7 - Histamine

Question 1

What is histamine?

Answer 1

A mediator of immediate allergic and inflammatory rxns.

Plays a role in gastric acid secretion.

Nt and neuromodulator.

Question 2

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

Answer 2

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.

Question 3

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

Answer 3

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.

Question 4

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

Answer 4

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

Minutes: BP recovers, hives appear

*signs of inflammation

Question 5

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

Answer 5

Occurs in response to an antigen-antibody reaction.

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

Question 6

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

Answer 6

Through an increase in intracellular calcium.

Question 7

What type of stimuli release histamine?

Answer 7

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

Question 8

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

Answer 8

Cromolyn sodium.

Prophylaxis for bronchospasm (allergen or exercise induced)

Question 9

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?

Answer 9

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.

Question 10

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?

Answer 10

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.

Question 11

What are the four subtypes of histamine receptors?

Answer 11

All GPCRs.

H1, H2, H3, and H4

Question 12

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

Answer 12

Vasodilation.

H1 : endothelial cells
H2 : vascular smooth muscle cells

Question 13

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

Answer 13

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.

Question 14

What histamine receptor is responsible for vasoconstriction of large vessels?

Answer 14

H1 receptors located on vascular smooth muscle cells.

Do this via an increase in intracellular calcium.

Question 15

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

Answer 15

Dilates

Fall in bp

Question 16

Which histamine receptor is responsible for increased vascular permeability?

Answer 16

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.

Question 17

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

Answer 17

H1 causes contraction and H2 causes minor relaxation.

Question 18

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

Answer 18

H2 activation causes gastric acid secretion.

Question 19

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

Answer 19

Ir activates them, causing pain and itching.

Causes an increase in arousal/wakefulness.

Question 20

What are the first gen Hi receptor blockers?

Answer 20

Diphenhydramine
Dimenhydrinate
Chlorpheniramine
Promethazine (also dopamine blocker)

Question 21

What are the second gen H1 receptor blockers?

Answer 21

Fexofenadine
Loratadine
Cetirizine
Desloratidine

Question 22

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

Answer 22

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).

Question 23

What are the major effects of H1 antagnosts?

Answer 23

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.

Question 24

What are other pharmacological side effects of H1 antagonists?

Answer 24

CNS: Most commonly slow reaction times and decreased alertness.

Peripheral: think about anticholinergic syndrome

Question 25

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

Answer 25

Terfenadine metabolized to Fexofenadine

Loratadine metabolized to desloratadine

Cetirizine active metabolite of hydroxyzine

Question 26

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

Answer 26

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)

Question 27

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

Answer 27

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

Question 28

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

Answer 28

Due to major CV toxicity and prolonged QT interval.

Question 29

What are therapeutic uses of H1 receptor antagonists?

Answer 29

Acute allergies.

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

Question 30

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?

Answer 30

Chlorpheniramine: most potent, less sedation

1st gen most sedation: Diphenhydramine

2nd gen most sedation: Cetirizine

Question 31

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

Answer 31

Because motion sickness involves muscarinic cholinergic transmission and H1 receptor antagonists can have an anti-cholinergic effects.

Dimenhydrinate (dramamine) and promethazine.

Question 32

What is the function of H2 receptor antagonists?

Answer 32

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+).

Question 33

What is the pharmacological profile for H2 antagonists?

Answer 33

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.

Question 34

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

Answer 34

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.

Question 35

What are adverse effects associated with H2 antagonists?

Answer 35

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.

Question 36

What is the major use of H2 receptor antagonists?

Answer 36

Uncomplicated gastroesophageal reflux disease (GERD)

Question 37

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

Answer 37

Cimetidine

Question 38

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

Answer 38

Diphenhydramine

Question 39

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

Answer 39

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