Diuretics
= compouns used for ↑ of urine excretion in order to ↓ the
excessive volume of extraceallular liquid or for other
therapeutical purposes
©assoc. prof. PharmDr. Oldřich Farsa, Ph.D. 2012
History
Mercury compounds
16th
century – Paracelsus – red HgO (?)
19th
century – Hg2Cl2 „calomel“
beginning of the 20th
century – less toxic organic compounds with covalently bound Hg
Cl Hg
OHO
OO Na
+
Cl
O
OO
NH Hg
OH
O
O
CH3
Na
+
Novasurol mersalyl
Salyrgan®
Classification of actually used diuretics
1. Saluretics
1.1. Sulfonamides
1.1.1 Sulfonamides with acyclic -SO2NH2 group
1.1.2 Thiazide diuretics
2. „Potassium conserving“ diuretics
3. „Loop“ diuretics (= diuretics acting in the loop of Henle)
3.1. Sulfonamides – amino(hetero)arenesulfonamide derivatives
3.2. Phenoxyacetic acid derivatives
4. Osmotic diuretics
(5. Purine alcaloida – xanthine derivatives)
1. Saluretics
•inhibit reabsorption (back resorption) of Na+
and Clin
more distal part of the
nephrone, ions bind water, which is then excreted
•they cause decrease of K+
in organism (exchange for Na+
and active secretion in
distal tubule)
1.1. Sulfonamides
•diuretic activity of antibacterial sulfonamides observed as a side effect before 1940
•1949 Schwartz: carbonic anhydrase inhibtion
CO2 + OH2
H2CO3 H3O
+
+ HCO3
-carbonic anhydrase +H2O
-H2O
inhibition
• the enzyme is inhibited ⇒ ↓ H2
CO3
⇒ ↓ H3
O+
, which normally exchanges for Na+
,
in glomerular filtrate ⇒ Na+
remains in the renal tubule together with HCO3
,
they
bind osmotic equivalent of water ⇒ excretion of a large quantity of urine
NH2
S
N
H
O O
H
N
N S
N
H
S
N
H
O O
H
CH3
O
N-(5-sulfamoyl-[1,3,4]thiadiazol-2-yl)-acetamide
1.1.1. Sulfonamides with acyclic -SO2NH2 group
sulfanilamide
(lead compound of antibacterial
sulfonamides)
acetazolamide
one of the firsr sulfonamide diuretics
Diluran®
- today treatment of glaucom
1.1.1. Sulfonamides with acyclic -SO2NH2 group - continued
chlorthalidone
Urandil®
•hypertension,
edema in heart
insufficiency
N
OH
O
S
N
H
O O
H
Cl
S
N
H
O O
H
Cl
O
N
RH
N
CH3
CH3
N
CH3
N
CH3
R =
clopamide
Crystepin®
(+ reserpin,
dihydroergocristin)
metipamide
Hypotylin®
indapamide
•also antioxidant efffect
Indap®
Noliprel®
(+ perindopril)
Prenewel ®
...
1.1.2 Thiazide diuretics
= sulfonamides with –SO2NH- group in a cycle
Elicitation of their structure
S
N
H
O
O
H
Cl
S
N
H
O
O
H
S
N
O O
H
Cl
S
N
H
O
O
H
N
S
N
O O
H
Cl
S
N
H
O
O
H
N
H
clofenamide
diuretic sulfonamide
with acyclic –SO2NH2
groups; today
obsolete
chlorothiazide
1st
„thiazide“
diuretic; today
obsolete
hydrochlorothiazide
most frequently
combined with
amiloride (Moduretic®
,
Rhefluin®
) or with
quinapril (Accuzide ®
)
for treatment of
hypertension
Activity
1 : 20
2. „Potassium conserving“ diuretics
•inhibit reabsorption of Na+
v distal tubule; retention of K+
occurs simultaneously
Aldosterone antagonists
O
CH3
O
OH OHO
O
O
CH3
CH3
O
S
CH3
O
OH
O
CH3
CH3
O
OH
H2O
- CH3COSH
aldosterone spironolactone
•prodrug of canrenoic acid
•hyperaldosteronemia
Verospiron®
tbl.
canrenoic acid
•active compound
Aldactone® inj. – K+
salt for parenteral
application (kalii
canrenoas)
Canrenon and canrenoic acid
•both forms are in an equilibrium
O
O
CH3
CH3
O
OH
O
CH3
CH3
O
OH
H2O
- H2O
3
4 6
17
canrenone
(lactone)
canrenoic acid
(a hydroxy acid)
2. „Potassium conserving“ diuretics - continued
N
NCl
NH2
NH2
N
H
O
NH2
NH N N
N
N
NH2
NH2
NH2
N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-
guanidine
2,4,7-triamino-6-phenylpteridine
amiloride
Amicloton®
, Moduretic®
, Loradur ®
(+
hydrochlorothiazide) …
triamterene
Dytac®
tbl.
3. „Loop“ diuretics
•inhibit absorption of elektrolytes (Na+
, K+
, H+
a Cl)
in the ascending limb of Henle loop
(⇒ hyponatraemia, hypokalaemia, hypochloraemia and alkalosis possible)
•efficient also in ↓ function of kidneys
3. „Loop“ diuretics
3.1. Sulfonamides – amino(hetero)arenesulfonamide derivatives
N
H
OH
O
S
Cl
NH2
O
O
O
S
NH
N
H
OO
N
N
H
O
CH3
CH3
CH3
furosemide
Furon®
tbl.
•oedema, chron. renal insufficiency
torasemide
syn. torsemide [USAN]
Trifas®
tbl.
3.2. Phenoxyacetic acid derivatives
Derivation of the structure: directly from mercury diuretics
Cl Hg
OHO
OO Na
+
O
OHO
Cl
O
Cl
CH2
CH3
O
O OH
O
Cl
S
Cl
Novasurol ethacrynic acid
Uregyt®
tbl.
tienilic acid
(syn. ticrynafen [USAN])
4. Osmotic diuretics
•osmotically active compounds, ↑ osmotic pressure of the glomerulal ultrafiltrate ⇒ ↓
its glomerular reabsorption
•administered only intravenously
•removal of intracranial hypertension in patients with brain oedema, treatment of
acute renal failure, forced diuresis in intoxications
NH2
NH2
O
OH
OH
OH
OH
OH
OH
H
H
H
HOH
OH
OH
H
OH
OH
OH
H
H
H
urea
Urea VUAB®
inf. sic.
D-mannitol
Osmofundin 15% N®
inf.
D-sorbitol
syn. D-glucitol
Infusio sorbitoli®
inf. sol.