxidase. Excess production in the body (

eg, in carcinoid syndrome) can be detected by measuring its major

metabolite,

5-hydroxyindole

acetic acid (5-HIAA), in the urine.

Serotonin plays a physiologic role as a neurotransmitter

in both the

CNS

and

the

enteric nervous system

and may have a role as a local hormone that modulates gastrointestinal activity.

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A. Receptors and Effects5-HT1 receptors

are most important in the brain and mediate synaptic inhibition via increased potassium conductance. Peripheral 5-HT1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues. 5-HT1 receptors are Gi-protein-coupled.5-HT2

receptors are important in

both brain

and peripheral tissues

. These receptors mediate synaptic excitation in the CNS and smooth muscle contraction

(gut, bronchi, uterus, some vessels) or relaxation

(other vessels).

Several mechanisms

are involved, including (in different tissues)

increased IP3

, decreased potassium conductance, and decreased

cAMP. This receptor probably mediates some of the vasodilation, diarrhea,

and bronchoconstriction that occur as symptoms of carcinoid

tumor,

a

neoplasm that releases serotonin and other substances.

In the CNS

, 5-HT2C receptors mediate a reduction in appetite that has been used in the treatment of obesity.

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A. Receptors and Effects

3. 5-HT3 receptors are found in the CNS, especially in the chemoreceptive area and vomiting center, and in peripheral sensory and enteric nerves. These receptors mediate excitation via a 5-HT-gated cation

channel. Antagonists acting

at this

receptor are extremely

useful antiemetic drugs.4. 5-HT4 receptors are

found in the gastrointestinal

tract

and play an important role

in

intestinal motility

.

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B. Clinical Uses

Serotonin has no clinical applications, but other more selective agonists are useful.1. 5-HT1D/1B agonists—Sumatriptan is the prototype. Almotriptan, eletriptan,

frovatriptan,

naratriptan

,

rizatriptan, zolmitriptan “-triptans

” are similar to sumatriptan

They

are the first-line treatment

for acute migraine

and cluster headache attacks

, an observation that strengthens

the association of serotonin abnormalities with these headache syndromes.These drugs are active orally;

sumatriptan is also availablefor nasal and parenteral administration.

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2. 5-HT2C agonists—Lorcaserin

has recently been approved for the treatment of obesity. It activates receptors in the CNS and appears to moderately reduce appetite. Older drugs, fenfluramine and dexfenfluramine, appear to act directly and by releasing neuronal5-HT or inhibiting SERT, and thereby activating central5-HT2C receptors.

They were withdrawn in the USA because their use was associated with damage to cardiac valves.

Dexfenfluramine was

combined with phentermine

, an amphetamine-like anorexiant, in a weight-loss product known as “dex-phen

.” Because of toxicity, this combination product is also banned in the USA.

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3. 5-HT4 Partial agonist—

Tegaserod is a newer drug that acts as an agonist in the colon. It was approved and briefly marketed for use in chronic constipation, but because of cardiovascular toxicity, its use is now restricted.4. Selective serotonin reuptake inhibitors (SSRI)—A number of important antidepressant drugs act to increase activity at central serotonergic synapses by inhibiting the serotonin reuptake transporter, SERT.

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C. Hyperthermic Syndromes

(serotonin syndrome)Serotonin and drugs with 5-HT agonist effects are sometimes associated with drug reactions with high fever, skeletal muscle effects, and cardiovascular abnormalities that can be life-threatening.3/15/201811

SEROTONIN ANTAGONISTS

A. Classification and PrototypesKetanserin, phenoxybenzamine, and cyproheptadine are effective 5-HT2 blockers.Ondansetron, granisetron

, dolasetron, and

alosetron

are 5-HT3 blockers. The ergot alkaloids

are partial agonists (and therefore have some antagonist effects) at 5-HT

and other

receptors (see later

discussion)

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B. Mechanisms and Effects

Ketanserin and cyproheptadine are competitive pharmacologic 5-HT2 antagonists. Phenoxybenzamine is an irreversible

blocker at this receptor.

Ketanserin

,

cyproheptadine, and phenoxybenzamine are poorly selective

agents. In addition to inhibition of serotonin effects, other actions include

α-

blockade

(

ketanserin

,

phenoxybenzamine) or H1-blockade (cyproheptadine).Ondansetron

, granisetron, and

dolasetron

are

selective

5-HT3 receptor blockers and have important antiemetic actions in

the area postrema of the medulla and also on peripheral sensory and enteric

nerves.

Although

it acts at the 5-HT3 receptor,

alosetron

appears

to lack these antiemetic effects.

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C. Clinical UsesKetanserin is used as an

antihypertensive drug.Ketanserin, cyproheptadine, and phenoxybenzamine may be of value (separately or in combination) in the treatment of carcinoid tumor: a neoplasm that secretes large amounts

ofserotonin (and peptides) and causes diarrhea,

bronchoconstriction, and

flushing

.Ondansetron and its congeners are extremely useful in

the control of vomiting

associated with

cancer chemotherapy

and postoperative vomiting

.

Alosetron

is used in the treatment of women

with irritable bowel syndrome associated with diarrhea.

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D. ToxicityAdverse effects of ketanserin are

those of α blockade and H1 blockade.The toxicities of ondansetron, granisetron, and dolasetron include diarrhea and headache.Dolasetron

has been associated with QRS and QTc

prolongation in the ECG

and should not be used in patients with heart disease

.Alosetron

causes significant

constipation

in

some patients

and has been associated with fatal bowel complications.3/15/2018

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ERGOT ALKALOIDS

These complex molecules are produced by a fungus found in wet or spoiled grain. They are responsible for the epidemics of “St. Anthony’s fire” (ergotism) described during the Middle Ages and recurring to the present time.There are at least 20

naturally occurring members of the family, but only a few of these and semisynthetic derivatives are used as therapeutic agents.

Most ergot

alkaloids are

partial agonists at α adrenoceptors and

5-HT receptors, and some are potent agonists at dopamine receptors.

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A. Classification and Effects3/15/2018

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1. Vessels— Ergot alkaloids can produce marked and prolonged α-

receptor–mediated vasoconstriction. Ergotamine is the prototype. An overdose can cause ischemia and gangrene of the limbs or bowel. Because they are partial agonists, the drugs may also block the α-agonist effects of sympathomimetics, and ergotamine can cause epinephrine reversal.2. Uterus—Ergot alkaloids produce powerful contraction in this

tissue, especially near term. Ergonovine is the prototype. In pregnancy, the uterine contraction is sufficient to cause abortion or miscarriage.

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3. Brain—Hallucinations may be prominent with the

naturally occurring ergots and with lysergic acid diethylamide (LSD), a semisynthetic prototypical hallucinogenic ergot derivative. Although LSD is a potent 5-HT2 blocker in peripheral tissues, its actions in the CNS are thought to be due to agonist actions at dopamine receptors. In the pituitary, some ergot alkaloids are potent dopamine-like agonists

and inhibit prolactin secretion. Bromocriptine

and

pergolide

are among the most potent semisynthetic ergot derivatives. They act as

dopamine D2 agonists in the pituitary and the basal ganglia

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B. Clinical Uses

1. Migraine—Ergotamine has been a mainstay of treatment of acute attacks and is still used in combination with caffeine.Methysergide, dihydroergonovine, and ergonovine have been used for prophylaxis. The triptan derivatives are now considered preferable to the ergots because of lower

toxicity.2. Obstetric bleeding—

Ergonovine

and ergotamine are effective agents for the

reduction of postpartum bleeding. They must not be given before delivery of the placenta.

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3. Hyperprolactinemia and

parkinsonism— Bromocriptine, pergolide, and cabergoline have been used to reduce prolactin secretion (dopamine is the physiologic prolactin release inhibitor). Pergolide has been withdrawn from the US market

.Bromocriptine also appears to reduce the size of pituitary

tumors of

the prolactin-secreting

cells.Bromocriptine and

cabergoline are used in

hyperprolactinemia

and

to

treat

acromegaly.

These drugs have been used in the treatment of Parkinson’s disease, but other drugs are preferred

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C. Toxicity:1. Vascular effects—

Severe prolonged vasoconstriction can result in ischemia and gangrene. The most consistently effective antidote is nitroprusside. 2. Gastrointestinal effects—Ergot alkaloids cause gastrointestinal upset (nausea, vomiting, diarrhea) in many persons.

3. Uterine effects—Marked uterine contractions more

sensitive to ergot

alkaloids during

pregnancy. 4. CNS effects—Hallucinations resembling psychosis are common with

LSD but less so with the other ergot alkaloids. Methysergide was occasionally used in the past as an LSD substitute

by users

of “recreational” drugs.

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