Medicinal chemistry of Diuretics

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diuretics

are drugs that increase the rate of urine formation primarily by inhibiting the reabsorption of ions (especially Na and CL) without affecting protein, vitamin, glucose, or amino acid reabsorption

diuretics

these drugs interfere with reabsorption of sodium and other ions from the LUMINA of the NEPHRONS, the functional unit of kidney

Lumina

diuretics interfere with reabsorption of sodium and other ions from the L_____ of the nephrons

structure of diuretic

diuretic determining factor in the amount of ion and accompanying water excreted as urine (S______ of D_____)

site of action

diuretic determining factor in the amount of ion and accompanying h20 excretion (S___ of A_____)

extracellular fluid

the amount of ion and h20 released are dependent on the salt intake of the patient and the amount of e_______ F______ present

diuretic

classified in use by chemical class

diuretic

classified by mechanism of action (carbonic anhydrase inhibitors, osmotics)

site of action

diuretics are classified mainly by S___ of _____

urine contents

diuretics can be classified based on effect of U____ C_____

osmotic

These diuretics are low molecular weight and highly water soluble compounds that are freely filtered through Bowman's capsule into renal tubules and NOT reabsorbed

osmotic

increase tonicity of tubular fluid, thereby causing the water to pass from the body into the tubule producing the diuretic effect

osmotic

diuretics which act on both the PROXIMAL TUBULE and the LOOP of HENLE (latter primary site of action)

osmotic

mannitol and urea have low bioavailability so they are given IV, classified as ? diuretics

osmotic

diuretics used to maintain kidney function and urine flow rate in early renal failure.

osmotic

diuretics used in the treatment of cerebral edema and to decrease intraocular pressure in glaucoma

carbonic anhydrase

ubiquitous ZINC enzymes that catalyze a simple physiological rxn; interconversion between carbon dioxide and bicarbonate

carbonic anhydrase

Involved in many crucial physiological processes; plays a key role in Bicarbonate reabsorption and acid secretion

16

how many different a-CA isoforms exist in mammals? (Clue 13 exhibit catalytic activity)

histidine

Human Carbonic anhydrase Zn(II) are coordinated by three _______ ligands

Zinc

? ion of CA is essential for catalysis.

basic

active form of the CA enzyme is ______, with hydroxide bound to Zn(II)

metal complexing anions

One of the two known classes of CAis (example thiocyanate)

unsubstituted sulfonamides

one of the two known classes of CAis (sulfonamide), which binds to the Zn(II) ion of the enzyme and inhibits activity

acidic NH

Monosubs. or Disubst. of sulfonamide portion results in a loss of diuretic activity, therefore the _____ __ function of SULFONAMIDE is important for diuretic activity

increase

functional groups that (increase/decrease) acidity of sulfonamide NH group were found to improve activity

CA inhibitors

? INHIBIT ACTIVITY OF CA, REDUCING FORMATION OF CARBONIC ACID WITHIN THE PROXIMAL AND DISTAL TUBULAR CELLS TO LIMIT NUMBER OF H+ IONS AVAILABLE TO PROMOTE NA RE ABSORPTION

Carbonic anhydrase

FOR DIURETIC RESPONSE TO BE OBSERVED MORE THAN 99% OF _____ _______ ACTIVITY MUST BE INHIBITIED

CA inhibitors

Prolonged use of __ i_______ leads to METABOLIC acidosis

Carbonic anhydrase

_____ ________ loses its effectiveness as a diuretic until normal acid base balance is restored

Carbonic anhydrase

inhibition of _____ ______ decreases the rate of formation of aqueous humor and consequently reduces intraocular pressure, therefore inhibitors of this enzyme find use in the treatment of OPEN ANGLE GLAUCOMA

Open angle glaucoma

carbonic anhydrase decreases the rate of formation of aqueous humor, so it is used to treat ?

CA inhibitor

used primarily in reducing IOP in the treatment of glaucoma and absence seizures (i.g. acetazolamide)

metazolamide

MORE potent that acetazolamide, is a METHYL derivative of acetazolamide, METHYLATION DECREASES POLARITY and permits a GREATER PENETRATION into the ocular fluid where it acts as a CAi decreasing IOP

CA inhibitors

Ethoxzolamide and Dichlorphenamide are other __ _______ whose properties and uses resemble those of acetazolamide

benzothiazides

synthesized in an effort to enhance potency of inhibitors of CA, unlike CA inhibitors which primarily increase bicarbonate excretion, were found to increase NACL excretion

thiazides

inhibitors of NA/CL symport

benzothiazides

DO NOT effectively inhibit CA activity, despite presence of sulfonamide group

DCT

expresses thiazide binding sites and is accepted as the PRIMARY site of action of thiazide diuretics, the proximal tubule may represent a secondary site of action

benzothiazides

compete for the chloride binding site of the NA/Cl symporter and inhibit the reabsorption of sodium and chloride ions

6

for thiazides an electron withdrawing group at position _ is necessary for diuretic activity

thiazides

little diuretic activity is seen with a hydrogen atom at position 6, whereas CHLORO or CF3 are highly active

Cf3

___ substituted diuretics are more lipid soluble and have a longer duration of action than their chloro substitued analogs

donating

Prescence of electron _____ group at position 6 reduces diuretic activity

7

replacement or removal of SULFONAMIDE group at position _ yields compounds with little or no diuretic activity (thiazides)

more

In regard to benzothiazides, saturation of the double bond to give 3,4 dihydro derivative produces a diuretic that is 10 times (more/less) active than UNsaturated derivatives

3

substitution at position _ with a lipophilic group increases diuretic potency of thiazides

lipid solubility

for thiazides haloalkyl, aralkyl, or thioether increases l____ S_____ of the molecule and yields compounds with a LONGER DURATION of ACTION

decreases, increases

For Thiazides: ALKYL SUBSTITUTION AT THE 2-N POSITION (INCREASES/DECREASES) POLARITY AND (INCREASES/DECREASES) DURATION OF ACTION

quinazolinone

benzothiazide derivatives in which the sulfone group at position 1 is replaced with a carbonyl group retains activity and increases duration of action

ring b

What ring is NOT an absolute requirement (analogs with open _ ring) for thiazide diuretic activity

quinazolinone

the structural difference between the q________ diuretics and thiazides is the replacement of the 4-sulfone group with a 4-keto group

quinazolinone

diuretic derivative which exhibit a LONG duration of action as a result of protein binding (18-24 hours)

indoline

contains a polar chlorobenzamide moiety and non-polar lipophilic methylindoline group

indapamide

IN CONSTRAST TO THIAZIDES, i_______ide DOES NOT CONTAIN A THIAZIDE RING

indapamide

exhibits a prolonged duration of action (up to 8 weeks) due to excessive binding of CA

loop diuretics

also known as high ceiling, produce a PEAK diuresis much greater than observed with other diuretics

loop diuretics

MAIN SITE OF ACTION: THICK ASCENDING LIMP of the LOOP OF HENLE

loop diuretics

inhibit luminal NA/K/2CL symporter

loop diuretics

characterized by a quick onset and short duration of action. Diuretic effect appears in about 30 minutes and lasts for about 6 hrs

K (potassium) sparing

diuretics in which on their own cause HYPERKALEMIA leading to a fatal arrhythmia

K sparing

diuretics gen. used in combo with OTHER diuretic drugs ie. loop that would otherwise LOWER potassium levels to dangerously low levels. Combo helps to maintain a normal reference range for potassium

Renal Epithelial Sodium Channel Inhibitors

Triamterine and amiloride are the ONLY two drugs of this class in clinical use (R__al E______lial S______ium Channel (i_______ors) (also works to maintain healthy K+ levels)

Triamterene

along with amiloride causes a SMALL increase in NACL excretion and usually are employed for their ANTIKAILURETIC actions to offset the effects of other diuretic that increase K+ excretion (T________erene)

aldosterone

promotes salt and water retention and potassium and hydrogen ion excretion

aldosterone

a substance that antagonizes the effects of a______ could conceivably be a good diuretic drug. SPIRINOLACTONE is such an antagonist

Spironolactone

Canrenone, active metabolite of aldosterone antagonist, _________

eplerenone

newer drug with structure similar to spironolactone and a similar mechanism of action

eplerenone

initially approved for use in the treatment of hypertension, now MAINLY used for treatment in pts. with LEFT VENTRICULAR SYSTOLIC DYSFUNCTION and CHF after myocardial infarction

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