Histamine and Antihistamine Flashcards
what chemical mediators are involved in inflammation?
complement Eicosanoids Cytokines histamine other agents
what role do eicosanoids have in inflammation?
eicosanoids -> prostaglandins -> main pathway
what other agents are involved in inflammation?
brankinin, platelet activating factors
what is 5-HT involved in?
haemostasis
what are leukotrienes involved in?
asthma
what are peptide mediators?
e.g. bradykinin
what are the 4 cardinal signs of inflammation?
dolor - heat
calor - redness
rubor - swelling
tumor - pain
(+ restriction of movement)
what are the most important cardinal signs of inflammation?
dalor, calor, rubor - drug targets. blood vessels
what is histamine?
a basic amine
where does synthesis of histamine occur?
mast cells and circulating basophils
where is histamine stored?
in granules in mast cells and circulating basophils
where is histamine found?
skin, lungs, face, GI tract and CNS
what complex does histamine occur in?
in a complex with heparin
how is histamine synthesised?
histidine —deoxycarbolates—> histamine
how is histamine released?
- > degranulation by mass
- > individual mediators
where is histamine metabolised?
locally
what is the half life of histamine?
~4 mins
what is the mechanism of the metabolism/excretion of histamine?
histamine -> Imidazoleacetic acid by Diaminase
oxidase
histamie -> N-methyl histamine by N-methyl transferase
-> N-methyl imidazoleacetic acid by Monoamine oxidase (MAO)
what is Monoamine oxidase (MAO)?
breaks down monoamine
what is Monoamine oxidase (MAO) associated with?
presynaptic neurone
what kinds of histamine receptors are there?
H1
H2
H3
H4
what is the location of H1?
Smooth muscle
Endothelium
Brain
what is the location of H2?
Gastric mucosa
Cardiac muscle
Mast cells
Brain
what is the location of H3?
Presynaptic: Brain
Myenteric plexus
Other neurones
what is the location of H4?
Hematopoetic cells
Gastric mucosa
what is the post receptor mechanism of H1?
Gq -> ↑IP3 DAG
what is the post receptor mechanism of H2?
Gs -> ↑ cAMP
what is the post receptor mechanism of H3?
Gi -> ↓ cAMP
what is the post receptor mechanism of H4?
Gi -> ↓ cAMP
what are the selective antagonists of H1?
Mepyramine
Triprolidine
Certirizine
what are the selective antagonists of H2?
Cimetidine
Ranitidine
Tiotidine
what are the selective antagonists of H3?
Thioperamide
Iodophenpropit
Impromidine
what are the selective antagonists of H4?
Tioperamide
what is the Triphasic skin response?
• Flush Red line at site of injury • Flare Redness extending around the site • Wheal Swelling due to local oedema
what is Flush-
Red line at site of injury?
liberation of mast cells in the skin
what is Flare-
Redness extending around the site?
due to vasodilation around site
vasodilators and dilation of sensory nerve -> release vasodilator -> dilation in blood vessel
what is Wheal-
Swelling due to local oedema?
increased vascular permeability
what is the difference in vasculature in normal/acute inflammation?
normal - closed precapillary sphincter, most capillaries empty
acute inflammation - open precapillary sphincter, most capillaries full
what is the mechanism of increased vascular permeability?
- endothelial cells contract
- separate at their boundaries
- basement membrane exposed
- gap formed
- leakage of fluid and plasma proteins
- oedema
5 effects of histamine
- vasodilation
- increased vascular permeability
- bronchoconstriction
- mucus secretion
- itching
how does histamine cause a fall in blood pressure?
1) histamine -> Vasodilation in microvasculature
-Direct effect via H1 receptors (rapid)
- Indirect effect via H2 receptors (slow)
- Fall in:
• peripheral resistance,
• venous return
• cardiac output
= fall in blood pressure
2) histamine -> Increased permeability in microcirculation
- oedema
-loss of blood volume
=fall in blood pressure
how does histamine cause itching?
stimulation of nerve endings - H1 receptor mediated
what do H1-histamine antagonists cause
oedema
itching
fall in blood pressure (so stop the fall in blood pressure)
what does the immunological release of histamine involve?
Mast cells & basophils
IgE molecules attached
Antigen exposure
=> degranulation.
how does an allergen cause inflammation?
allergen -> B cell -> release of IgE antibodies -> antibodies bind to mast cell surface -> rexposure to allergen -> Antigen-antibody complex causes degranulation -> histamine and other mediators -> inflammation
how can you DISPLACE histamine?
basic amines- displace histamine from the
histamine-heparin complex.
e.g. Tubocurarine and Morphine
(Receptors are not involved)
(release is not associated with mast cell damage or degranulation)
what is tubocarine?
muscle relaxant
how can you DEGRANULATE histamine?
Compound 48/80, a diamine polymer
specifically releases histamine from mast cells
by exocytotic degranulation
what is a physiological antagonist of histamine?
adrenaline
what are release inhibitors of histamine?
Cromolyn
Nedrocromil
what are receptor antagonists of histamine?
H1:- Mepyramine
H2:- Ranitidine
what is the difference between physiological and pharmacological antagonist of histamine?
physiological - creating opposing affect
pharmacological - blod H1 receptor
what do H1 Antihistamines do?
(in vitro):
- reduce contraction of bronchial smooth muscle by histamine
- reduce histamine-induced contraction of intestinal and uterine smooth muscle
- reduce vascular permeability caused by histamine
what other receptors do H1 Antihistamines work as antagonists at?
muscarinic, 5-HT and alpha-1 adrenoceptors
what would be an adverse effect of blocking H1 receptor?
sedating -useful to reduce awareness of itching
travel sickness
what would be an adverse effect of blocking muscarinic receptor?
(muscarinic - parasympathetic)
loss of GI motility - constipation
dry mouth
urinary retention
what would be an adverse effect of blocking alpha-1 adrenoreceptor?
(vasoconstriction)
so would cause vasodilation
leads to reflex tachycardia, fainting
what are the uses of H1 antihistamines in allergic reactions?
- hay fever
- Urticaria
- Insect bites
- Drug hypersensitivites
Histamine = main mediator: H1 antihistamines effective
what is the use of H1 antihistamines in asthma?
H1 antihistamines not v. effective
what is the use of H1 antihistamines in
- Motion sickness
- Morning sickness
- Vertigo
Cyclizine, cinnarizine
• Promethazine
Act via CNS H1 receptors.
Antimuscarinic effects may also play a part
how do you combat sedation?
-blood brain barrier
lipid solubility
molecular size
efflux pumps
what are antimuscarinic effects?
dry mouth
blurred vision (loss of accommodation)
anti-nausea
antiparkinson
2 older antihistamines that produce antimuscarinic effects and sedation?
Promethazine, mepyramine
what are newer antihistamines?
Loratadine, certirizine
what is the difference in newer antihistamines than older?
Fewer CNS effects - cross BBB only slowly
Negligible antimuscarinic effects
what are H2 Receptor Antagonists used for?
treatment/prevention of gastric and duodenal ulcers
what is an example of an H2 Receptor Antagonist?
cimetidine and ranitidine
how do H2 Receptor Antagonists affect gastric ulcers?
Reduce secretion of gastric acid stimulated by histamine, gastrin, ACh
how do H2 Receptor Antagonists affect duodenal ulcers?
Promote healing of duodenal ulcers
what is the dosage of H2 Receptor Antagonists?
Once (ranitidine) or twice (cimetidine) daily
how do H2 receptor antagonists work?
histamine ->
vagal stimulation ->
cholinomimetics ->
gastrin ->
H2 receptor antagonists block -»»> acid secretion
