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58 Cards in this Set

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A molecule secreted locally to increase or decrease the activity of nearby cells.
Autacoid
Synthesized from L-histidine
Histamine
Catalyzes the decarboxlation of histidine to histamine.
Histidine decarboxylase
Where is histamine synthesized
Mast cells, basophils, ECL cells in gastric mucosa, and certain neurons in CNS.
What can be measured in the urine to assess the amt of histimine released systematically?
Imidazole
Where is the slow turning over pool of histimine? Why is it named such?
Mast cells and basophils, stored in granules. Several weeks are required to replenish the stores of histamine after degranulation.
Where is the fast turning over pool of histimine? Why is it named such?
Gastric ECL cells and histaminergic CNS neurons (for gastric secretions and neurotransmission) This histimine is made when it is used.
Effects smooth muscle, vascular endothelium, afferent nerve terminals, heart, GI tract and CNS.
Histamine
What does histamine do to bronchial smooth muscle?
People with asthma?
Causes it to contract
Can be 1000X more sensitive.
Effect of histamine on terminal arteriols and postcapillary venules? On Veins?
Dialates
Constricts
Though not clinically significant, smooth muscle in the bowel, bladder, iris and uterus ________ due to histamine.
contract
Vascular endothelial cells _________ due to histamine, causing edema.
Contract
Histamine on vascular smooth muscle, vascular endothelial cells, and nerve terminals are responsible for the:
wheal and flare noted following histamine release in the skin.
Inotropy
an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.
Cardiac effects of histamine:
Minor increases in force and rate of contraction.
Enhancement of Ca++ influx into cardiac myocytes (inotropy)
(Increase in phase 4 depolarization in SA nodal cells)
Three molecules that regulate acid secretion in the stomach:
Histamine
Gastrin
Acetylcholine
What does histamine cause in the stomach?
Activation of histamine receptors --> increase in intracellular Ca++ in parietal cells --> increase in HCL secretion by gastric mucosa.
(CNS) Histidine decarboxylase and histamine receptors are expressed in the:
Hypothalamus
Believed to be important in the maintenance of wakefulness and to act as an appetite suppressant.
histamine
Histamine receptor subtypes are ___ ___ ___ ___ and all four are ________________
H1 H2 H3 H4
seven transmembrane G protein coupled receptors
Where are H1 receptors found and what cascade do they start?
Vascular sm muscle, vascular endothelium, Lungs, peripheral nerves.
Hydrolysis of phosphitidylinositol, leading to increased IP3 & DAG.
IP3 --> increased Ca++.
DAG--> PKC phosphorylates cytosolic target proteins.
Does activation of H1 receptor effect transcription factor NFkB?
Yes, which promotes the expression of adhesion molecules and proinflammatory cytokines such as IL1 & TNF
3 tissue specific responses to H1 receptor stimulation:
Edema
Bronchoconstriction
Sensitization of primaryafferent nerve terminals
What do H1 receptors do in the hypothalamus?
function as autoreceptors to inhibit further histamine release
Major fx of H2 receptor?
Cascade effect?
mediate gastric acid secretion, therefore expressed in parietal cells in gastric mucosa.
cAMP cascade
Where are H2 receptors found?
Parietal cells
Cardiac muscle cells
Some immune cells
Certain presynaptic neurons
H? receptors suppress neuronal firing and histamine release. Downstream effects of H? receptor activation are mediated via decrease in Ca++
H3
H? receptors have been localized to presynaptic histaminergic neurons (supressing neuronal firing and histamine release) in the CNS and ECL cells in stomach.
H3
H? are localized to cells of hematopoietic, primarily mast cells, basophils and eosinophils.
H4
H? leads to decreased cAMP, activation of phospholipase CB, and eventual increased intracellular Ca++.
H4
histamine plays a major role in what type of hypersensitivity reactions?
Type I, also known as IgE mediated hypersensitivity reactions
Sensitization:
Allergen stimulates B lymphocytes via T helper cells, and B cells produce IgE ab that are specific for the allergen. That IgE then bindsto Fc receptors on:
Mast cells and basophils. After sensitization the allergen thus triggers degranulation.
Mast cells or basophils?
Degranulation can also occur as a response to local tissue damage, in the absence of a humoral immune response.
Mast cells
Responsible for initiation of certain inflammatory disorders, including allergic rhinitis and acute urticaria.
IgE mediated hypersensitivity reaction.
In anaphylaxis, the histamine release causes:
What should you treat it with?
Systemic vasodilation resulting in hypotension
Bronchoconstriction
Epiglottal swelling
Epinephrine
Antihistamines are typically
inverse agonists or competative antagonists selective for H1-H4
What are cromolyn and nedocromil used for? How do they work?
To prevent asthma attacks by preventing mast cell degranulation inducedby binding ofan antigen to the IgE/Fc receptor complex on mast cells, and then disrupting the Cl transport across mast cells (a key step in the degranulation process).
Why is epinephrine used to treat anaphylaxis?
Bc it is an adrenergic agonist, and so induces bronchodilation and vasoconstriction.
H1 antihistamines are
inverse agonists, shifting equilibrium towards the inactive state.
First generation H1 antihistamines consist of 6 main subgroups:

They are typically:
Ethanolamines, ethylenediamines, alkylamiines, piperazines, phenothiazines and piperidines.
Neutral compounds that can cross the BBB
4 most frequently used First generation H1 antihistamines
Diphenhydramine
Hydroxyzine
Chlorpheniramine
Promethazine
Widely used second generation H1 antihistamines (3)
What is the advantage of the second generation H1 antihistamines?
Loratadine
Cetirizine
Fexofenadine
They do not cause CNS depression (drowsiness), because they do not cross the BBB.
Hydroxyzine and doxepin are
potent ANTIPURITIC agents.
Can H1 antihistamines be used as the sole therapy for asthma?
Nope
H1 antihistamines (dimenhydrinate, diphenhydramine, meclizine, and promethazine) can be usefula as
antiemetics
H1 antihistamines such as diphenhydramine, doxylamine and pyrilamine can be used to treat
insomnia (cns effects)
Oral antihistamines are absorbed readily from the GI tract and most are metabolized in the liver. Therefore,
Dose adjustments should be ocnsidered in pts with severe liver disease.
H1 antihistamines are inducers of
hepatic cytochrome P450 enzymes.
Second generation H1 antihistamines are less likely to cross the BBB. Why?
They are less lipophillic than 1st gen.
The are ionized at pH 7.4 and so do not diffuse readily.
They exhibit high binding to albumin and are therefore less free to diffuse.
Former 2nd gen H1 antihistamines were pulled from the market bc
they caused prolonged QT intervalsthat sometimes led to ventricular arrhythmias.
General adverse effects of H1 antihistamines
Pupillary dilation, dry eyese, dry mouth, and urinary retention and hesitancy.
Cimetidine and ranitidine are two of the most commonly used

Significant side effect of cimetidine:
H2 receptor antagonists for acid reflux and peptic ulcer disease.

Inhibition of cytochrome P450 mediated drug metabolism
H? receptors are thought to provide feedback inhibition
H3
Second generation H1 antihistamines are less likely to cross the BBB. Why?
They are less lipophillic than 1st gen.
The are ionized at pH 7.4 and so do not diffuse readily.
They exhibit high binding to albumin and are therefore less free to diffuse.
Former 2nd gen H1 antihistamines were pulled from the market bc
they caused prolonged QT intervalsthat sometimes led to ventricular arrhythmias.
General adverse effects of H1 antihistamines
Pupillary dilation, dry eyese, dry mouth, and urinary retention and hesitancy.
Cimetidine and ranitidine are two of the most commonly used

Significant side effect of cimetidine:
H2 receptor antagonists for acid reflux and peptic ulcer disease.

Inhibition of cytochrome P450 mediated drug metabolism
H? receptors are thought to provide feedback inhibition
H3