Histamines

Question 1

How is histamine stored

Answer 1

Decarboxylation of the amino acid L-histidine catalyzed by the enzyme histadine decarboxylase. Histamine is made and either stored or it is inactivated

Question 2

two categories of synthesis and storage

Answer 2

Intracellular Granules - biologically inactive until released:

mast cells - in tissues

basophils - in blood

Non-mast cell histamine:

brain - neurotransmitter.

stomach - enterochromaffin-like (ECL) cells and released in response to gastrin, acetylcholine or secretagogues

Question 3

Significance of Histamine receptors

Answer 3

The histamine molecule looks the same no matter where it acts, it is the receptor that creates a different response. There are two main types of histamine receptors: H1 receptors are more commonly located in the intestine/bronchial smooth muscle and H2 receptors mediate gastric secretion. H3 and H4 receptors are currently of lesser importance

Question 4

Conditions That Cause Histamine Release

Answer 4

Tissue Injury - when tissues injury, mast cells immediatey degranulate

Allergic reactions - exposure of an antigen to a previously sensitized antibody. When antigen complexes with sensitized IgE antibody on cell membranes, the cell with degranulate releasing histamine.

Drugs and other foreign substances

Question 5

Mechanism for type 1 hypersensitivity

Answer 5

Initial exposure to allergen (sensitization phase) leads to production of IgE by plasma cells differentiated from allergen-specific B cells (not shown). The secreted IgE binds IgE-specific receptors on blood basophils and tissue mast cells. Re-exposure to allergen leads to cross-linking of membrane-bound IgE (effector phase). This cross-linking causes degranulation of cytoplasmic granules and release of mediators that induce vasodilation, smooth muscle contraction, and increased vascular permeability. These effects lead to the clinical symptoms characteristic of type I hypersensitivity.

Question 6

Role of histamines outside of immune response

Answer 6

Non-mast cell histamines exist in the CNS where they are neurotransmitters. They function in neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep/arousal.

Histamines are also in the fundus of the stomach, within the enterochromaffin-like (ECL) cells. ECL cells release histamine, one of the primary gastric acid secretagogues, to activate the acid-producing parietal cells of the mucosa.

Question 7

H1 Location, Type, Effect, Symptoms, Treatment

Answer 7

Question 8

H2 Location, Type, Effect, Symptoms, Treatment

Answer 8

Question 9

Impact of H2 receptors in the heart

Answer 9

In the heart they can cause arrhythmias in large doses.

Question 10

H3 Location, Type, Effect, Symptoms, Treatment

Answer 10

Negative feedback for histamine

Question 11

H4 Location, Type, Effect, Symptoms, Treatment

Answer 11

these receptors regulate the levels of leukocyterelease from bone marrow. They have also been show to direct mast cells.

Question 12

What is a wheal and flare response

Answer 12

If you were to inject histamine locally, you will see a red spot with an erythematous (red) base and a central flare (or raised skin) through H1

Erythema is caused by vasodilation within a few seconds.

Flare is the spread of erythema more than 1cm beyond the site - caused by both direct vasodilation and indirect axonal reflex. This is when the itching begins.

Wheal forms within a few mintues and is localized edema a raised area due to increased capillary permeability.

Question 13

Mechanism of allergic reaction

Answer 13

Vasodilation and edema lead to inflamed mucosal tissues which can cause paroxysms of sneezing, rhinorrhea, nasal obstruction, and nasal itching.

The same mechanism can inflame conjunctival tissue leading to scleral injection, watery eye drainage and itching.

Question 14

What is urticaria

Answer 14

Similar cause as in allergic rhinitis, but present on the skin. Diagnostic criteria is that these itchy, raised lesions will migrate and not stay in the same place for longer than 24 hours.

Urticaria can come from many causes, both external and internal.

External - new topical exposures (clothing, detergents, soaps, etc.), medications, foods, infections (VERY common to see in children with a viral illness).

Internal - often the cause behind chronic urticaria - no single cause could be isolated yet prolonged (over 6 months) duration of hives

Question 15

Anaphylaxis criteria

Answer 15

Question 16

treatment for anaphylaxis

Answer 16

high-dose steroids are used combat the inflammatory response. Epinephrine serves as an alpha-agonist to combat vasodilation causing hypotension.

Question 17

Histamine and hypotension

Answer 17

Decrease in blood pressure is caused by the direct vasodilatory action of H1 on arterioles and precapillary sphincters.

Vasodilation and tachycardia may also cause flushing, a sense of warmth, and headache may also occur during histamine administration. This is caused by release of nitric oxide from the endothelium.

Question 18

Histamine and tachycardia

Answer 18

Hypotension contributes to a reflex tachycardia (as the body attempts to increase cardiac output by increasing heart rate).

Higher doses of histamine activate H2 cAMP production:

Inceased cAMP leads to increased Ca2+ which increases the force of contraction of both atrial and ventricular muscle, this hastens the diastolic depolarization in the sinoatrial (SA) node.

Slow atrioventricular (AV) conduction, to increase automaticity, and in high doses especially, to elicit arrhythmias.

Question 19

Histamine reactions outside skin/heart

Answer 19

Question 20

Use of H1 receptor blockers (first-gen)

Answer 20

seasonal allergies, medication-associated allergies, hives, itching, anaphylaxis, vomiting. They are rapidly absorbed after oral administration with peak blood concentrations ocurring in 1-2 hours

Question 21

H1 receptor blocker side effects

Answer 21

They do have a fair number of side effects. Most of these are because of the lipophilic nature of this molecule that allows first-generation antihistamines to cross the blood-brain-barrier - this also allows them to be helpful for CNS symptoms such as vertigo or motion-sickness. They also have anti-cholinergic adverse effects. These adverse effects are worsened in the elderly population.

Question 22

What are Ethylenediamines (first gen) and uses

Answer 22

Diphenhydramine (Benadryl) - the big bad, daddy of them all. This is the oldest on the market and one of the hardest-working antihistamines! Helpful with allergies, anaphylaxis, hives, nausea and also used for sedation and antiparkinsonism effects( typically medication-induced extrapyramidal side effects). Used in many over the counter sleep aids due to the sedating side effect (Tylenol PM).

Doxylamine - strong sedating agent; in various over the counter sleep aids (Unisom and Nyquil). Combined with Vitamin B6 for morning sickness (Diclegis). Prominent anti-cholinergic adverse effects.

Dimenhydrinate (Dramamine) - anti-emetic with strong sedating properties; often used for motion sickness. This is a salt of diphenhydramine.

Clemastine - over the counter anti-allergy and itching medications (Dayhist, Tavist). Less side effects than many other first generation antihistamines.

Question 23

Alkylamines (first gen) and uses

Answer 23

less sedating and GI adverse effects; more CNS side effects

Chlorphenamine - allergies and a common ingredient in otc cold medications. Interestingly, we have this to thank for serotonin-selective reuptake inhibitors (the most prevalent antidepressant class). Researchers noticed that it inhibited the reuptake of serotonin and when combined with other serotonin-increasing agents serotonin syndrome can arise.

Brompheniramine - (Dimetapp) over the counter rhinnitis/allergy treatment (as a child of the 90’s I very much remember this grape-flavored medicine).

Triprolidine - in otc cold meds

Pheniramine - hay fever, hives, found in Visine

Question 24

Piperazines (first gen) and uses

Answer 24

significant anti-cholergic effects so used for motion sickness, nausea, vertigo

Cyclizine (Cyclivert) - used for motion sickness and vertigo. Less often for post-operative nausea given newer anti-emetic agents.

Hydroxyzine (Atarax, Vistaril) - commonly used for itching but also commonly as an anti-anxiety medication.

Meclizine - antiemetic, most commonly prescribed medication for many causes of vertigo.

Question 25

Tricyclics (first gen) and uses

Answer 25

related to tricyclic antidepressants (which explains their anti-cholinergic side effects)

Promethazine (Phenergan) - used as an anti-emetic or a sedative due to extremely strong anticholinergic and sedative effects. Like Benadryl, this can be a sought after drug in the IV formulation. Benadryl + Phenergan are often combined with a strong NSAID (Toradol or ketorolac) or Metoclopramide for migraine headaches - called a migraine cocktail.

Cyproheptadine (Periactin) - antihistamine AND serotonin antagonist; helps with allergies and migraines, but it is mainly used for appetite stimulation.

Question 26

Mechanism of second-gen antihistamines

Answer 26

These are newer drugs are more selective for the peripheral antihistamine receptors involved in allergies so they spare many of the sedating side effects of the first generation. They are bulkier and less lipophilic so don’t cross the blood brain barrier as readily. They may also have an antiinflammatory activity that helps in allergic asthma - this may be more due to H4 receptors.

Question 27

Second gen drugs and uses

Answer 27

Cetirizine (Zyrtec) - common allergic rhinitis medication (really anything you might use Benadryl for), available over the counter and often used in children.

Loratidine (Claritin) - the first second-generation antihistamine available over the counter - daily dosing (diphenhydramine is dosed every 8 hours).

Fexofenadine (Allegra) - anti-allergy medication

Azelastine (Astelin) - mast cell stabilizer. Available as a nasal spray and an ophthalmic drop.

Olopatadine (Patanol) - ophthalmic drop for allergic conjunctivitis

Ketotifen (Zatidor) - primarily used in the ophthalmic form for allergic conjunctivitis.

Question 28

Mechanism of third gen antihistmamines

Answer 28

Derived from second-gen antihistamines; either the active enantiomer or metabolite of the second generation drug designed to have increased efficacy and fewer side effects

Question 29

Third gen drugs and uses

Answer 29

Levocetirizine (Xyzal) - active isomer of cetirizine with fewer side effects (less drowsiness); also it is not metabolized so will not likely cause drug interactions. Helpful in asthmatics.

Desloratidine (Clarinex) - active metabolite of loraditine; howver no evidence that it is clinically more effective