Histamines Flashcards
How is histamine stored
Decarboxylation of the amino acid L-histidine catalyzed by the enzyme histadine decarboxylase. Histamine is made and either stored or it is inactivated
two categories of synthesis and storage
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
Significance of Histamine receptors
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
Conditions That Cause Histamine Release
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
Mechanism for type 1 hypersensitivity
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.
Role of histamines outside of immune response
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.
H1 Location, Type, Effect, Symptoms, Treatment
H2 Location, Type, Effect, Symptoms, Treatment
Impact of H2 receptors in the heart
In the heart they can cause arrhythmias in large doses.
H3 Location, Type, Effect, Symptoms, Treatment
Negative feedback for histamine
H4 Location, Type, Effect, Symptoms, Treatment
these receptors regulate the levels of leukocyterelease from bone marrow. They have also been show to direct mast cells.
What is a wheal and flare response
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.
Mechanism of allergic reaction
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.
What is urticaria
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
Anaphylaxis criteria
treatment for anaphylaxis
high-dose steroids are used combat the inflammatory response. Epinephrine serves as an alpha-agonist to combat vasodilation causing hypotension.
Histamine and hypotension
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.
Histamine and tachycardia
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.
Histamine reactions outside skin/heart
Use of H1 receptor blockers (first-gen)
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
H1 receptor blocker side effects
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.
What are Ethylenediamines (first gen) and uses
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.
Alkylamines (first gen) and uses
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
Piperazines (first gen) and uses
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.
Tricyclics (first gen) and uses
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.
Mechanism of second-gen antihistamines
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.
Second gen drugs and uses
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.
Mechanism of third gen antihistmamines
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
Third gen drugs and uses
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
