Flashcards in Histamine Deck (44)
Many tissues, mainly in mast cells.
Highest amounts found in lungs, skin, nasal and gastrointestinal mucosa.
Have high affinity IgE binding sites on their plasma membranes.
Also target parasites
Histamine synthesis and storage
Histamine is formed by decarboxulation of the amino acid histidine.
Histamine is stored in granules.
Release of Histamine
Released with several other chemical mediators.
Histamine can be released by trauma, allergies (Antibodies), anaphylaxis, cold, bacterial toxins, bee sting, venoms, and drugs.
Histamine release from mast cells-Cytolytic release
The plasm membrane is damaged.
Not energy dependent, no calcium is required.
Leakage of cytoplasmic contents
Inducers- phenothiazines and narcotic analgesics
Histamine release from mast cells- noncytolytic release
Requires energy (ATP) and calcium, and occurs by exocytotic release from granules.
IgE antibodies binding to antigen-histamine release
Release of Histamine
Certain substances and drugs stimulate histamine release from mast cells without prior sensitization.
Mass cells degranulation protein (from bee venom)
Radiocontrast media (imaging uses)
d-tubocurare, succinylcholine, morphine, codeine, doxorubicin, promate.
Vancomycin causes red man syndrome
Red man syndrome
Involves flushing, pruritis, chest pain, muscle spasm, and hypotension during infusion. Pretreatment with IV antihistamines attenuates the sx of red-man syndrome
Drugs that block the release of histamine from mast cells
Cromolyn and nedocromil- inhalation of a poweder.
Stablizes mast cells preventing noncytolytic degranulation.
Decreases sx of allergic rhinitis. Prophylactiv use to block asthmatic rxns but not useful in managing an acute asthmatic attack.
Poorly absorbed- few adverse effects
Effective only is used BEFORE a challenge
Four types of histamine receptors
H1 receptors- phospholipase C mechanism (respiratory and allergic reactions)
H2 receptors- adenylyl cyclase mechanism parietal cell acid secretion.
H3 receptors- on neurons and inhibit the release of histamine (feedback inhibition)
H4 receptors- proinflammatory activity
Histamines role in allergy and anaphylaxis- Stimulation of secretions
Stimulation of secretions
H1 increases mucus in nasal cavity and bronchi resulting in respiratory sx.
H2 stimulates gastric acid secretions
Histamines role in allergy and anaphylaxis- Constriction of smooth muscle
H1 constricts bronchi and intestines (cramps, diarrhea)
Histamines role in allergy and anaphylaxis- stimulation of sensory nerve endings
itching and pain caused by H1
Histamines role in allergy and anaphylaxis- dilation of smooth muscle in blood vessels
H1 decreased blood pressure (vasodilator)
H1 increases nitric oxide (vasodilator)
Histamines role in allergy and anaphylaxis- stimulating heart rate and contractility
Histamine directly increased HR and contractility by increasing the influx of calcium.
Histamine indirectly increases HR and contractility by baroreceptor-mediated increase in sympathetic tone in response to histamine induced vasodilation
Histamines role in allergy and anaphylaxis- Release of catecholamines
NE and epinephrine from the adrenal gland
Histamines role in allergy and anaphylaxis- Dilation and increased permeability of capillaries
Caused by H1 and H2 and gives red appearance
Histamine causes endothelial cells to contract and expose permeable basement membrane.
Leakage of proteins and fluid into surrounding tissues resulting from the permeable basement membrane.
Gaps b/w the endothelial cells also permit passage of blood cells that are recruited to tissue during mast-cell response "bulk flow"
Challenge with an allergen (bug bit, histamine, allergy test)- if positive skin test- "triple response of lewis"
Triple response of lewis
Red line/spot- dilates arterioles producing where injected (w/in seconds, maximal 1 min)
Flare- histamine stimulates nerve endings, which leads to dilations of arterioles 1-2cm distant from the injection. A greater area of redness is the third response.
Wheal- increase in capillary permeability due to local edema.
Typical target are mast cells and basophils
Allergic response consists of
An antigen producing the formation of IgE antibodies which bind to high affinity receptors specific for these IgE antibodies and activate tyrosine kinase.
This leads to an increase in intracellular calcium which triggers exocytosis of the contents of secretory granules in the mast cells (degranulation)
Other mediators of inflammation released in hypersensitivity reactions
Activation of phospholipase A2 which produces leukotrienes and prostaglandins.
Leukotrienes contract smooth muscle of the bronchi.
Main difference b/w allergic rxn and anaphylactic repsonse
Location of the sites from which mediators are released
Results from histamine release in a specific area.
Ex- nasal cavity
Results from histamine being released rapidly and diffuses via the blood
Intense warmth, skin reddens, marked effect on palms, hands, face, scalp, and ears; hives, nausea, decreased BP, Increased HR, bronchospasm, and constriction
Assess nasal and bronchial reactivity
Positive control injection (allergy skin testing- must discontinue antihistamines, tricyclic antidepressants, corticosteroids, and benzodiazepines)
Antihistamines- 1st generation drugs
Histamine HI receptor blockers, widely used, effective and inexpensive.
Trirolidine, DIPHENHYDRAMINE (benydryl), PROMETHAZINE, HYDROXYZINE, chlorpheniramine
Antihistamines- 2nd generation drugs
Loratadine (claritin OTC), desloratadine (clarinex), azelastine (astelin), cetirizine (Zyrtec OTC), fexofenadine (allegra, OTC)
Less CNS toxicity or side effects compared to first generations since they do not cross the blood brain barrier or are excluded by p-glycoprotein (cause less drowsiness.
Terfenadine (Seldane) process
Terfenadine undergoes first-pass metabolism to fexofenadine.
Terfenadine blocks potassium channels in myocardium, which causes a prolonged QT interval and increases the risk of ventricular tachyarrhythmias. (torsades de pointes)
FDA approved antihistamines
Do not prolong the QT interval
H1 blockers-reversible competitive blockers of H1 receptors
H1 blockers antagonize all actions of histamine except those mediated solely by H2 receptors.
Less effective on bronchoconstriction and vasodilation which are regulated predominately by prostagladins and leukotrienes
H1 blockers- tolerance
No tolerance to the suppressive effect on skin test reactivity to allergens.
Tolerance to sedative effects occur
Therapeutic effects may be restored by switching to another class of antihistamines.
Major differences between 1st and 2nd generation H1 blockers
1st generation- anticholinergic, CNS sedation, short acting
2nd generation- no anticholinergic, no CNS sedation, longer acting
Allergic conjunctivitis- ophthalmic antihistamines (H1)
Common form of allergic occular disease, usually associated with rhinitis- itching, hyperemia, tearing, mucus, and lid edema
Side effects- burning/redness/itching of the eyes.
Therapeutic uses antihistamines (H1)
Drug of choice-sx of allergic rhinitis and urticaria
Ineffective in tx of asthma by may help if the triggers of the attachs are allergens
Allergic drug rxn- itching and edema and prophylactic tx when a drug known to release histamine must be given
Local anesthetic actions
Blocks sodium channels
Adverse rxns of histamines
Antimuscarinic & sedative actions (usually absent or lower with second generations)
Most frequent side effects- 1st generation antihistamines
Other CNS effects- fatigue, dizziness, blurred vision
CNS sedation correlates with H1 receptor binding in brain= doxepin (50-90% H1 receptors in CNS bound), cetirizine (30% bound), fexofenadine (o% bound)
Dry mouth and nasal passages, constipation, blurred vision, and urinary retention
Can occur in children due to not completely developed brain and differences that result in extreme excitation.
Mainly 1st generation H1 blockers.
Combining CNS H1 agonists with other sedating medications may be dangerous (drivering performance impaired by 50 mg diphenhydramine, and military/civilian pilots are prohibited from using these during flights.)
H1 antagonists potentiate (enhance the effect/makes more potent) all other CNS depressants