Med Chem - Diuretics Flashcards
name 6 classes of antihypertensives
diuretics
ACE inhibitors
ARBS
Sympatholytics
calcium channel blockers
vasodilators
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
3 major uses of diuretics
-mild HTN
-edema caused by CHF
-edema caused by renal and liver disorders
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)
basic functional unit of the kidney
nephron
3 functional parts of the nephron
-glomerulus (enclosed in bowman’s capsule)
-renal tubule (PCT and loop of henle)
-collecting tubule
3 components of the loop of henle
descending limb
thick ascending limb
distal convoluted tubule
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
name 2 diuretics whose site of action is the PCT (proximal convoluted tubule)
carbonic anhydrase inhibitors
osmotic diuretics
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
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
class of diuretic whose site of action is the collecting duct
name 1 drug in the class
potassium sparing diuretics
spironolactone
sulfanilamide
a carbonic anhydrase inhibitor
originally an antibacterial, but discovered to have mild diuretic effect by inhibiting this enzyme
name 2 ways that enable sulfanilamide to inhibit the carbonic anhydrase enzyme
-similar STRUCTURE to carbonic acid
-both sulfanilamide and carbonic anhydrase are ACIDIC
true or false
sulfanilamide gives non competitive inhibition of the carbonic anhydrase enzyme to give its diuretic effect
FALSE
competitive
competes with carbonic acid
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
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
site of action sulfanilamide to produce diuretic effect
PCT
SAR studies of sulfanilamide leads to ____ (how many) groups of carbonic anhydrase inhibitors?
name these groups
2:
-simple heterocyclic sulfonamides
-meta-disulfamoylbenzene derivatives
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
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
