Med Chem - Diuretics Flashcards by amanda kastel

name 6 classes of antihypertensives

diuretics
ACE inhibitors
ARBS
Sympatholytics
calcium channel blockers
vasodilators

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define what a diuretic is

drug that increases rate of urine formation. does so by decreasing the reabsorption of sodium ions into the body

thus, the osmotic equivalent of water’s reabsorption is also inhibited (water follows salt!) and is secreted from the body as urine

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3 major uses of diuretics

-mild HTN
-edema caused by CHF
-edema caused by renal and liver disorders

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3 main functions of the kidneys

-regulate volume and composition of body fluids

-maintain pH of body fluids

-eliminate water soluble metabolic products (non-electrolytes)

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basic functional unit of the kidney

nephron

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3 functional parts of the nephron

-glomerulus (enclosed in bowman’s capsule)

-renal tubule (PCT and loop of henle)

-collecting tubule

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3 components of the loop of henle

descending limb
thick ascending limb
distal convoluted tubule

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diuretics are classified based in their…..

name 4 of these classifications
(no drugs yet)

site of action:

-PCT
-thick ascending loop of henle
-DCT
-collecting duct

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name 2 diuretics whose site of action is the PCT (proximal convoluted tubule)

carbonic anhydrase inhibitors
osmotic diuretics

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class of diuretic whos site of action is the thick ascending loop of henle

name 1 drug in this class

High-ceiling or loop diuretics

furosemide

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class of diuretic whose site of action is the DCT (distal convoluted tubule)

name 1 drug in the class

thiazides and thiazide-like diuretics

hydrochlorothiazide

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class of diuretic whose site of action is the collecting duct

name 1 drug in the class

potassium sparing diuretics

spironolactone

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sulfanilamide

a carbonic anhydrase inhibitor

originally an antibacterial, but discovered to have mild diuretic effect by inhibiting this enzyme

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name 2 ways that enable sulfanilamide to inhibit the carbonic anhydrase enzyme

-similar STRUCTURE to carbonic acid

-both sulfanilamide and carbonic anhydrase are ACIDIC

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true or false

sulfanilamide gives non competitive inhibition of the carbonic anhydrase enzyme to give its diuretic effect

FALSE

competitive

competes with carbonic acid

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explain the similarity in binding to the CA enzyme between sulfanilamide and the natural substrate, carbonic acid

both attach via 2 H bond donors and 2 H bond acceptors

sulfanilamide prevents carbonic acid from binding - competitively blocks the site

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explain the mechanism in which carbonic anhydrase inhibitors like sulfanilamide are able to produce a mild diuretic effect

normally, carbonic anhydrase would break down into protons and bicarbonate ions.

the H+ ions (protons) leave the PCT in exchange for sodium, which gets reabsorbed back into the body

however, by inhibiting the CA enzyme, we’re also inhibiting for formation of the breakdown products of protons + bicarbonate ions, so therefore, sodium cannot get reabsorbed because there’s no proton for it to exchange with and keep equilibrium on either side

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site of action sulfanilamide to produce diuretic effect

PCT

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SAR studies of sulfanilamide leads to ____ (how many) groups of carbonic anhydrase inhibitors?

name these groups

-simple heterocyclic sulfonamides

-meta-disulfamoylbenzene derivatives

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explain the general structure and SAR of “simple heteroaromatic sulfonamides” and “Meta-disulfamoyl benzene derivatives”

(derived from the SAR of sulfanilamide. carbonic anhydrase inhibitors)

N-containing group-heteroaromatic ring - sulfonamide. N must be unsubstituted for diuretic activity, and sulfonamide must be there to inhibit CA

1,3 disubstituted benzene (with 2 sulfonamides) and CAN have substitutions on R1, R2, R3

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what was the precursor to the thiazide diuretics?

a meta disulfamoyl benzene derivative (derived from SAR of sulfanilamide)

aside from inhibiting sodium reabsorption, name another use for diuretics

they can increase the rate of noxious weak acids by alkanalizing (raising pH) of the urine

relationship between diuretics and uric acid

diuretics can actually maintain the solubility of uric acid (weak acid) – poor solubility in water. due to alkalinizing effect

3 adverse effects of diuretics

metabolic acidosis
hypokalemia
sulfonamide hypersensitivty

true or false diuretics can cause metabolic alkalosis

FALSE metabolic acidosis (too much acid)

target in the nephron of thiazide and thiazide like diuretics

distal convoluted tubule DCT

thiazides were developed from the study of.....

meta-disulfamoyl benzenes amide substutuent introduced at the ortho position -- then cyclized to give chlorothiazide -- leading to new class of THIAZIDES

3 different "types" of thiazides based on structure

-thiazide analogs - have double bond between position 3 and 4 and follow thiazide SAR -hydrothiazide analogs - have NO double bond between positions 3 and 4 (increases diuretic activity 10 fold!) -thiazide-likes (most do NOT have 2 fused rings. just have the ring with sulfonamide attached. ALSO, if they do have 2 fused rings, there will be a carbonyl at not sulfonyl on the right ring

true or false if sulfonyl has been replaced with carbonyl, the molecule is AUTOMATICALLY a thiazide like

true

true or false if there is a 2nd fused ring, the molecule is automatically a thiazide (NOT thiazide-like)

FALSE can still be a thiazide-like if the sulfonyl has been replaced with carbonyl - watch closely!!

true or false if there is a sulfonyl at the 1 position, the molecule is automatically a thiazide (NOT thiazide-like)

FALSE can still be thiazide-like if the portion is acyclic

true or false most thiazides and thiazide-likes are well absorbed orally

true

true or false thiazides and thiazide-likes are not very highly protein bound

FALSE - they are the profile for being highly protein bound is to be hydrophobic and acidic --- and these are the 2 main components that we try to maximize in making thiazides

what is the name of the acidic group contained in thiazide drugs

sulfonamide

true or false sulfonamide is neutral

FALSE - acidic

onset and peak effect of thiazides

rapid - 1-2 hour onset peak effect 3-6 hours

2 ways in which thiazides achieve high luminal fluid concentrations

-glomerular filtration -OATS (organic anion transport system( in the proximal tubule where they inhibit Na/Cl cotransport system

target of thiazides

Na+/Cl- co-transport system

the difference in potency between the thiazides is determined by what structural feature?

the lipophilicity at position 3 (R1)

the difference in DURATION OF ACTION between thiazides is determined by what 2 things

-degree in which they are plasma-protein bound -lipophilicity of the molecule

***explain the MOA of thiazide and thiazide-like diuretics

block the reabsorption of sodium ions in the DCT by inhibiting the Na+/Cl- co-transport system

true or false in regards to diuretic activity, meta-disulfamoyl benzene derivatives and thiazides have different mechanisms

TRUE -- despite being structurally very similar meta-disulfamoyl benzene derivatives are carbonic anhydrase inhibitors

true or false thiazides inhibit the Na+/Cl- co transport system in the proximal convoluted tubule

FALSE distal

which class of diuretics work at the collecting duct?

potassium sparing diuretics

name the 3 chemically distinct diuretics which act at the COLLECTING DUCT

aldosterone antagonists pteridines (triamterene) aminopyrazines (amiloride)

true or false amiloride is a pteridine potassium sparing diuretic

FALSE aminopyrazine potassium sparing diuretic

explain the name "potassium sparing diuretics" explain MOA

they inhibit sodium reabsorption WITHOUT also promoting a urinary loss of potassium (like thiazides) they "plug" the sodium channels in the luminal membranes by MIMICKING SODIUM IONS at physiologic pH, the potassium-sparing diuretics will be charged - have a lot of hydrogens

2 ways that triamterene and amiloride reach the luminal fluid

-glomerular filtration -active tubular secretion by OCTS (organic CATION transport system) - both have lot of H and are positively charged at physiologic pH!!

most serious side effect of potassium sparing diuretics

hyperkalemia potassium supplements are CONTRAINDICATED

how is triamterene unique among potassium sparing diuretics

can form renal stones - therefore not given to patient with impaired renal function

primary clinical use of potassium sparing diuretics

in conjunction with with other diuretic drugs to improve diuresis and to prevent too much potassium loss