histamine Flashcards
Lewis triple reaction
flush flare wheal
few seconds:
flush
vasodilatory substance rsuch as histamine from cells distrubed by the stimulus
flare: 30 - 60 seconds
neurogenic inflammation
antidromial along collateral branches to release vasodilatory subtances
orthodromially to cause pain sensation.
(sectioning of the central branch will prevent perception of the stimulsus but the falre will continue to cocur until the nerve degenerates )
few minutes:
localised swelling
increased permeability of the endothekium due to histamine
dermatographic urticaria
exaggerated triple response
idiopathic
H1 receptor antagonists
omalizumab - monoclonal antibody against IgE
histamine
2(1H imidazol-4-yl) ethanamine
made from histidine by histidine decarboxylase
made in: mast cells, basophils, ECL in gut and histaminergic neurons in the brain
= in acidic granules with high molecular wright heparin macroheparin
release of histamine from mast cells
C3a, C5a - bind alpha i GPCR, by activates PLC beta
substance P act through Mrgx2 - GPCR alpha q
activate PLC beta
allergen induced igE crosslinking
Fc epsilon I induce phosphorylation fo LAT which activates PLC beta
effects oh histamine
H1 - PLC beta - IP3 + DAG - inflammation
H2 - Gs - adenylate cyclase - cAMP, PKA - acid secretion
H3 - Gi - important inhibitory autoreceptor for CNS
H4 - Gi - chemotaxs
H1
smooth muscle contraction in ileum bronchioles and uterus
blood vessel dilation - endothelial NO
triple response
itching - activation of distinct sensory nerves - pruritoceptors H1
H2 -
HR increase
gastric acid
brain NTS - predominantly H1-3 but also H4
metabolism of histamine
histaminase / diamine oxidase:
oxidative deamination to imidazole acetaldehyde
histamine N=methltransferase
methyl group to N of the imidazole ring - Nt - methylhistamine
Both = inactive
pathologies involving histamine
allergic reactions - ie rhinitis, urticaria, allergies such as nut allergy, penicillin allergy
responses: swelling, itchiness, nasal congestion. watery eyes, poor coat quality
severe anaphylaxis - throat swells, HR increases and BP drops - need emergency adrenaline treatment
mastocytosis
mastocytosis
too many mast cells
heat cold stress infection exercise drugs trigger allerg ylike reaction
gain of function in c-kit/CD117 - R tyr kinase D816V
can be due to tumours or non tumour causes in cas and dogs .
drugs: sodium cromoglycate
omalizumab
imatinib
B2 antag
sodium cromoglycate
mast cell stabiliser
treat: mastocytosis, eye drops for hay fever ie Opticrom
occasionally for asthma
but has to be give 4 times a day
does not produce additive effects with corticosteroids
use for asthma replaced by leukotriene receptor antag
mechanism:
inhibit inward Cl- current needed to have low enough MP to enable a substained influxes of EC Ca2+
raise cAMP ( to prevent degranulation of mast cells )
asthma
salbutamol and formoterol
9 via beta 2 agonists
theophylline - PDE inhibitors
( some effects only, as main effect is via bronchodilatation )
omalizumab
block IgE
decrease mast cell degranulation
H1 antag
clasical antihistamines
inflammatory and allergic conditions
mepyramine
terfenadine
fexofenadine
mepyramine
1st generation anti-histamine
caused drowsiness as could cross BBB
used in topical creams for treating insect bites.
cold/flu medication to aid sleeping
terfenadine
2o generation
cannot cross BBB
increasing evidence of dveelping torsade de points
long QT syndrome
sudden cardiac death
sudden death seem to terfenadine involve Kv11.1 hERG which is important for repolaristaion of the cell
prodrug
to texofenadine
by Cytochrome 450 3A4
conditions of decreased texofenadine = increased risk of death
the enzyme CYP3A4 is inhibited by many drugs ie Bergamottin from grapefruit juice
every new drug now undergoes screening against hERG before going to whole organism trials
fexofenadine
loratadine
3rd generation
anti histamine
no cardiac side effects
non drowsy
use: hayfever, allergy and urticaria
antihistamines little use in cattles - not part of underlying pathology?
adrenaline use
+ co hydrocortisone
use for anaphylaxis
relieves bronchospasm
systemic vasodilatation
reduction in tissue perfusion
NA is too compotent a vasoconstrictor would lead to bradycardia reflex
Imatinib
mastocytosis
FDA approved
only when patient does not have common D816V c-kit mutation ( in kinase domain)
bind TK active site - so the substrate cannot bind
chronic myeloid leukaemia
Oclacitinib
allergic reaction in dogs - 10%
where H1 antag inefficacious
atopic dermatitis
inhibits JAK ( JAK1 )
lowers pro-inflammatory signalling
( ie il-6–> JAK1,2–>STAT)
acute phase proteins release
alternative to corticosteroids and ciclosporins
H2 antag
gastric acid secretion inhibitors
act on H2R on parietal cells block histamine from ECL cells
cimetidine - first used
but inhibits cytochrome p450
use taken over by ranitidine
proglumide
CCK2R inhibitor
directly reduce histamine secretion
ranitidine
zantac
primary use for gastric ulcers
H2R antag
cimetidine
first used H2R inhibitor
but inhibits cytochrome p450
use taken over by ranitidine
drug interactions
affects metab of methadone higher BP and greater side effects
hydroxychoroquine - antimalarial
increase toxicity of tricyclic antidepressants
omeprazole
proton pump inhibitor
can be used on horses
antacids
gaviscon
neutralise stomach acid
cholinergic blockade
vagotomy
obsolete use
eradication of h.pylori
clarithromycin
inhibits 50s of ribosome
inhibits peptidyl transferase activity
interferes with amino acid translocation
H.heilmannii also present
arthrotec
used for rheumatoid arthritis
NSAID diclofenac + misoprostol
misoprostol can also be given to dogs
ways to treat peptic ulcers
CCK2R antag H2R antag prostaglandin analogue vagotomy + anti-AChR ( obsolete) proton pump inhibitor antacids eradication of H.pylori
