LLecture 25: Antihistamines Flashcards
Histamine synthesis
-in mast cells and basophils
-histidine to histamine
-catalyzed by L-histidine decarboxylase
Histamine is stored in
granules
histamine is released from granules in response to
-antigens
-cell lysis
Metabolism of Histamine
-N-methylation
-Oxidation
-or imidazoleacetic acid 5’phosphoribosyl transferase
Slide 6
Slide 6
Distribution of mast cells
-skin
-mouth
-nose
-lungs
-intestinal mucosa
Stored histamine
-complexed with sulfated-polysaccharides, heparin sulfate, chondroitin sulfate, and proteases
Non-mast cell histamine
-nerve terminals in some areas of brain (NT)
-fundus of stomach: specialized cells store histamine for stimulation of acid secretion
Release of histamine from mast cells
-antigen mediated
-non-antigen mediated
antigen mediated release of histamine from mast cell
-binding of antige/allergen to antibodies on surface (IgE)
-other inflammatory agents are also released
non-antigen mediated release of histamine from mast cells
-thermal or mechanical stress
-cytotoxic agents (venoms)
-various drugs (high dose morphine)
Mast cell degranulation requires:
-binding of IgE to FcER
-binding of antigen to IGE
-clustering of FCER receptors
-influx of Ca2+ via CRAC
CRAC
ca release activated channels
Binding of antigen to antibody molecules causes cytoplasmic Ca2+ concentration:
to increase
Drugs that prevent histamine release
-cromolyn sodium
-nedocromil
-B agonists
Cromolyn sodium
-Rx- mastocytosis (oral)
-OTC: allergic rhinitis (nasal spray)
Nedocromil
-Rx- allergic conjunctivitis (eye drops)
acetylcholine effect on histamine
-stimulate
B-agonist effect on histmaine
-inhibit release
Histamine receptors
-4 subtypes
-all GPCRs
H1 receptor location
-distributed throughout CV, respiratory systems, GI, smooth muscle
H1 linked to
-smooth muscle contraction
-vasodilation
-stimulation of sensory nerves
H1 activation that causes smooth muscle contraction
-Gq –> PLC –> IP3 –> DAG
-inc Ca2+ –> phospho MLC
H1 vasodilation mech
-inc NO release
-NO diffuses to vasc smooth muscle
=inc cGMP and dec Ca2+
H1 sensory nerve stimulation mech
-Hist + H1 binding in cutaneous or nasal nerve ending
-causes itching and sneezing
H2 receptor distribution
-CV system
-GI smooth muscle
-stomach
H2 receptor linked to:
-relaxation of vasc smooth muscle
-gastric secretion
H1 and H2 colocalization
? slide 14
H3 receptor location
CNS
H3 linked to
-inhibition of neurotransmitter release
-inhibition of adenylyl cyclase
H3 mech
-Gi/Go
-dec Ca2+
H4 location
-mast cells
-basophils
-eosinophils
-coupled to Gi/Go
H4 linked to
-histamine-induced chemotaxis
-promising target for new anti-inflammatory drugs
Histamine effect on heart
-tiny inc in rate and force of contraction
-H2 inc SA conduction, reflex tachycardia
Histamine effect on vasodilation
-H1 in endothelium
-H2 in smooth muscle
bronchial constriction
H1
acid release in stomach
H2
Anaphylaxis
-hypotension
-loss of fluid to intersitial space
-dec in effective blood volume; swelling
Histamine positive chronotropy + inotropy mech
-inc diastolic depolarization current
-inc HR
-inc cAMP
-inc Ca
-inc force
Vasodilation of endothelium
-high affinity H1 receptors
-signal via NO pathway
vasodilation of smooth muscle
-H2
-PKA pathway
histamine causes vasoconstriction of
veins
Histamine inc capillary permeability mech
-H1 endothelial contraction
-tight-junction disruption
-releases plasma proteins, fluid
-occurs in small vessels
-results in edema
-enhances immune cell ability to respond to antigen
Histamine cardiovasc effects
-positive intropy
-positive chronotropy
-vasodilation (constrict veins tho)
-inc capillary permeability
Histamine effects in skin
-triple response
-uticaria
-dermatographia
-flushing (erythema)
triple response
- red spot at point of injection
- Red flare radiating ~1 cm from injection site
- wheal (welt) at injection site
insect bites
-flare and edma
uticaria
-hives
-rash
-welts
dermatographia
-redness/welt with mechanical stimulation
flushing (erythema)
-redness in skin due to vasodilation
Histamine effect in the lungs
-H1
-Smooth muscle contraction
-bronchoCONSTRICTION
-Ca2+ mobilization
Systemic anaphylaxis
-hypersensitivity/allergic rxn
-severe
-histamine and autocoids released
-skin, respiratory, GI, CV, etc
anaphylaxis treatment
-epinephrine injection
-use of antihistamines is often not effective
H1 antagonists referred to as
antihistamines
H2 antagonists referred to as
acid blockers
