HISTAMINE,SOROTONIN AND THE ERGOT ALKALOIDS Flashcards by Ivinn karl Raranggol

Mediator of immediate allergic andinflammatory reactions
 Has a role in gastric acid secretion
 As a neurotransmitter and neuromodulator
 Role in immune functions and chemotaxis of white blood cells
anaphylactic reaction

HISTAMINE

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Formed by decarboxylation of the amino acid L–histidine,

a reaction catalyzed by the enzyme histidine decarboxylase

HISTAMINE

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The major metabolic pathways of histamine

N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic
acid (IAA).

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what are the neoplasms associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites.

systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia

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Mast cells are especially rich at sites of potential tissue injury

nose, mouth, and feet; internal body surfaces; and blood vessels,
particularly at pressure points and bifurcations.

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Non-mast cell histamine is found in several tissues, including the?

brain, where it functions as a neurotransmitter. Strong
evidence implicates endogenous neurotransmitter histamine in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep
and arousal

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A second important nonneuronal site of histamine storage and release is the?

enterochromaffin-like (ECL) cells of the fundus of the stomach
activate the acid-producing parietal
cells of the mucosa

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account for the most important pathophysiologic mechanism of mast cell and basophil histamine
release.

Immunologic processes/Immunologic Release

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Immunologic Release of histamine requires?

energy and calcium

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By a negative feedback control mechanism mediated by ___ histamine appears to modulate its own release and that of other mediators from sensitized mast cells in some tissues.

H2 receptors,

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Upon injury to a tissue,

released histamine causes?

local vasodilation and leakage of

plasma-containing mediators of acute inflammation (complement, C-reactive protein) and antibodies.

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Release of peptides from nerves in response to

inflammation is also probably modulated by histamine acting on?

H3 receptor

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Certain amines, including drugs such as ___ and___ can displace histamine from its bound form within cells.

morphine and tubocurarine

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distribution: Smooth muscle, endothelium, brain
postreceptor mechanism: Gq, ↑ IP3, DAG
partially selective agonist: Histaprodifen
partially selective antagonist: Mepyramine,1
triprolidine, cetirizine

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D:H2 Gastric mucosa, cardiac muscle, mast cells, brain Pm: Gs, ↑ cAMP
PSA: Amthamine
PSAn: Cimetidine,1 ranitidine,1 tiotidine

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D: Presynaptic autoreceptors and heteroreceptors:
brain, myenteric plexus, other neurons
Pm:Gi, ↓ cAMP
PSA:R-α-Methylhistamine, imetit, immepip
PSAn:Thioperamide,1 iodophenpropit, clobenpropit,1 tiprolisant,1 proxy

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D:Eosinophils, neutrophils, CD4 T cells Gi,
Pm:↓ cAMP
PSA: Clobenpropit, imetit, clozapine
PSAn”Thioperamide

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H1 and H3 receptors paly an important role in?

appetite
satiety
nociception

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An investigational inverse H3 agonist ___ appears to reduce drowsiness in patients
with narcolepsy.

pitolisant (BF2649)

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is an important component of
the urticarial response and reactions to insect and nettle stings.
Some evidence suggests that local high concentrations can also
depolarize efferent (axonal) nerve endings

H1-mediated effect

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Vasodilation elicited by small doses of histamine is caused ___ activation and is mediated mainly by release of nitric oxide from the endothelium

H1-receptor a

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can block bronchoconstriction effect of histamine

ganglion blocking agents

H1-receptor antagonists

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other organs affected by the release of histamine?

eyes
genitourinary tract
uterus

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Histamine has long been recognized as a
powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of?

H2 receptors

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H3-receptor absence in mice results in increased?

food intake, decreased energy expenditure, and obesity,insulin resistance and increased blood levels of leptin and insulin.

—Intradermal injection of histamine | causes a characteristic red spot, edema, and flare response

The “triple response”

cell types involved in triple response

smooth muscle in the microcirculation capillary or venular endothelium sensory nerve endings.

examples of histamine receptor antagonist?

epinephrine, cromolyn and nedrocromil, beta 2 agonist

Compounds that competitively block histamine or act as inverse agonists at H1 receptors

H1-RECEPTOR ANTAGONISTS

- enter the CNS readily - strong sedative effects - block autonomic receptors - metabolized in the microsomal system in the liver - rapidly absorbed by oral administration - widely distributed 1-2 hours

1st Generation H1 receptor antagonists

``` less sedating reduced distribution in the CNS metabolized by CYP3A4 drug interaction with KETOCONAZOLE 4-6 hrs duration less lipid-soluble, cant enter the BBB ```

2nd generation H1 receptor blocker

Carbinoxamine (Clistin) -4-8 mg- Slight to moderate sedation Dimenhydrinate-50 mg-Marked sedation; anti-motion sickness activity Diphenhydramine(Benadryl)-25–50 mg- Marked sedation; anti-motion sickness activity

Ethanolamines | FIRST-GENERATION ANTIHISTAMINES

Loratadine (Claritin, etc), desloratadine (Clarinex)-10 mg (desloratadine, 5 mg)— Longer action; used at 5 mg dosage Cetirizine (Zyrtec, etc) 5–10 mg

Miscellaneous | SECOND-GENERATION ANTIHISTAMINES

Hydroxyzine (Atarax, etc) 15–100 mg nd- Marked sedation Cyclizine (Marezine) 25–50 mg — Slight sedation; anti-motion sickness activity Meclizine (Bonine, etc) 25–50 mg-Slight sedation; anti-motion sickness activity

Piperazine derivatives | FIRST-GENERATION ANTIHISTAMINES

Brompheniramine (Dimetane, etc) 4–8 mg + Slight sedation | Chlorpheniramine (Chlor-Trimeton, etc)4–8 mg + Slight sedation; common component of OTC “cold” medication

Alkylamines | FIRST-GENERATION ANTIHISTAMINES

Fexofenadine (Allegra, etc) 60 mg —

Piperidin | SECOND-GENERATION ANTIHISTAMINES

have significant acute suppressant effects on the extrapyramidal symptoms associated with certain antipsychotic drugs. This drug is given parenterally for acute dystonic reactions to antipsychotics

Antiparkinsonism effects— diphenhydramine

have significant atropine-like effects on peripheral muscarinic receptors. This action may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision

Antimuscarinic actions— ethanolamine and ethylenediamine

This action may cause orthostatic hypotension in susceptible individuals

Adrenoceptor-blocking actions- H1 antagonists,

Serotonin-blocking actions—Strong blocking effects at | serotonin receptors have been demonstrated for some first generation H1 antagonists, notably?

cyproheptadine.

—Several first-generation H1 antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine.

Diphenhydramine and promethazine

have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain

terfenadine, acrivastine

are the most effective agents available for the | prevention of motion sickness

Scopolamine

It has been claimed that the antihistaminic agents effective in prophylaxis of motion sickness are also useful in what syndrome?

Méniére’s syndrome

occurred in several patients taking either of the early second-generation agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin.

Lethal ventricular arrhythmias

inhibits CYP3A4 and has been | shown to increase blood levels of terfenadine significantly

Grapefruit juice

may be of value in sleep disorders, | narcolepsy, obesity, and cognitive and psychiatric disorders

H3 receptor antagonists

- 5-hydroxytryptamine (5-HT) - This was called enteramine - metabolite of 5-hydroxytryptophan - local hormone in the gut - thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome.

Serotonin

serves as a precursor of melatonin, a melanocyte-stimulating hormone that has complex effects in several tissues. produced in the PINEAL GLAND

Serotonin

over 90% of the serotonin | in the body is found in?

enterochromaffin cells | others: platelets, raphe nuclei,

serotonin is depleted by?

reserpine

serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed. Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the?

chemoreceptor reflex | also known as the Bezold-Jarisch reflex

directly causes the contraction of vascular smooth muscle, mainly through 5-HT2 receptors. In humans, serotonin is a powerful vasoconstrictor except in skeletal muscle and the heart, where it dilates blood vessels

Serotonin

also constricts veins, and venoconstriction with | increased capillary filling appears to be responsible for the flush

Serotonin

a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. This action is caused by the direct action of serotonin on 5-HT2 smooth muscle receptors plus a stimulating action on ganglion cells located in the enteric nervous system

Serotonin

is associated with skeletal muscle contractions and precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class

serotonin syndrome

Buspirone - nonbenzodiazepine anxiolytic dexfenfluramine - appetite suppressant Lorcaserin - weight loss medication triptans- migrains Flibanserin -treatment of hypoactive sexual deisre disorder in women Cisapride- used in the treatment of GERD and motility disorders Tegaserod - partial agonist for irritable bowel syndrome

serotonin agonists

Serotonin synthesis can be inhibited by

p-chlorophenylalanine | and p chloroamphetamine.

Storage of serotonin can be inhibited by the use of

reserpine

is the major therapeutic approach to conditions of serotonin excess.

receptor blockade

has a long-lasting blocking action at 5-HT2 receptors.

Phenoxybenzamine

resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1-receptor-blocking as well as 5-HT2-blocking actions

Cyproheptadine

blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or H1 receptors blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin

Ketanserin

its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy

Ondansetron

are produced by Claviceps purpurea, a fungus that | infects grasses and grains—especially rye

ERGOT ALKALOIDS

Claviceps purpurea synthesizes?

histamine,acetylcholine, tyramine

dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion.

St. Anthony’s fire (ergotism).

Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified

the amine alkaloids and the | peptide alkaloids

The oral dose of ergotamine is about 10 times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with

caffeine

naturally occurring alkaloids are powerful hallucinogens. ____ is a synthetic ergot compound that clearly demonstrates this action

Lysergic acid diethylamide | LSD; “acid”

have the highest selectivity for the pituitary dopamine receptors. These drugs directly suppress prolactin secretion from pituitary cells by activating regulatory dopamine receptors

bromocriptine, cabergoline, and pergolide

have partial agonist effecrts at 5HTS vascular receptors

Ergotamine, Ergonovine, methysergide

sensitivity of the uterus to the stimulant effects of ergot increases dramatically during ___? because of the dominace of alpha1 receptors

pregnancy

agent of choice in obstetric applications of the ergot drugs less prefered than oxytocin

Ergonovine

ergotamine can be effective when give during the ___ of an attack but lees effective if delayed

prodrome

highly specific for migraine pain; they are | not analgesic for any other condition

Ergot derivatives

ergot alkaloids dosage

no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week. For very severe attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intravenously or intramuscularly. Dihydroergotamine, 0.5–1 mg intravenously, is favored by some clinicians for treatment of intractable migraine.

is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases.

Bromocriptine

similar but more potent than Bromocriptine

Cabergoline

ergot alkaloids that can be given in postpartum hemorrhage

ergonovine maleate, 0.2 mg | given intramuscularly

given intravenously has been used to produce | prompt vasoconstriction during coronary angiography

Ergonovine

has been promoted for many years for the relief of signs of senility and, more recently, for the treatment of Alzheimer’s dementia

Dihydroergotoxine

ergot alkaloid toxicity?

The most common toxic effects of the ergot derivatives are gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved.

Vasospasm caused by ergot is refractory to most vasodilators, but infusion of large doses of ____ or nitroglycerin has been successful in some cases.

nitroprusside

associated with connective tissue proliferation in the retroperitoneal space, the pleural cavity, and the endocardial tissue of the heart

methysergide

ergot alkaloids are contraindicated in the following diseases

obstructive vascular diseases collagen diseases pregnancy