Exam 1: Lecture 4, Medical Chemistry of Diuretics Flashcards
Osmotic diuretics
Have low-molecular weight
Highly water soluble
freely filtered through Bowman’s capsule into renal tubules and not reabsorbed due to being very polar
increase tonicity of tubular fluid, causing water to pass from body into tubule
Mannitol
Has low bioavailability (10-20%)
Given mostly by IV
inert polar functionality attracts a lot of water, so brings water with it = how it works
Glycerin and isosorbide
given orally
High bioavailability, 80%
Osmotic diuretic uses
maintain kidney función and urine flow rate in early renal function
cerebral edema (excessive water in spaces of brain)
decrease intraocular pressure in glaucoma
Osmotic diuretics side effects
Rapid admin can cause excessive fluid shift into blood causing congestive heart failure
Carbonic anhydrase is….
zinc enzyme that catalyzes interconversion between CO2 and bicarbonate ion.
Plays a key role in NaHCO3 reabsorption and acid secretion
Major site of action for CA inhibitors
Proximal Tubule
5 Families of Carbonic anhydrase
alpha, beta, gamma, delta, and E
how many alpha-CA isoforms?
at least 16 different
Carbonic anhydrase enzyme requires….
zinc for its action, if you block zinc then it will not work.
This is how CA inhibitors work
Histidine ligands important for zinc binding in CA
His 94,96, and his 116
proton shuttle resides surround these and are important for the catalytic cycle and binding of substrates/inhibitors
Mechanism for CA catalyzed CO2 hydration
- Zinc will attract water molecule, and proton shuttle will take proton out
- Enzyme comes in contact with CO2 and creates a complex which will then dissociate to form carbonate ion which gets released.
- This makes 4th site of zinc available again for water to attach
two main classes of CA inhibitors
metal complexing anions (thiocyanate) and unsubstituted sulfonamides
both bind to Zn and inhibit its activity, forming covalent bond
SAR of Sulfanilamide
mono- or di-substitution of sulfonamide portion = loss of diuretic activity, so the acidic NH function is important for diuretic activity
Functional groups that increase acidity of NH group found to improve activity
CA inhibitors Mechanism of action
inhibit activity of CA, reducing formation of carbonic acid.
leads to reduced H ions to promote Na reabsorption
in order to have diuretic response, more than 99% of CA has to be inhibited. prolonged use leads to metabolic acidosis (urine becomes alkaline and blood becomes acidic)
CA drugs lose effectiveness until normal acid base balance is restored
CA mechanism in glaucoma
inhibition of CA also decreases rate of formation of aqueous humor and reduces intraocular pressure
topically acting sulfonamides (anti glaucoma drugs)
Acetazolamide = used primarily in reducing IOP in treatment of glaucoma and absence seizures
Metazolamide (more potent than acetazolamide)
Ethoxzolamide and Dichlorphenamide (30 X more potent by making more acidic) properties and uses similar to acetazolamide
Why is metazolamdie more potent than acetazolamide?
Because methylation will decrease the polarity and permits a greater penetration into the ocular fluid
Benzothiazides
synthesize from an effort to enhance potency of CA inhibitors
found to increase NaCL excretion
DCT has thiazide binding sites, primary site of action
these drugs compete for the chloride binding site of Na/Cl symporter and inhibit the reabsorption of Na and Cl ions
SAR benzothiazides
EWG necessary at 6 position for diuretic activity
EDG at 6 will reduces diuretic activity
SAR benzothiazides:
Saturation of double bond will make….
10 times more active
SAR benzothiazides:
removing sulfonamide at position 7 will….
cause zero or little diuretic activity
SAR benzothiazides:
substitution with lipophilic group at position 3 will….
increase diuretic potency
Haloalkyl, aralkyl or thither substitution increases lipid solubility of molecule and yields compounds with a longer duration of action
SAR benzothiazides:
Alkyl substitution at the 2-N position….
decreases polarity and increases duration of diuretic action
SAR benzothiazides:
Ring B is….
not a requirement, and analogs with open ring exhibit diuretic activity
SAR benzothiazides: Quinazolinone derivatives (sulfone group at p1 replaced with carbonyl group) will....
retain activity and increase duration of action
SAR benzothiazides:
compounds with trifluoromethyl substitution are….
about 10 times more active than chlorophyll-substitued analogs
Difference between quinazoline and thiazides is…
the replacement of the 4-sulfone group with a 4-keto group
Quinazoline derivatives have….
long duration of action as a result of protein binding
Indolines (indapamide)….
has prolonged duration of action (up to 8 wks) due to its extensive binding to CA
is “thiazide like” because it doesn’t have thiazide ring
Loop Diuretics
also known as High-ceiling due to producing peak diuresis much greater than other drugs
Main site of action for Loop diuretics….
Tick Ascending limb,
inhibit the luminal Na,K,2Cl symporter
have quick onset and short duration ( about 30 min, last about 6 hrs)
2 important points of loop diuretics
- some don’t have good bioavailability
- Strongly bind to plasma protein due to polar group and when blood is filtered, these drugs stick to protein and do not get filtered and go back into circulation.
Potassium sparing diuretics use alone will….
increase K levels, causing hyperkalemia and fatal arrhythmia
generally used in combo with other diuretics that would otherwise tend to lower k levels. This combo helps maintain normal range of K
2 types of Potassium sparing drugs
inhibitors of renal Epithelial Na Channels
antagonists of mineralocorticoid receptors
Inhibitors of Renal Epithelial Na Channels
These drugs block sodium channels.
Triamterene and amiloride, used for antikaliuretic actions
Antagonists of mineralocorticoid receptors
Aldosterone promotes salt and water retention, and potassium and hydrogen excretion
these drugs mimic aldosterone
Spironolactone, eplerenone
Metabolism of Spironolactone
metabolized into Canrenone (active metabolite aldosterone antagonist) then into Canrenoic acid anion
Eplerenone
newer drugs with similar structure and mechanism to spironolactone
