7 - Histamine Flashcards by Ashley Matter

What is histamine?

A mediator of immediate allergic and inflammatory rxns.

Plays a role in gastric acid secretion.

Nt and neuromodulator.

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How is histamine synthesized? What can happen to the degrading enzymes that metabolize histamine?

From L-histidine via histidine decarboxylase.

Alterations in histamine degrading enzymes can account for histamine intolerance (1% pop).

Can have genetic or acquired impairment of enzymes that degrade it.

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What is the location of histamine in the body? Describe the turnover speed in each location?

Highest amounts in the lung, skin, and GI tract. In tissues it’s within mast cells.

In blood it’s synthesized and stored in secretory granules. (slow turnover).

In non-mast cells such as gastric mucosa cells, epidermis, and neurons: continuously synthesized and released with rapid turnover.

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What are the effects of histamine release within seconds and within minutes?

Seconds: burning itching sensation, *intense warmth, *skin redness, *BP decrease, HR increase.

Minutes: BP recovers, hives appear

*signs of inflammation

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What is the mechanism by which histamine is released from mast cells?

Occurs in response to an antigen-antibody reaction.

Dependent on prior exposure, other mediators, and is calcium dependent.

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How do drugs, peptides, and venoms promote histamine release from mast cells directly without prior exposure?

Through an increase in intracellular calcium.

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What type of stimuli release histamine?

Cold urticaria (hives)
Cholinergic urticaria - increased sympathetic nervous activity
Solar urticaria
Non-specific cell damage

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What anti-inflammatory agent prevents histamine release by preventing mast cell degranulation? What is the therapeutic use of this drug?

Cromolyn sodium.

Prophylaxis for bronchospasm (allergen or exercise induced)

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What anti-inflammatory agent decreases the amount of antigen specific IgE that binds and sensitizes mast cells? What is the therapeutic use?What are adverse effects? What type of monoclonal antibody is it?

Omalizumab - an IgG antibody for which the antigen is the Fc region of the IgE antibody.

Used to severe asthma or with pts with severe concomitant allergic rhinitis.

Anaphylaxis.

Humanized Ab against immune cells.

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Normally what occurs in receptor mediated mast cell degranulation? What is the mechanism of action of Omalizumab? What is this monoclonal antibody derived from and what does it work against?

Normally IgE activates high-affinity receptor (FceRI) on mast cell and low-affinity receptors (FcERII, CD23) on other inflammatory cells.

Omalizumab decreases amount of IgE that sensitizes mast cells. This may also stop other immune cells involved in inflammation because they also have activation via IgE.

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What are the four subtypes of histamine receptors?

All GPCRs.

H1, H2, H3, and H4

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What is the function of H1 and H2 histamine receptor activation?

Vasodilation.

H1 : endothelial cells
H2 : vascular smooth muscle cells

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How can stimulation of both H1 and H2 receptors elicit vasodilation?

H1 increases Ca 2+ in endothelial cells and activation of NO synthase; NO is a vasodilator in vascular smooth muscle.

H2 increases cAMP in vascular smooth muscle to inhibit constriction.

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What histamine receptor is responsible for vasoconstriction of large vessels?

H1 receptors located on vascular smooth muscle cells.

Do this via an increase in intracellular calcium.

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In terms of H1 and H2 receptors and blood pressure: In general, histamine ______ resistance vessels and causes an overall ____ in BP.

Dilates

Fall in bp

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Which histamine receptor is responsible for increased vascular permeability?

H1 receptors located on post-capillary venules-endothelial cells.

Increased in Ca2+ causes endothelial cells to contract and expose BM; they are then freely permeable to plasma proteins and fluid.

What effect do H1 and H2 receptor activation have on the bronchioles?

H1 causes contraction and H2 causes minor relaxation.

What effect does H2 activation have on GI secretory tissue (parietal cells)?

H2 activation causes gastric acid secretion.

What effect does H1 activation have on peripheral nerve endings? What are the neuroendocrine effects of H1 activation?

Ir activates them, causing pain and itching.

Causes an increase in arousal/wakefulness.

What are the first gen Hi receptor blockers?

Diphenhydramine
Dimenhydrinate
Chlorpheniramine
Promethazine (also dopamine blocker)

What are the second gen H1 receptor blockers?

Fexofenadine
Loratadine
Cetirizine
Desloratidine

What is the pharmacology of H1 receptor blockers? How are they given?

Specific reversible competitive antagonists; given orally w/ rapid absorption- peak at 1-2 hours.

1st gen: have over non-specific effects unrelated to H1 receptor blockade.

2nd gen: little to no CNS effects (less likely to enter brain).

What are the major effects of H1 antagnosts?

Reduce symptoms associated with allergic response/inflamm.

Histamine release causes blood vessel dilation during allergic rxn resulting in redness, swelling, itching, and changes in secretions of nasal tissue.

These drugs inhibit the vascular permeability and suppress itching.

What are other pharmacological side effects of H1 antagonists?

CNS: Most commonly slow reaction times and decreased alertness.

Peripheral: think about anticholinergic syndrome

Which second generation H1 antagonists are metabolized to active metabolites in the liver?

Terfenadine metabolized to Fexofenadine Loratadine metabolized to desloratadine Cetirizine active metabolite of hydroxyzine

What is a major side effect of H1 receptor antagonist? Which generation of drugs is this most common with?

Sedation: most common in 1st gen because they enter the CNS and block H1 receptors that mediate arousal Also because they are non-specific and have structures that allow them to block cholinergic receptors in the CNS (anticholinergic effect)

What anti-muscarinic (anticholinergic) side effects can occur with some 1st gen H1 antagonists?

Dry mouth, dryness of respiratory passages, and urinary retention.

Why are terfenadine and astemizole no longer marketed in the US?

Due to major CV toxicity and prolonged QT interval.

What are therapeutic uses of H1 receptor antagonists?

Acute allergies. Seasonal allergies, but drugs less affective is allergens are abundant, exposure is prolonged, and nasal congestion is prominent.

Which H1 receptor antagonist is the most potent with less sedation? Which 1st gen drug has the most sedative effects? Which 2nd gen drug has the most sedative effects?

Chlorpheniramine: most potent, less sedation 1st gen most sedation: Diphenhydramine 2nd gen most sedation: Cetirizine

Why can H1 receptor antagonists help with motion sickness? Which two drugs are used to treat it?

Because motion sickness involves muscarinic cholinergic transmission and H1 receptor antagonists can have an anti-cholinergic effects. Dimenhydrinate (dramamine) and promethazine.

What is the function of H2 receptor antagonists?

Relief of symptoms of peptic ulcer disease and gastroesophageal reflux disease. Does this by inhibiting H2 receptors on parietal cells, which normally increase cAMP to increase acid (H+).

What is the pharmacological profile for H2 antagonists?

Oral, rapid. Reversible competitive inhibitors for H2 receptors. that inhibit nocturnal gastric acid secretion and are a large determinant in healing of ulcers. Reduce volume of gastric acid and H+ concentration.

What is an "inverse agonist"? What is required for something to be considered an increase agonist?

Drug that bind to the receptor but produces opposite effect of agonist. Receptor must have constitutive activity (in absence of ligand) for drug to be considered an inverse agonist.

What are adverse effects associated with H2 antagonists?

Low incidence, except for cimetidine which inhibits P450 metabolism and prolongs half-life of other drugs that are substrates for P450 metabolism. Any drug that inhibits gastric acid secretion (or pH) can alter bioavailability of other drugs.

What is the major use of H2 receptor antagonists?

Uncomplicated gastroesophageal reflux disease (GERD)

Name a drug that treats GERD and may increase risk of bleeding associated with warfarin?

Cimetidine

Your pt is having trouble sleeping; which drug would be the best choice to prescribe this patient to help her sleep?

Diphenhydramine

What would happen to vascular tone if H1 receptors were located on a vascular smooth muscle cell?

Vascular tone will increase because H1 receptors increase calcium which causes contraction (because there's not nitric oxide synthase system in vasculature).