Antihistamines (L20)

Question 1

what is histamine?

Answer 1

a chemical mediator produced by cells of the immune system

small compound

Question 2

what cells are involved in histamine release?

Answer 2

basophils

mast cells

Question 3

what do basophils do?

Answer 3

promotion of allergic responses and augmentation of anti-parasitic immunity

Question 4

what do mast cells do?

Answer 4

release granules containing histamine and active agents

Question 5

what does histamine do?

Answer 5

released following immunological stimuli or mechanical injury, acts by binding to 1 or more of the histamine receptors

Question 6

what are the 4 histamine receptors?

Answer 6

H1
H2
H3
H4

they are all GPCRs

Question 7

what does H1 receptor do?

Answer 7

mediate inflammatory and allergic reactions

Question 8

what does H2 receptor do?

Answer 8

mediate gastric acid secretion

Question 9

what does H3 receptor do?

Answer 9

presynaptic receptors, inhibit neurotransmitter release

Question 10

what do histamine receptor antagonists do?

Answer 10

block the effects of histamine

Question 11

what is diphenhydramine?

Answer 11

first generation antihistamine

abused as a deliriant in the USA

Question 12

what is the H1 receptor coupled to?

Answer 12

phospholipase 2

increases intracellular calcium
increases vascular permeability

Question 13

what is the H2 receptor coupled to?

Answer 13

adenyl cyclase

increases cAMP
increases gastric acid secretion

Question 14

what is the H3 and H4 receptors coupled to?

Answer 14

adenyl cyclase

work in the opposite way to H2

they are hard to target as they are promiscuous - bind to lots of different ligands

Question 15

what are the 2 ways of making histamine from histidine?

Answer 15

using aromatic amino acid decarboxylase

using histidine decarboxylase

both remove the carboxyl group

Question 16

what does histamine cause?

Answer 16

• dilation of arterioles
• constriction of venules
• increased vascular permeability
• results in oedema

Question 17

what are the 3 types of H1 antagonists?

Answer 17

1st generation

2nd generation

3rd generation

Question 18

1st generation antagonists

Answer 18

not very selective for H1

some muscarinic binding

not very well tolerated - lots of side effects

eg. diphenhydramine - motion sickness treatment

Question 19

2nd generation antagonists

Answer 19

less sedation

fewer side effects

hydrophilic (polar) at body pH so cannot cross the blood brain barrier

eg. cetirizine

Question 20

3rd generation antagonists

Answer 20

active metabolites

less cardiotoxicity and muscarinic activity

more targeted to H1 receptors - less side effects

e.g.. fexofenadine

Question 21

how do you get fexofenadine?

Answer 21

by converting the cardiotoxic terfenadine to fexofenadine (its active metabolite) by CYP3A4

Question 22

H2 antagonists

Answer 22

turns off H2 receptors

cause a decrease in gastric acid production by 90%

promotes peptic ulcer healing

e.g. ranitidine and cimetidine

Question 23

what do parietal cells do?

Answer 23

do the secreting of the acid in the stomach

Question 24

how do you stimulate parietal cells to produce acid?

Answer 24

stimulate them with histamine, gastrin or acetylcholine

you get an increase in H+ (acid)

needs up regulation of the proton pump

Question 25

treatment strategies for peptic ulcers

Answer 25

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

Question 26

what bacteria cause peptic ulcers?

Answer 26

helicobacter pylori

Question 27

advantages and disadvantages of H2 antagonists

Answer 27

advantages 
• cheap 
• relatively safe 
• effective acidity regulators 
• rapid onset of action (1 hour)

disadvantages
• off target effects
• short mechanism of action (12 hours)

Question 28

advantages and disadvantages of PPIs

Answer 28

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