Histamine, Serotonin & the Ergot Alkaloids

Histamine
Source/substrate: histidine Storage: vesicles of mast cells (high concentrations) Metabolized by: Monoamine oxidase & Diamine oxidase Major metabolite: imidazoleacetic acid used to measure excess production of histamine in the body (systemic mastocytosis); measured in the urine

Histamine
Functions:
Allergic reaction (In response to IgE)
Seasonal rhinitis (hay fever), urticaria & angioneurotic edema

Control of acid secretion in the stomach Neurotransmitter

Use: NONE

Receptors and Effects

H1 Receptor G-coupled receptor Second messengers Response to stimulation YES Gq-coupled receptor IP3 and DAG H2 Receptor YES Gs-coupled receptor Adenylyl cyclase (leading to increase cAMP) Gastric acid secretion by parietal cells; cardiac stimulation; reduces histamine release from mast cells (negative feedback) Presynaptic modulation of histaminergic neurotransmission in the CNS; modulates the release of other transmitters (in the periphery) H3 Receptor

Bronchoconstriction, vasodilation (due to NO, the major component of endothelium-derived relaxing factor), increase vascular permeability leading to local edema

Histamine H1 antagonists
Classification
1st Generation:
Older members: diphenhydramine & doxylamine
Highly sedating agents with significant autonomic receptor blocking effects

Newer subgroups: chlorpheniramine and cyclizine

Less sedating; less autonomic effects

2nd Generation: fexofenadine, loratadine & cetirizine

Far less lipid-soluble than the 1st generation agents Mostly free of sedating & autonomic effects

Histamine H1 antagonists
Used in chronic conditions, active by oral route Most are metabolized by the liver Half life:
Older H1 blockers: 4-12hrs Fexofenadine, cetirizine, loratadine: 12-24hrs

Histamine H1 antagonists
Mechanism:
blocks H1 receptors No effect on histamine release from storage sites More effective if given before histamine release occurs Also blocks autonomic receptors (muscarinic and alpha adrenoreceptors) A few blocks serotonin receptors

Histamine H1 antagonists
Effects:
1st generation
most are sedating Some have anti-motion sickness effects

Many are potent local anesthetics Have negligible effects at H2 receptors

Histamine H1 antagonists
Clinical Use:
Immediate type hypersensitivity
Hay fever, urticaria

Anti-motion sickness drugs

Diphenhydramine, dimenhydrinate, cyclizine, meclizine, & promethazine

Chemotherapy-induced vomiting
diphenhydramine

Histamine H1 antagonists
Toxicity
Sedation: diphenhydramine, doxylamine & promethazine Antimuscarinic effects: dry mouth, blurred vision
Some 1st generation drugs

Blockade of alpha receptors: orthostatic hypotension Excessively high concentrations lethal arrhythmias

Histamine H1 antagonists
Interactions:
Older antihistamines & benzodiazepines and alcohol Azole antifungal drugs; CYP3A4 inhibitors
Interfere with the metabolism of astemizole & terfenadine (2nd generation agents; already withdrawn from the US market)

Histamine H2 antagonists
Prototype: cimetidine Slightly less toxic agents: ranitidine, famotidine, nizatidine Orally active Half life: 1-3hrs Relatively non toxic, can be given in large doses duration of action: 12-24hrs

Histamine H2 antagonists
Mechanism:
Blocks H2 receptors No blockade at H1 or autonomic receptors

Effect:
Reduction of gastric acid secretion Also blocks cardiovascular & mast cell H2 receptor-mediated effects (no clinical significance)

Histamine H2 antagonists
Clinical Use:
Acid peptic disease (esp. duodenal ulcer)
Reduce symptoms, accelerate healing, prevent recurrences

Acute ulcer: treated with 2 or more doses/day

Recurrence of the ulcer: single bedtime dose

Zollinger-Ellison syndrome
Large doses are required; not as effective as PPI (proton-pump inhibitors)

Zollinger-Ellison Sydrome - Characterized by acid hypersecretion, severe recurrent peptic ulceration, GI bleeding & diarrhea
GERD
Not as effective as PPIs

Histamine H2 antagonists
Toxicity:
Cimetidine
potent inhibitor of hepatic drug metabolizing enzymes May also reduce hepatic blood flow Antiandrogen effects in patients receiving high doses

Ranitidine
Weaker inhibitory effect on hepatic drug metabolism

Serotonin (5-HT)
Source/substrate: tryptophan Storage: vesicles in the enterochromaffin cells of the gut & neurons of the CNS Metabolized by: monoamine oxidase Major metabolite: 5-hydroxyindoleacetic acid (5HIAA)
Measured in the urine

Neurotransmitter (CNS & ENS) Local hormone (modulates GI activity) No clinical use

Serotonin Receptors
5-HT1 receptors
Most important in the brain
Mediate synaptic inhibition via K conductance

Peripheral 5-HT receptors

Mediate both excitatory & inhibitory effects on various smooth muscle tissues

G1-protein coupled receptors

Serotonin Receptors
5-HT2 receptors
Important in brain and peripheral tissues Mediate synaptic excitation in the CNS & smooth muscle contraction (gut, bronchi, uterus, vessels) or dilation (vessels) Mechanism: IP3, K conductance, cAMP Probably mediates some of the vasodilation, diarrhea & bronchoconstriction that occur as symptoms of carcinoid tumor (a neoplasm that releases serotonin & other substances

Serotonin Receptors
5-HT3 receptors
Location:
CNS (chemoreceptive area & vomiting center) Peripheral sensory & enteric nerves

Function:
Excitation via a 5-HT gated cation channel

Blocked by antiemetic drugs

Serotonin agonists
5-HT1D agonists
Prototype: Sumatriptan (substituted indole compound)
Oral and parenteral route

Naratriptan, rizatriptan
For acute migraine & cluster headache attacks

Orally active

Serotonin agonists
Serotonin reuptake inhibitors
Some antidepressant drugs Dexfenfluramine
Appetite-reducing effect Causes cardiac toxicity (sunendocardial fibroplasia& valve dysfunction) & neurologic damage Withdrawn

Fen-phen
Dexfenfluramine + phentermine (amphetamine-like anorexiant) Weight-loss product

Serotonin Antagonists
5-HT2 and alpha-receptor blockers:
Ketanserin Phenoxybenzamine

5-HT2 and H1 receptor blocker

Cyproheptadine

5-HT3 blockers
Ondansetron, granisetron, dolasetron, alosetron Have a central-emetic action in the area postrema of the medulla & also on peripheral sensory & enteric nerve Ergot alkaloids partial agonists at 5-HT & other receptors

Serotonin Antagonists
Mechanisms:
Ketanserin & cyproheptadine
competitive pharmacologic antagonists

Phenoxybenzamine
irreversible blocker

Ketanserin, cyproheptadine & phenoxybenzamine

weakly selective agents

Serotonin Antagonists
Clinical Uses:
Ketanserin: antihypertensive drug Ketanserin, cyproheptadine & phenoxybenzamine
Carcinoid tumor (Separate or in combination)
A tumor that causes diarrhea, bronchoconstriction & flushing

Ondansetron & its congeners

Control of vomiting associated with cancer chemotherapy & postoperative vomiting

Alosetron
Irritable bowel syndrome in women; withdrawn

Serotonin Antagonists
Toxicity:
Ketanserin (alpha and H1 blockade effects) Ondansetron, granisetron, dolasetron
Diarhea & headache

Dolasetron
QRS & QT prolongation Not used in patients with heart disease

Alosetron
constipation

Ergot Alkaloids
Complex molecules that are produced by a fungus found in wet or spoiled grain
Responsible for the epidemics of St. Anthonys fire (ergotism) during the Middle Ages

20 naturally occurring members Partial agonists at alpha-adrenoreceptors & 5HT receptors Some are also agonists at the dopamine receptor

Ergot Alkaloids
3 major subgroups on the basis of the target organ in which they have their primary effects:
Brain (hallucinations and chemical psychoses)
Agents: semisynthetic drugs LSD & bromocryptine

Uterus
Very sensitive as term pregnancy nears but less so at other times Ergonovine (prototypical oxytocic ergot alkaloid)

Blood vessels
Ergotamine (prototype)

Ergot Alkaloids
Effects
Vessels
Marked & prolonged alpha receptor-mediated vasoconstriction Overdose ischemia and gangrene of the limbs

Uterus
Ergonovine & ergotamine causes uterine contraction; administered after delivery of the placenta to reduce blood loss

Brain
Hallucinations (naturally-occurring ergots and LSD) LSD (potent 5-HT2 blocker in peripheral tissues) dopamine receptor agonist Dopamine D2 receptors in the Pituitary
Bromocriptine & pergolide D2 receptor agonists, inhibit prolactin secretion

Dopamine receptors in the basal ganglia: Bromocriptine

Ergot Alkaloids
Clinical Uses:
Migraine
Ergotamine (mainstay tx of acute attacks) Methylsergide & ergonovine (prophylaxis)

Obstetric bleeding
Ergonovine & ergotamine

Hyperprolactinemia & parkinsonism

Bromocriptine & pergolide reduces prolactin secretion Bromocriptine reduces the size of pituitary tumors of the prolactin-secreting cells; Parkinsons disease

Carcinoid tumor
Methylsergide Dopamine is the physiologic prolactin release inhibitor

Ergot Alkaloids
Toxicity
Vascular effects
Severe prolonged constriction ischemia & gangrene
Nitroprusside (only consistently effective antagonist)

Unusual hyperplasia of connective tissues (retroperitoneal, retropleural or subendocardial) leads to hydroneprosis or cardiac valvular & conduction system malfunction
Mediated by agonist effects at serotonin receptors Caused by methylsergide when used for long periods

 Toxicity
GI effects
GI upset (N/V, diarrhea) most ergot alkaloids

Uterine effects
Abortion

CNS effects
Hallucinations resembling psychosis LSD Methysergide occasionally been used as an LSD substitute by users of recreational drugs