LECTURE 25 & 26 - antihistamines Flashcards
Describe the synthesis of histamine
Histidine → Histamine
Catalyzed by L-histidine decarboxylase
Synthesized in mast cells and basophils
Describe the mechanism by which histamine is stored
Stored in granules
- complex w/ sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases
Stored in:
- mast cells in skin, nose, mouth, lungs, intestinal muscosa
- non-mast cells
Nerve terminals in some areas of the brain (NT)
Fundus of stomach - for stimulation of acid secretion
Name the causes of histamine release from mast cells / basophils
Antigen-mediated
Non-antigen mediated
Describe antigen-mediated histamine release from mast cells / basophils
- Binding of antigen (allergens) to antibodies bound to the cell surface (IgE)
- Other inflammatory agents are also released (kinins, serotonin, leukotrienes, PGs)
Describe non-antigen-mediated histamine release from mast cells / basophils
- Thermal or mechanical stress
- Cytotoxic agents - venoms, various drugs (ex. high dose morphine)
What is required for histamine release?
- Binding of IgE antibodies to FcεR
- Binding of antigen to IgE antibodies
- Clustering of FcεR receptors
- Influx of Ca2+ via CRAC (Ca2+ release activated channels)
– Binding of antigen to antibody molecules causes an increase in cytoplasmic Ca2+ concentration
Describe the effects of histamine due to stimulation of H1 receptors
Distributed throughout cardiovascular & respiratory systems, GI smooth muscle
- Linked to phosphoinositol pathway
Activation causes contraction of smooth muscle - Linked to vasodilation
- Linked to stimulation of sensory nerves
In cutaneous or nasal mucosal nerve endings
Causes sneezing & itching (pruritus)
Describe the effects of histamine due to stimulation of H2 receptors
- Distributed in cardiovascular system, GI smooth muscle and stomach
- Linked to relaxation of vascular smooth muscle & gastric secretion
Describe the effects of histamine on the respiratory system
H-1 mediated constriction of bronchial smooth muscle
Describe the cardiovascular effects of histamine on the heart
moderate increase in both rate & force of contraction
- H2 = increase in SA conduction, reflex tachycardia
Describe the cardiovascular effects of histamine on the vasculature
Vasodilation
H-1 → endothelium (NO pathway)
H-2 → smooth muscle (PKA pathway)
Describe the cardiovascular effects of histamine on the capillaries
H1-mediated endothelial contraction
Results in edema
List the secondary pharmacological effects of 1st generation antihistamines
Sedation
Anticholinergic effects
Other effects specific to structural classes
List the specific secondary pharmacological effects of promethazine
local anesthetic
extrapyramidal effects (dystonia, akathisia)
List the specific secondary pharmacological effects of pyrilamine
local anesthetic
List the specific secondary pharmacological effects of cyproheptadine & azatidine
anti-serotonin –> headaches
List the specific secondary pharmacological effects of phenothiazines
a-adrenergic antagonism (hypotension)
extrapyramidal effects (dystonia, akathisia)
What information about H1 antagonists should be shared with patients?
- Report history of glaucoma, urinary retention, pregnancy
- May cause drowsiness, dizziness (need patient history)
- Avoid with alcohol & other CNS depressants
- Report any involuntary movements with phenothiazine (H-1 blockers)
List the contraindications of 1st generation H1 antagonists
urinary retention, narrow angle glaucoma
Describe the side effect profile of 2nd generation H1 antagonists
Little or no sedation
No anti-muscarinic actions
No anti-emetic actions
No anti-motion sickness action
(efflux from CNS by P-glycoprotein transporter)
Describe the role of T-cells in allergic rhinitis
Involved in the late-phase response
Release of chemo-attractant factors
Inflammatory cell infiltration
Release of proinflammatory factors
Allergic inflammation
Congestion
Describe the mechanism of action of glucocorticosteroids in the treatment of allergic rhinitis
- Decrease release of cytokines by T-cell response to antigen binding
- Decreases the secretion of mucin by goblet cells in the nasal passageways
Describe Cromolyn Sodium
Prevents histamine release
Rx: mastocytosis (oral)
OTC: allergic rhinitis (nasal spray)
Describe Nedrocromil
Rx: allergic conjunctivitis (eye drops)
List examples of first-generation antihistamines
- brompheniramine (Dimetapp)
- cyproheptadine (Periactin)
- diphenhydramine (Benadryl)
- promethazine (Phenergan - Rx only)
- hydroxyzine (Atarax - Rx only)
- pyrilamine
Name 3 antihistamines that exhibit anti-cholinergic effects
diphenhydramine
atropine
acetylcholine
List second-generation H1 antagonists
- loratadine (Claritin)
- desloratadine (Clarinex)
- fexofenadine (Allegra)
- cetirizine (Zyrtex)
- levocetirizine (Xyzal)
Describe the role of histamine Allergic Rhinorrhea (runny nose)
histamine indirectly stimulated mucus discharge via H-1 receptors on nerve endings
Describe the role of histamine in Rhinorrhea (runny nose) caused by the common cold
a virus stimulates reflex independent of peripheral H1 receptors.
– 1st gen. drugs act in the brain to inhibit rhinorrhea and sneezing, so 2nd generation drugs may not be as effective
List topical H-1 receptor antagonists
- azelastine (Astelin)
- ketotifen (Zaditor)
- olopatadine (Patanol)
Name glucocorticosteroids used in the treatment of allergic rhinitis
- fluticasone (Flonase
- budesonide (Rhinocort)
