HISTAMINE,SOROTONIN AND THE ERGOT ALKALOIDS Flashcards
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
Formed by decarboxylation of the amino acid L–histidine,
a reaction catalyzed by the enzyme histidine decarboxylase
HISTAMINE
The major metabolic pathways of histamine
N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic
acid (IAA).
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
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.
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
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
account for the most important pathophysiologic mechanism of mast cell and basophil histamine
release.
Immunologic processes/Immunologic Release
Immunologic Release of histamine requires?
energy and calcium
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,
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.
Release of peptides from nerves in response to
inflammation is also probably modulated by histamine acting on?
H3 receptor
Certain amines, including drugs such as ___ and___ can displace histamine from its bound form within cells.
morphine and tubocurarine
distribution: Smooth muscle, endothelium, brain
postreceptor mechanism: Gq, ↑ IP3, DAG
partially selective agonist: Histaprodifen
partially selective antagonist: Mepyramine,1
triprolidine, cetirizine
H1
D:H2 Gastric mucosa, cardiac muscle, mast cells, brain Pm: Gs, ↑ cAMP
PSA: Amthamine
PSAn: Cimetidine,1 ranitidine,1 tiotidine
H2
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
H3
D:Eosinophils, neutrophils, CD4 T cells Gi,
Pm:↓ cAMP
PSA: Clobenpropit, imetit, clozapine
PSAn”Thioperamide
H4
H1 and H3 receptors paly an important role in?
appetite
satiety
nociception
An investigational inverse H3 agonist ___ appears to reduce drowsiness in patients
with narcolepsy.
pitolisant (BF2649)
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
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
can block bronchoconstriction effect of histamine
ganglion blocking agents
H1-receptor antagonists
other organs affected by the release of histamine?
eyes
genitourinary tract
uterus
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
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
