lectures 25-26 (antihistamines) Flashcards
exam 3
histamine synthesis
synthesized in mast cells and basophils
rxn is catalyzed by L-histidine decarboxylase
histidine –> histamine +CO2
histamine metabolism
- N-methylation on an imidazole nitrogen by histamine N-methyltransferase
- oxidation by diamine oxidase
- imidazoleacetic acid 5’-phosphoribosyl transferase
histamine –> N-methylhistamine –> N-methylimidazole acetic acid
or
histamine –> imidazole acetic acid –> imidazole acetic acid riboside
histamine storage
- stored in granules for rapid release in response to antigens and cell lysis
- complexed with sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases
- mast cells in high numbers in skin, nose, mouth, lungs, intestinal mucosa
- non-mast cell histamine: nerve terminals in some areas of the brain (NT), fundus of stomach (specialized cells store histamine for stimulation of acid secretion)
histamine release
antigen mediated:
- binding of antigen (allergens) to antibodies bound to the cell surface (IgE)
- other inflammatory agents are also released (kinins, serotonin, leukotrienes, prostaglandins)
non-antigen mediated:
- thermal or mechanical stress
- cytotoxic agents (venoms)
- various drugs (high-dose morphine)
mechanism of histamine release
requires:
- binding of IgE antibodies to FceR
- binding of antigen to IgE antibodies
- clustering of FceR receptors
- influx of Ca2+ via Ca2+ release activated channels (CRAC)
binding of antigen to antibody molecules cause an increase in cytoplasmic Ca2+ concentration
β-adrenergic agonists can inhibit antigen-induced histamine release while Ach can stimulate histamine release from mast cells
histamine stimulation of H1 receptors
H1 receptors distributed throughout CV and respiratory systems, GI smooth muscle
- linked to phosphoinositol pathway, activation causes contraction of smooth muscle
histamine + H1 –> Gq –> PLC –> IP3 +DAG –> increase Ca2+ –> increase Ca2+-calmodulin –> phospho MLC
- also linked to vasodilation
hist. H1 (vascular endothelial cells) –> inc. NO release –> NO diffuses to vsm –> inc. cGMP –> dec. Ca2+
- also linked to stimulation of sensory nerves
hist. + H1 (in cutaneous or nasal mucosal nerve endings) –> sneezing and itching (pruitis)
histamine stimulation of H2 receptors
distributed in CV system, GI smooth muscle, and stomach
- linked to relaxation of vsm and gastric secretion
hist. + H2 –> Gs –> inc. AC –> inc. cAMP
- H1 and H2 colocalization (eg. vascular smooth muscle and endothelium)
H1 in vascular endothelium –> inc. NO and inc. contraction of endothelial cells
H2 in vascular muscle –> relaxation (vasodilation)
effects of histamine on the respiratory system
H1 mediated constriction of bronchial smooth muscle
effects of histamine on the CV system
heart:
moderate increase in rate and force of contraction
H2 increase in SA conduction, reflex tachycardia (positive chronotropy)
vasodilation:
H1 in endothelium
H2 in smooth muscle
increased capillary permeability
1st gen H1 antagonists
brompheniramine
brand: dimetapp
structure: alkylamine
cyproheptadine
brand: periactin
structure: piperaDINE
diphenhydramine
brand: benadryl
structure: ethanolamine
promethazine
brand: phenergan
structure: phenothiazine
hydroxyzine
brand: atarax
structure: piperaZINE
pyrilamine
brand: midol
structure: ethylenediamine
secondary pharmacological effects of 1st gen. antihistamines
sedation:
- CNS effect, block of H1/H2 receptors in wakefulness-promoting circuits
- different from sedative/hypnotics, but can still interact with alcohol, anxiolytics, and antipsychotics
- most sedating: ethanolamines and phenothiazines (DIPHENHYDRAMINE AND PROMETHAZINE)
- no correlation b/w sedation and peripheral antihistamine activity
- PARADOXICAL EXCITATION IN CHILDREN
anti-cholinergic:
- more lipid soluble- increases CNS access
- anti-motion sickness and anti-emetic effects likely derived from this (PROMETHAZINE is potent; DIPHENHYDRAMINE)
- only in 1st gen. drugs
- typical anticholinergic effects: decreased urination, dry mouth
other adverse effects/drug interactions:
- local anesthetic: pyrilamine, promethazine
- anti-serotonin: cyproheptadine, azatidine (headaches)
- ⍺ adrenergic antagonism: phenothiazines (hypotension)
- extrapyramidal: phenothiazine, promethazine (dystonia, akathisia)
2nd generation antihistamines
loratadine (claratin)
desloratadine (clarinex)
fexofenadine (allegra)
cetirizine (zyrtec)
levocetirizine (xyxal)
- decreased lipid solubility
- efflux from CNS by P-glycoprotein transporter
- little or no sedation
- no anti-muscarinic, anti-emetic, or anti-motion sickness action
active metabolites:
- fexofenadine (terfenidine), cetirizine (hydroxyzine), may also block LTC4, neutrophil migration, eosinophil infiltration, maybe H4 block
clinical uses of antihistamines in allergic states
seasonal and perennial allergic rhinoconjunctivitis
chronic urticaria
motion sickness
- dramamine, antivert, phenergan
adjunct with epinephrine to treat anaphylaxis
- epi is a physiological antagonist to histamine
- diphenhydramine also given parenterally
adverse effects and drug interactions
- sedation
- ethanolamines and phenothiazines (diphenhydramine, promethazine)
- interactions with other sedatives (alcohol, anxiolytics, antipsychotics)
- 1st gen drugs tend to enhance CNS depression, 2nd gen do not
- paradoxical excitation in children at normal dose - anticholinergic effects
- 1st gen drugs contraindicated in urinary retention, narrow angle glaucoma - patient information
- report history of glaucoma, urinary retention, or pregnancy
- may cause drowsiness, dizziness
- avoid alcohol and other CNS depressants
- report any involuntary movements with phenothiazine (promethazine)
H2 receptor antagonists
famotidine, cimetidine, nizatidine, and ranitidine
therapeutic uses:
- reduce gastric acid secretion
- treat peptic ulcers and GERD
severe side effects:
- CNS dysfunction
- antiandrogen (gynecomastia, galactorrhea)
- impotence
- blood dyscrasias
- hepatotoxicity
role of T cells in allergic rhinitis
TH2 cells stimulate release of chemoattractants
late phase response
- inflammatory cell infiltration
- release of pro-inflammatory molecules
- allergic inflammation
- congestion
allergic rhinitis treatment
glucocorticoids:
- fluticasone (flonase) and budesonide (rhinocort)
- nasal sprays (Rx and OTC strengths)
- slow onset- max benefit may take several days to develop
- fluticasone has very low systemic absorption from intranasal dose
- budesonide ~1/3 of dose is absorbed in <1h
- both may suppress HPA axis with prolonged, high doses
- inhibit TH2 cytokine release, mast cells, and mucin secretion from goblet cells and glands
topical:
- olopatadine#* (patanol)
- azelastine#* (astelin)
- ketotifen* (zaditor)
- eye drops# and nasal spray*
- indicated for treatment of seasonal allergic rhinitis and conjunctivitis
- azelastine and ketotifen approved for systemic
