Diuretics Flashcards
Is xanthine diuretics well used?
No, because low efficacy
Mercurial diuretics MOA
R-C-C-Hg
React with sulfhydryl groups in cells of ascending limb of henle, inhibiting Cl- transport
Very strong diuretic
Is mercurial diuretics still used?
No, because of Hg toxicity
Osmotic diuretics MOA
Osmotically impair proximal tubule fluid re-absorption, giving lower Na+ concentration in ascending limb of loop of henle and distal tubule
Decrease osmotic reabsorption in the loop of henle
IV ONLY
modest effect
Whatare Carbonic anhydrase inhibitors derived from?
From sulphonamide antibacterials
What is an example of carbonic anhydrase inhibitor?
acetazolamide
orally active, high effective
How come the CAI does not have sulphur cross sensitivities?
because of no arylamine
SAR of CAI
ACYL group larger than acetyl (CH3CO-) increases SE
MOA of CAI
At the proximal tubule, it decrease more than 80% of HCO3- reabsorption
small diuretic effect
Thiazides/ benzothiadiazides SAR
Weak acidic
H atoms at N2 is most acidic due to neighbouring sulfone (s=o) group (e- withdrawing effect)
Less acidic in sulfonamide Group at C7
What is the purpose of acidic protons?
formation of water soluble sodium salt for IV dosing
K+ sparing diuretic
aldosterone antagonist
structurally related to aldosterone (lactone group on C17) –> spiro nomenclature
What does non-aldosterone antagonist molecules have?
pteridines (two benzene rings with 4 N - triamterene)
or pyrazine (benezene ring with 2N - amiloride)
e.g. triamterene
Most modification in SAR of triamterene (non-aa)
decreases activity
Maintain activity of triamterene by
replace amine group with a lower alkylamine
Decrease acitivity by 50% by..
adding p-CH3 group to phenyl ring
Making triamterene INACTIVE by…
adding p-OH group on phenyl ring
MOA of triamterene
interefere with cationic exchange by blocking Na+ channels
actively transport into lumen of proximal tubule
act only in collecting duct
induce a modest increase in Na+ excretion with Cl-
little change in K+ excretion
Examples of of High ceiling loop diuretics
ethacrynic acid, frusemide, bumetanide
What does the ethacrynic acid mimic?
mimic mercurial diuretic
Increase activity of ethacrynic acid by
adding electron withdrawing group (Cl-) ORTHO to unsaturated ketone
Most action in ORTHO and META
Efficacy in relation to structure
Site of action predicts efficacy
multiple sites of action with one effect
What is the therapeutic strategy for diuretic?
combination of diuretics - multi-modal site of action
What is essential in thiazides
Electron withdrawing group at position 6
Removing halogen on C6 on thiazide will
make the compound inactive
Swapping C6 group to electron donating will
decrease potency
Replacing one halogen to more electronegative halogen will have
no change in potency
but longer DOA
Saturation of the thiadiazine ring to give 3,4-DIHYDROderivative will
increase activity by 10 fold
hydrochlorothiazide
Substituting R3 with a lipophilic group (alkyl) in thiazides will
increase potency and DOA
Making R2 and R3 with CH3 and halogenated alkyl group in thiazides will
increase potency by 10-20x
Replacing benzene ring with pyridine (benzene ring with N) in thiaizide will
decrease activity
Replacing or removing sulfonamide group at 7C will
give little or no activity
Alkyl substitution on 2N wiill
decrease POLARITY,
increase DOA
How is bumetanide different to other loop diuretics like ethacrynic acid and frusemide?
Bumetanide does not have Cl-
