Antihistamines (L20) Flashcards
what is histamine?
a chemical mediator produced by cells of the immune system
small compound
what cells are involved in histamine release?
basophils
mast cells
what do basophils do?
promotion of allergic responses and augmentation of anti-parasitic immunity
what do mast cells do?
release granules containing histamine and active agents
what does histamine do?
released following immunological stimuli or mechanical injury, acts by binding to 1 or more of the histamine receptors
what are the 4 histamine receptors?
H1
H2
H3
H4
they are all GPCRs
what does H1 receptor do?
mediate inflammatory and allergic reactions
what does H2 receptor do?
mediate gastric acid secretion
what does H3 receptor do?
presynaptic receptors, inhibit neurotransmitter release
what do histamine receptor antagonists do?
block the effects of histamine
what is diphenhydramine?
first generation antihistamine
abused as a deliriant in the USA
what is the H1 receptor coupled to?
phospholipase 2
increases intracellular calcium
increases vascular permeability
what is the H2 receptor coupled to?
adenyl cyclase
increases cAMP
increases gastric acid secretion
what is the H3 and H4 receptors coupled to?
adenyl cyclase
work in the opposite way to H2
they are hard to target as they are promiscuous - bind to lots of different ligands
what are the 2 ways of making histamine from histidine?
using aromatic amino acid decarboxylase
using histidine decarboxylase
both remove the carboxyl group
what does histamine cause?
- dilation of arterioles
- constriction of venules
- increased vascular permeability
- results in oedema
what are the 3 types of H1 antagonists?
1st generation
2nd generation
3rd generation
1st generation antagonists
not very selective for H1
some muscarinic binding
not very well tolerated - lots of side effects
eg. diphenhydramine - motion sickness treatment
2nd generation antagonists
less sedation
fewer side effects
hydrophilic (polar) at body pH so cannot cross the blood brain barrier
eg. cetirizine
3rd generation antagonists
active metabolites
less cardiotoxicity and muscarinic activity
more targeted to H1 receptors - less side effects
e.g.. fexofenadine
how do you get fexofenadine?
by converting the cardiotoxic terfenadine to fexofenadine (its active metabolite) by CYP3A4
H2 antagonists
turns off H2 receptors
cause a decrease in gastric acid production by 90%
promotes peptic ulcer healing
e.g. ranitidine and cimetidine
what do parietal cells do?
do the secreting of the acid in the stomach
how do you stimulate parietal cells to produce acid?
stimulate them with histamine, gastrin or acetylcholine
you get an increase in H+ (acid)
needs up regulation of the proton pump
treatment strategies for peptic ulcers
1970s: standard therapy
• H2 antagonist
• recurrence common
• repeated treatment needed
1987: triple therapy
• 1 week duration
• H2 agonist + antimicrobial + bismuth
• no recurrence
now: PPIs (proton pump inhibitors)
• arrhythmia risk eliminated
• have other risks
what bacteria cause peptic ulcers?
helicobacter pylori
advantages and disadvantages of H2 antagonists
advantages • cheap • relatively safe • effective acidity regulators • rapid onset of action (1 hour)
disadvantages
• off target effects
• short mechanism of action (12 hours)
advantages and disadvantages of PPIs
advantages
• highly effective
• long duration of action (24 hours - 3 days)
• irreversible inhibition of pump
disadvantages
• can cause nutrient deficiencies
• increased risk of gut infection
• delayed onset of action
