Histamine, Serotonin & the Ergot Alkaloids

Histamine, Serotonin & the Ergot AlkaloidsHistamineSource/substrate: histidineStorage: 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 urineHistamineFunctions: Allergic reaction (In response to IgE)Seasonal rhinitis (hay fever), urticaria & angioneurotic edema Control of acid secretion in the stomachNeurotransmitter

Use: NONE

Receptors and EffectsH1 ReceptorH2 ReceptorH3 ReceptorG-coupled receptorYESGq-coupled receptorYESGs-coupled receptorSecond messengersIP3 and DAGAdenylyl cyclase (leading to increase cAMP)Response to stimulationBronchoconstriction, vasodilation (due to NO, the major component of endothelium-derived relaxing factor), increase vascular permeability leading to local edemaGastric 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)Histamine H1 antagonistsClassification1st Generation:Older members: diphenhydramine & doxylamineHighly sedating agents with significant autonomic receptor blocking effectsNewer subgroups: chlorpheniramine and cyclizineLess sedating; less autonomic effects2nd Generation: fexofenadine, loratadine & cetirizineFar less lipid-soluble than the 1st generation agentsMostly free of sedating & autonomic effects

Histamine H1 antagonistsUsed in chronic conditions, active by oral routeMost are metabolized by the liverHalf life:Older H1 blockers: 4-12hrsFexofenadine, cetirizine, loratadine: 12-24hrs

Histamine H1 antagonistsMechanism: blocks H1 receptorsNo effect on histamine release from storage sitesMore effective if given before histamine release occursAlso blocks autonomic receptors (muscarinic and alpha adrenoreceptors)A few blocks serotonin receptors

Histamine H1 antagonistsEffects:1st generationmost are sedatingSome have anti-motion sickness effectsMany are potent local anestheticsHave negligible effects at H2 receptors

Histamine H1 antagonistsClinical Use: Immediate type hypersensitivityHay fever, urticariaAnti-motion sickness drugsDiphenhydramine, dimenhydrinate, cyclizine, meclizine, & promethazineChemotherapy-induced vomitingdiphenhydramine

Histamine H1 antagonistsToxicitySedation: diphenhydramine, doxylamine & promethazineAntimuscarinic effects: dry mouth, blurred visionSome 1st generation drugsBlockade of alpha receptors: orthostatic hypotensionExcessively high concentrations lethal arrhythmias

Histamine H1 antagonistsInteractions:Older antihistamines & benzodiazepines and alcoholAzole antifungal drugs; CYP3A4 inhibitorsInterfere with the metabolism of astemizole & terfenadine (2nd generation agents; already withdrawn from the US market)

Histamine H2 antagonistsPrototype: cimetidineSlightly less toxic agents: ranitidine, famotidine, nizatidineOrally activeHalf life: 1-3hrsRelatively non toxic, can be given in large doses duration of action: 12-24hrsHistamine H2 antagonistsMechanism:Blocks H2 receptorsNo blockade at H1 or autonomic receptors

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

Histamine H2 antagonistsClinical Use:Acid peptic disease (esp. duodenal ulcer)Reduce symptoms, accelerate healing, prevent recurrencesAcute ulcer: treated with 2 or more doses/dayRecurrence of the ulcer: single bedtime doseZollinger-Ellison syndromeLarge 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

GERDNot as effective as PPIs

Zollinger-Ellison Sydrome- Characterized by acid hypersecretion, severe recurrent peptic ulceration, GI bleeding & diarrhea14Histamine H2 antagonistsToxicity:Cimetidinepotent inhibitor of hepatic drug metabolizing enzymesMay also reduce hepatic blood flowAntiandrogen effects in patients receiving high dosesRanitidineWeaker inhibitory effect on hepatic drug metabolism

Serotonin (5-HT)Source/substrate: tryptophanStorage: vesicles in the enterochromaffin cells of the gut & neurons of the CNSMetabolized by: monoamine oxidaseMajor metabolite: 5-hydroxyindoleacetic acid (5-HIAA)Measured in the urineNeurotransmitter (CNS & ENS)Local hormone (modulates GI activity)No clinical useSerotonin Receptors5-HT1 receptorsMost important in the brainMediate synaptic inhibition via K conductancePeripheral 5-HT receptorsMediate both excitatory & inhibitory effects on various smooth muscle tissuesG1-protein coupled receptors

Serotonin Receptors5-HT2 receptorsImportant in brain and peripheral tissuesMediate synaptic excitation in the CNS & smooth muscle contraction (gut, bronchi, uterus, vessels) or dilation (vessels)Mechanism: IP3, K conductance, cAMPProbably mediates some of the vasodilation, diarrhea & bronchoconstriction that occur as symptoms of carcinoid tumor (a neoplasm that releases serotonin & other substances

Serotonin Receptors5-HT3 receptorsLocation:CNS (chemoreceptive area & vomiting center)Peripheral sensory & enteric nervesFunction: Excitation via a 5-HT gated cation channelBlocked by antiemetic drugs

Serotonin agonists5-HT1D agonistsPrototype: Sumatriptan (substituted indole compound)Oral and parenteral routeNaratriptan, rizatriptan For acute migraine & cluster headache attacksOrally active

Serotonin agonistsSerotonin reuptake inhibitorsSome antidepressant drugsDexfenfluramineAppetite-reducing effectCauses cardiac toxicity (sunendocardial fibroplasia& valve dysfunction) & neurologic damageWithdrawnFen-phenDexfenfluramine + phentermine (amphetamine-like anorexiant)Weight-loss product

Serotonin Antagonists5-HT2 and alpha-receptor blockers:KetanserinPhenoxybenzamine5-HT2 and H1 receptor blockerCyproheptadine5-HT3 blockersOndansetron, granisetron, dolasetron, alosetronHave a central-emetic action in the area postrema of the medulla & also on peripheral sensory & enteric nerveErgot alkaloids partial agonists at 5-HT & other receptors

Ergot alkaloids partial agonists at 5-HT & other receptors22Serotonin AntagonistsMechanisms:Ketanserin & cyproheptadine competitive pharmacologic antagonistsPhenoxybenzamine irreversible blockerKetanserin, cyproheptadine & phenoxybenzamineweakly selective agents

Serotonin AntagonistsClinical Uses:Ketanserin: antihypertensive drugKetanserin, cyproheptadine & phenoxybenzamineCarcinoid tumor (Separate or in combination)A tumor that causes diarrhea, bronchoconstriction & flushingOndansetron & its congenersControl of vomiting associated with cancer chemotherapy & postoperative vomitingAlosetronIrritable bowel syndrome in women; withdrawn

Serotonin AntagonistsToxicity:Ketanserin (alpha and H1 blockade effects)Ondansetron, granisetron, dolasetronDiarhea & headacheDolasetronQRS & QT prolongationNot used in patients with heart diseaseAlosetronconstipation

Ergot AlkaloidsComplex molecules that are produced by a fungus found in wet or spoiled grainResponsible for the epidemics of St. Anthonys fire (ergotism) during the Middle Ages20 naturally occurring membersPartial agonists at alpha-adrenoreceptors & 5-HT receptorsSome are also agonists at the dopamine receptorErgot Alkaloids3 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 & bromocryptineUterusVery sensitive as term pregnancy nears but less so at other timesErgonovine (prototypical oxytocic ergot alkaloid)Blood vesselsErgotamine (prototype)

Ergot AlkaloidsEffectsVesselsMarked & prolonged alpha receptor-mediated vasoconstrictionOverdose ischemia and gangrene of the limbsUterusErgonovine & ergotamine causes uterine contraction; administered after delivery of the placenta to reduce blood lossBrainHallucinations (naturally-occurring ergots and LSD)LSD (potent 5-HT2 blocker in peripheral tissues) dopamine receptor agonistDopamine D2 receptors in the PituitaryBromocriptine & pergolide D2 receptor agonists, inhibit prolactin secretionDopamine receptors in the basal ganglia: Bromocriptine

Ergot AlkaloidsClinical Uses:MigraineErgotamine (mainstay tx of acute attacks)Methylsergide & ergonovine (prophylaxis)Obstetric bleedingErgonovine & ergotamineHyperprolactinemia & parkinsonismBromocriptine & pergolide reduces prolactin secretionBromocriptine reduces the size of pituitary tumors of the prolactin-secreting cells; Parkinsons diseaseCarcinoid tumorMethylsergideDopamine is the physiologic prolactin release inhibitor

Dopamine is the physiologic prolactin release inhibitor29Ergot AlkaloidsToxicityVascular effectsSevere prolonged constriction ischemia & gangreneNitroprusside (only consistently effective antagonist)Unusual hyperplasia of connective tissues (retroperitoneal, retropleural or subendocardial) leads to hydroneprosis or cardiac valvular & conduction system malfunctionMediated by agonist effects at serotonin receptorsCaused by methylsergide when used for long periods

ToxicityGI effectsGI upset (N/V, diarrhea) most ergot alkaloidsUterine effectsAbortionCNS effectsHallucinations resembling psychosis LSDMethysergide occasionally been used as an LSD substitute by users of recreational drugs