Exam 1: Lecture 4, Medical Chemistry of Diuretics

Question 1

Osmotic diuretics

Answer 1

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

Question 2

Mannitol

Answer 2

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

Question 3

Glycerin and isosorbide

Answer 3

given orally

High bioavailability, 80%

Question 4

Osmotic diuretic uses

Answer 4

maintain kidney función and urine flow rate in early renal function

cerebral edema (excessive water in spaces of brain)

decrease intraocular pressure in glaucoma

Question 5

Osmotic diuretics side effects

Answer 5

Rapid admin can cause excessive fluid shift into blood causing congestive heart failure

Question 6

Carbonic anhydrase is….

Answer 6

zinc enzyme that catalyzes interconversion between CO2 and bicarbonate ion.

Plays a key role in NaHCO3 reabsorption and acid secretion

Question 7

Major site of action for CA inhibitors

Answer 7

Proximal Tubule

Question 8

5 Families of Carbonic anhydrase

Answer 8

alpha, beta, gamma, delta, and E

Question 9

how many alpha-CA isoforms?

Answer 9

at least 16 different

Question 10

Carbonic anhydrase enzyme requires….

Answer 10

zinc for its action, if you block zinc then it will not work.

This is how CA inhibitors work

Question 11

Histidine ligands important for zinc binding in CA

Answer 11

His 94,96, and his 116

proton shuttle resides surround these and are important for the catalytic cycle and binding of substrates/inhibitors

Question 12

Mechanism for CA catalyzed CO2 hydration

Answer 12

1. Zinc will attract water molecule, and proton shuttle will take proton out
2. Enzyme comes in contact with CO2 and creates a complex which will then dissociate to form carbonate ion which gets released.
3. This makes 4th site of zinc available again for water to attach

Question 13

two main classes of CA inhibitors

Answer 13

metal complexing anions (thiocyanate) and unsubstituted sulfonamides

both bind to Zn and inhibit its activity, forming covalent bond

Question 14

SAR of Sulfanilamide

Answer 14

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

Question 15

CA inhibitors Mechanism of action

Answer 15

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

Question 16

CA mechanism in glaucoma

Answer 16

inhibition of CA also decreases rate of formation of aqueous humor and reduces intraocular pressure

Question 17

topically acting sulfonamides (anti glaucoma drugs)

Answer 17

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

Question 18

Why is metazolamdie more potent than acetazolamide?

Answer 18

Because methylation will decrease the polarity and permits a greater penetration into the ocular fluid

Question 19

Benzothiazides

Answer 19

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

Question 20

SAR benzothiazides

Answer 20

EWG necessary at 6 position for diuretic activity

EDG at 6 will reduces diuretic activity

Question 21

SAR benzothiazides:

Saturation of double bond will make….

Answer 21

10 times more active

Question 22

SAR benzothiazides:

removing sulfonamide at position 7 will….

Answer 22

cause zero or little diuretic activity

Question 23

SAR benzothiazides:

substitution with lipophilic group at position 3 will….

Answer 23

increase diuretic potency

Haloalkyl, aralkyl or thither substitution increases lipid solubility of molecule and yields compounds with a longer duration of action

Question 24

SAR benzothiazides:

Alkyl substitution at the 2-N position….

Answer 24

decreases polarity and increases duration of diuretic action

Question 25

SAR benzothiazides:

Ring B is….

Answer 25

not a requirement, and analogs with open ring exhibit diuretic activity

Question 26

SAR benzothiazides:
Quinazolinone derivatives (sulfone group at p1 replaced with carbonyl group) will....

Answer 26

retain activity and increase duration of action

Question 27

SAR benzothiazides:

compounds with trifluoromethyl substitution are….

Answer 27

about 10 times more active than chlorophyll-substitued analogs

Question 28

Difference between quinazoline and thiazides is…

Answer 28

the replacement of the 4-sulfone group with a 4-keto group

Question 29

Quinazoline derivatives have….

Answer 29

long duration of action as a result of protein binding

Question 30

Indolines (indapamide)….

Answer 30

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

Question 31

Loop Diuretics

Answer 31

also known as High-ceiling due to producing peak diuresis much greater than other drugs

Question 32

Main site of action for Loop diuretics….

Answer 32

Tick Ascending limb,

inhibit the luminal Na,K,2Cl symporter

have quick onset and short duration ( about 30 min, last about 6 hrs)

Question 33

2 important points of loop diuretics

Answer 33

1. some don’t have good bioavailability
2. 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.

Question 34

Potassium sparing diuretics use alone will….

Answer 34

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

Question 35

2 types of Potassium sparing drugs

Answer 35

inhibitors of renal Epithelial Na Channels

antagonists of mineralocorticoid receptors

Question 36

Inhibitors of Renal Epithelial Na Channels

Answer 36

These drugs block sodium channels.

Triamterene and amiloride, used for antikaliuretic actions

Question 37

Antagonists of mineralocorticoid receptors

Answer 37

Aldosterone promotes salt and water retention, and potassium and hydrogen excretion

these drugs mimic aldosterone

Spironolactone, eplerenone

Question 38

Metabolism of Spironolactone

Answer 38

metabolized into Canrenone (active metabolite aldosterone antagonist) then into Canrenoic acid anion

Question 39

Eplerenone

Answer 39

newer drugs with similar structure and mechanism to spironolactone