H2RA's Flashcards

1
Q

Peptic Ulcer formation (Duodenal and gastric ulcer)

A
  1. Parietal cells release acid in stomach stimulating
    - Gastrin receptors
    - H2 receptors
    - Muscarinic receptors
    K+H+ATPase pump exchanges K+ for H+
  2. Muscarinic and gastrin receptors also have an effect on ECL cells
    - Stimulates release of Histamine
    - which causes release of Gastrin
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2
Q

H2RA

A

Treat Helocibacter pylorii infection and NSAID’s induced peptic ulcer

  • Competitive inhibition
  • Suppress basal and meal stimulated gastric acid secretion
  • Highly selective (only effect H2)
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3
Q

SAR for H2R

A

Three nitrogen atoms are required for H2R agonist effect

  • Three binding regions proposed for receptor - 1 imidazole binding region and 2 polar binding regions
  • 1 polar binding region accessed by agonist and other by an antagonist
  • Antagonist polar binding region is further from imidazole binding region
  • 5 membered aromatic ring
  • Short chain with sulfur
  • H bond donor
  • Double bond with electron withdrawing group
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4
Q

N-guanylhistamine

A

Binds as an agonist in one mode and as an antagonist in the other mode (partial agonist/partial antagonist)

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5
Q

Cimetidine

A
  • Imidazole ring binds to iron centre of haem of cyp450
  • inhibits cyp450
  • increases levels of other drugs
  • Has more adverse effects (capable of crossing blood brain barrier through lipophilicity)
  • side effects: hallucinations in elderly, sexual dysfunction and
  • males develop gynaecomastia which is development of breast tissue
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6
Q

Inverse agonist

A

CIMETIDINE

  • Causes conformational change
  • Brings activity right down (close to zero)
  • Reduces acid release
  • Dimmer rather than off
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7
Q

2nd generation anti-histamine

A

CETIRIZINE

  • Has COOH
  • Prevents crossing of blood-brain barrier
  • Makes it non-drowsy
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8
Q

STAGE 1 IN DISCOVERY

A

N-guanylhistamine was discovered

- Prevents histamine from releasing HCl

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9
Q

STAGE 2 IN DISCOVERY

A

Buremomide was discovered

  • More active as an antagonist
  • Established the existence of H2R
  • Chain extension proved good activity as an antagonist and better overlap of thiourea group
  • Activity too low for oral use ( had to be injected )
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10
Q

STAGE 3 IN DISCOVERY

A

Metiamide was discovered

  • Adding methyl at C4 proved effective as it makes N in position 3 protonated and N-1 becomes less basic (due to sulfur)
  • led to 1 death (granulocytosis)
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11
Q

STAGE 4 IN DISCOVERY

A

Cimetidine was discovered

  • Replaced C=S with C=N behaving as
  • Electron withdrawing effect of CN has an inductive effect most felt at neighbouring N so it is less likely to form a H bond
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12
Q

Thiaburimamide

A

Sulfur is slightly electron withdrawing making it harder to protonate imidazole

  • This keeps it the right tautomer (Ntal)
  • N pi is inactive and has no antagonist effect
  • Adding methyl in position
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