Diuretics
Diuretics
Diuretics
Diuretics are the hetero cyclic chemical therapeutic agents which promotes the excretion of sodium & water by action on the four major anatomical sites,results the increases the rate of urine formation
Diuretics are the hetero cyclic chemical therapeutic agents which promotes the excretion of sodium & water by action on the four major anatomical sites,results the increases the rate of urine formation
History of Diuretics
Greek word flow of a drop. Medicinal use starts from 400BC-metalic mercury 1949-Sulfanilamide(diuretics & natriuretics) 1950s -the new hetero compounds
Classification
SITE-1 Carbonic anhydrous inhibitors SITE-2 Loop or high ceeling Diuretics SITE-3 Thiazide or thiazide like diuretics SITE-4 Potassium sparing diuretics Xanthine diuretics Osmotic diuretics Miscellaneous
intertitial nephritis
About 650ml of plasma flow through the kidneys each minute Approximately 125ml/min of which are filter through the glomerular capillaries The remaining four-fifths(80%) of the renal plasma flow is directed into the peritubular capillaries Each minute 125mlof 1 ml of glomerular filtrate urine
The reabsorption of the Na takes place y 3 distinct process The counter transport by the action of interacellular CA are exchanged by the Na+-K+ ATPase in antiluminal membrane Na+ H+ H+ + HCO3 H2CO3 CO2 + H2O
go to PT
Na moves out of the luminal fluid by the co-transport into proximal tubule along with glucose, amino acid or phosphate-against concentration gradient Along with the Cl- ionsmove paracellularly
65-70% of Na,Cl,H2O,Ca: 80-90%of bicarbonates,phosphates 100% of glucose,amino acids & low Mr proteins
Carbonic anhydrase enzyme is a zinc containing enzyme catalysing the reversible hydration of CO2 & the dehydration of carbonic acid CO2 + H2O H2CO3 H+ +HCO3es in H+ ions to Inhibits intracellular CA be exchanged for luminal Na+.So Na+ is not reabsorbed Inhibition of CA on the brush border membrane of proximal tubule cells
es production of CO within the luminal fluid the 2
. .
CLASSES
Sulfamoyl nitrogen atomCA inhibition for in vivo & invitro activities Methylation of N in the thiadiazole ring-more active R''RN The moiety to which sulfamoyl group is attached must posses aromatic character Highest lipid/water partition coefficient & lowest pKa values have the greast activity.
SO 2NH 2 N
NH H3C N O H3C
+
SO 2NH 2
NH H3C N O
SO 2NH 2 N
NH
SO 2NH 2 N
Ethoxazolamide
Benzolamide
The parent 1,3disulfamoylbenzen lacked the activity R2-the substituted with Cl,Br,CF3 NO 2 increases(F,NH2,CH3 OCH3) At position R1 substitution with NH2 increase the salurectic activity,but decrease the CA inhibitory activity
R2
R1
H2NO 2S
SO 2NH 2
Cl Cl
H2NO 2S
Cl
NH2
Chloraminophenamide -
H2NO 2S
SO 2NH 2
Pharmacokinetics
Adverse effects Inhibit the luminal fluid exchange Hyperkalemia Mild metabolic acidosis Gynecomastia Menstrual distribution USE Edema fluid in congestive heart failure & liver cirrhosis Combined with hydrochlorothiazides
Therapeutical applications
Prophylactically used to counteract acute mountain sickness As an adjuvants for the treatment of epilepsypH rise the amount of cabondioxide in brain & lowering the sedation
SITE-2:-The thick ascending limb of Henles loop The tubular cells are impermiable to water
& posses a capacious luminal membrane bound transport system. Major driving force-interacellur deficit of Na-K ATPase The electroneutral Na/K/Cl cotransport system located on the membrane of thick ascending limb transport Na along with K &Cl from the luminal fluid-1:1:2 Reabsorbtion of Na to the thick ascending limb by actively Cl ions enters the interstitium through Cl channel in the antilumenal membrane & by co transport with K+ ions The luminal K+ions that accopanies Na&Cl into the thick ascending limb cells recycles passively downhill back inti the luminal fluid 3Na+ & 6 Cl- ions generates the lumen-+ve transepithelial voltage 20-25% Na 20-30% Ca
Inhibits the 1Na/1K/2Cl cotransport system located in luminal membrane The carboxylate moieties of furosemide & bumetamide are compete with Cl for the Cl- bindig site on the 1Na/1K/2Cl cotransport system. Destroy the hypertonicity of the medullary interstitium. inhibits the Na reabsorbtion The diuretics increase the total renal blood flow by enhancing thr intra renal release of vasodilatory prostaglandins. Decrease the lumen-positive transepithelial voltage which interferes the Ca transport
Classification
5-sulfamoyl-3-aminobenzoic Acid
Bumetanide Piretanide
4-amino-3-pyridinesulfonylureas
Torsemide Triflocin
Phenoxyacetic Acids
Ethacrynic Acid
Substitusion at position 1 must be acidic(carboxyl gps max activity) X NH 5 position always bear the R sulfomyl gps 4 th position substitution H2NO 2S COOH with Cl /CF3 5- Sulfamoyl-2-aminobenzoic Acid` R-must be
Furfuryl > benzyl > thienylmethyl
NH R
H2NO 2S
COOH
Cl
NH
CH 2
Cl
NH
CH 2
H2NO 2S
COOH
H2NO 2S
N N NH N
Furosemide
Azosemide
Substitusion at position 1 must be acidic(carboxyl gps max activity) 5 position always bear the sulfomyl gps 4 th position substitution with Cl /CF3 R-must be a wide variety of alkyl group
R . N X .
H2NO 2S
COOH
5- Sulfamoyl-2-aminobenzoic Acid`
R . N X .
H2NO 2S
COOH
HN O
H2NO 2S
COOH
H2NO 2S
COOH
Bumetanide
Piretanide
Pharmacokinetics
Bumetanide is more potent than furosemide Bumetanide produces equieffective diuresis in about 1/4th dose Bioavailability of furosemide 60-69% Bioavailability of bumetanide 80-90% Both having rapid onset of action( 3-5 min) after parentral adm Duration of action(parentral adm) furosemide -2hrs bumetanide -3.5-4hrs Oral adm :-30-60min furosemide -6-8hrs bumetanide -4-6hrs Extensive plasma protein binding for both Furosemide 88% excreted by kidney smal % by glucuronide conjugation Bumetanide undergo extensive biotransformation --81% in urine
45% as unchanged drug
NH
SO 2
NH
C O
CH3
Triflocin
N
NH
COOH
PHARMACOKINETICS
TORSEMIDE-quick absorption & 80% bioavailability after oral adm 98-99%plasma protein binding t1/2 =3-4hrs Peak serum conc. Attained with in 1hrs Metabolism by hepatic Cy P450 system by oxidation of aromatic methyl group to hydroxy & carboxyl derivative & para hydroxylation of methyl phenyl amino moiety ADR
Fatigue , dizziness ,muscles cramps Nausea , orthostatic hypotension Ototoxicity
Cl O H5C2 C
Cl
H2C
Oxyacetic acid gp on the 1st positionof the benzene A sulfhydryl reactive acryloyl moeity is located para to the oxyacetic acid gp Activating (gp:Cl/CH3) occupy either the 3 position or 2 or 3 position Alkyl substituents of 2-4 C atoms in length occupy the position to the carbonyl on the acryloyl moeity H atom occupy the terminal position of the C=C of the acryloyl moeity
Excellent oral absorption Rapid onset of action for both oral( 2-3hrs) & I V(3-5hrs) >95% of plasma protein binding Metabolism to its cysteine adduct after oral administration has much greater activity than parent compound. Ethacrynic acid alkylated the thio gp of glutathione & the resulting conjugate is converted to the ethacrynic acid-cysteine ðacrynic acid-N-acetyl cysteine conjugates Excreated by kidney in the form of cysteine adduct, small amount through bile. ADR-Ototoxicity, GI haemorrhage.
Indacrinone
Cl
HOOC
Is a derivative of ethacrynic acid Both enantiomers have uricosuric activity (-) enantiomer is more potent diuretic
CH 2
CH 2 O
CH 2
CH 2 O
OH
CRE10904
SO 3-
These compounds undergo bioconversion to a sulphated active metabolite Secreted by OATS in proximal tubular & hence attains high levels in luminal fluid Highly vely charged sulfate moiety binds to Cl- binding site on luminal membrane- bound 1Na/K/Cl co transport system of thick ascending limb & macula densa
H3C
MK-447
CH 2 NH2
H3C
H3C OH I
H3C O I SO 3-
Etozoline
Ozolinone
N O N H3C
H O S N C C O CH 2CH 3 H3C
H S C C O-
H O
H O
Etozoline undergo hydrolyzed to ozolinone, which acts the transport process in the cells of the thick ascending limb, of Henles loop. Ozolinone secreted actively into proximal tubule luminal fluid by the OATS The high conc. Of ozolinone delivered to thick ascending limb & inhibit the luminal membrane-bound1Na/1K/2Cl- co transport system
Adverse effects Hypokalemic alkalosis Short term- tubuloglomerular feedback mechanism long term-reduce the plasma volume Gout- bcoz diuretic induce plasma volume reduction leads to increased reabsorbtion of solutes by proximal tubule( uric acid) Hypersensitivity reaction urticaria , drug fever , intertitial nephritis USE Pulmonary edema associated with heart failure Edema by cirrhosis of liver , nephrotic syndromes
5-8%of Na Water impermiable MAJOR DRIVING FORCE The luminal membrane bound Na/Cl- co transport Na down hills Cl up hills Reaction completed when the anti luminal membranebound Na+,K+ATPase actively pumps into the interstitium
THIAZIDE DIURETICS
1. 2. 3.
THIAZIDE DIURETICS
Weakly acidic 2nd position small alkyl gps (CH3),es polarity 3rd position-determine the potency & R1 N duration of action (lipophilic gps -es diuretic ) eg:NH haloalkyl,arylalkyl or thioether gps H2NO 2S S benzothiazide.>>chlorthiazide O O Saturation of C=N b/w 3&4 es the potency 3-10 times Substitution at 4,5,8 with alkyl es Benzothiadiazine-1, 1-dioxide nucleus 6th position with activating gp es 7th position with sulfamoyl-diuretic
R2
Cl
Chlorthiazide
NH H2NO 2S O S O
Benzthiazide
Cl N
CH 2SCH 2
NH H2NO 2S O S O
HYDROTHIAZIDES Saturation of C=N-es the potency 6th position with Cl, Br or CF3-es with H or NH2 ,weakly active 3rd position with alkyl, cycloalkyl, haloalkyl -- es action (hydrophobic)
R1
H N
H R2 N
H2NO 2S O
S O
R3
Cl
H N
Cyclopenthiazide
CH 2 N C5H9
H2NO 2S O
S O
R3
Cl
H N
CH3 CH 2 HC N CH3 R3 O
Buthiazide
H2NO 2S O
Cl
OH CH3 NH
Xipamide -salicylanilide
H2NO 2S
C O H3C
Clopamide-Benhydrazides
Cl H3C
Indapamide
NH H2NO 2S C O N
2-3%Na,H+ The nephron in the connecting tubules composed of 2 distinct cell type Principal cells Na reabsorption & K+ secreation Intercalate cells H +generation & secreation
The carbonic acid ionizes to H+ & bicarbonate The H+ ions can be pumped actively into the luminal fluid by the luminal membrane bound H+ -ATPase`
3Na PC
2K+ IN
IN
PC
Mineralocorticoids
Luminal fluid flow rate & % of the filtered load of Na present to the exchange site the greater the flow rate & the load of Na the greater the amount of exchange
Acid Base states of the indivitual acidosis favours exchange of Na & H ion alkalosis favours exchange of Na & K ion
H3C H H
Pharmacokinetics O S Well oral absorption- bioavailability >90% Biotransformation by liver ~80% -Canrenone Site of action Inhibition of aldosterone Action is slow-12-72hrs(last for 2 or 3 days)
C O
CH3
FATE OF SPIRONOLACTONE
O O
O O
metabolite
H
H3C H
H3C
Canrenone
Spironolactone
Triamterene
2,4,7-Triamino-6-arylpteridines
H2N N
2,4,7-TRIAMINO-6-PHENYLPTERIDINE
SAR Pteridine analogues N H N Structural similarities to folic acid & dihydrofolate reductase
2
NH 2
A-gastrointestinal tract D-bound to plasma protein M-under biotransformation in liver E- biliary route & renal route Site of action Plugs the Na+ channels in luminal membrane of principal cells Adverse effects Hyperkalemia Kidney stone.
Amiloride. HCl
3,5-diamino-N-(aminoiminomethyl)6-chloropyrazinecarboxamide monohydrochloride dehydrate Cl
Pyrazinoylguanidines
O N C NH -ClH 2N
+
NH 2
H2N
NH 2
SAR
6 position-with Cl optimal activity Amino gps in 3 &5 are unsubstituted The guanidino nitrogen are not multiply substituted with alkyl gps
Pharmacokinetics
Passive diffusion of uncharged drugs Contains the stronger basic guanidine moiety,pKa value-8.7 Bound with the plasma proteins no biotransformation Action with in 2hrs,last for 24hrs SITE OF ACTION Inhibits the electrogenic entry of filtered load of Na into the principal cells of CT & Cortical collecting tubule by plugging the Na channel in the luminal membrane
USE Mild edema associated with congestive heart failure, cirrhosis of the liver Combination with other diuretics
New drug
O
H3C
H O C O O CH3
Eplerenone
XANTHINE DIURETICS
Theophylline is a weak diuresis by stimulation of cardiac function & by direct action on the nephron Adenosine receptor antagonism( adenosin produces antidiuretics & antinatriuretic respons ) Renal action of adenosine is due to the stimulation of adenosine A1 receptor
O H3C N O
+
N H3C
N H
A1 receptor antagonists
O H3C N H N
N O H3CH 2CH 2C
O H3CH 2CH 2C N H N
8-Cyclopentyl1-3-dipropyl xanthine
O H3CH 2CH 2C
Osmotic Diuretics
Undergo limited reabsorbtion in the renal tubules Metabolically & pharmacologically inert This agents hinders salt & water reabsorbtion from the proximal tubules
Mannitol CH 2OH Non electrolyte of low molecular weight Rise osmolarity of plasma & HO . tubular fluid HO . Freely filtered through the . OH glomerulus & undergo limited reabsorbtion . OH Expands extracellular fluid volumeincrease g.f.r & inhibits renin release CH 2OH Increases renal blood flow, specially to the medulla medullary hypertonicity is reducedcorticomedullary osmotic gradient is dissipatedpassive salt reabsorption is reduced Retains water isoosmotically in PTdilutes luminal fluid which opposes NaCl reabsorption Inhibits transport prosses in the thick AscLH by an unknown mechanism
USE
In prophylaxis of acute renal failure---500-1000ml To low intraocular pressure in ophthalmologic procedures (increase intra cranial or intraocular tensionacute congestive glaucoma ,head injury , stroke etc.)---1-1.5g/kg To counteract low osmolarity of plasma/e.c.f due to rapid haemodialysis or peritoneal dialysis Eg:- isosorbide} glycerol} 1.5g/kg as oral solution
Drug Interactions
hypokalemia potentiates digitalis toxicity non-steroidal antiinflammatory drugs: reduced diuretic efficacy beta-blockers: potentiate hyperglycemia, hyperlipidemias corticosteroids: enhance
Thiazide
hypokalemia
patients)
Loop
hypokalemia metabolic alkalosis hypomagnesemia hyperuricemia dehydration (hypovolemia), leading to hypotension dose-related hearing loss (ototoxicity)
hypokalemia potentiates digitalis toxicity non-steroidal antiinflammatory drugs: reduced diuretic efficacy corticosteroids: enhance hypokalemia aminoglycosides: enhance
ototoxicity, nephrotoxicity
K+-sparing
hyperkalemia ACE inhibitors: potentiate hyperkalemia metabolic acidosis gynecomastia (aldosterone non-steroidal antiinflammatory drugs: antagonists) reduced diuretic efficacy gastric problems including
peptic ulcer
Atrial Natriuretic Peptides is a 28-amino acid peptides that released into circulation from the heart aterial distensions ANP exerts natriuretic , diuretic , vasorelaxant & suppresses renin & aldosterone levels ANP increases the GFR significantly by vasodialation of afferent arterioles & vasoconstriction of efferent vessels
ANP also inhibits Na reabsorption in collecting tubules ANP is eliminated from circulation by enzymatic degradation
NEPNeutral Endo Peptidase NEP is a zinc-metallopeptidase that cleaves -amino bond of hydrophobic amino acidsis a major degradative enzyme ANP Clearance Receptor Blockers SC46542is a biologically inactive analogue of ANP that has similar affinity for c-receptor as ANP, thus HS prolong the t1/2 of the ANP. Both R & S enantiomers of thiorphan have same enzyme inhibitory potency
NH O
COOH
Thiorphan
CONCLUSION
In medicine, diuretics are used to treat heart failure, liver cirrhosis, hypertension and certain kidney diseases. Some diuretics, such as acetazolamide, help to make the urine more alkaline and are helpful in increasing excretion of substances such as aspirin in cases of overdose or poisoning. Diuretics are often abused by sufferers of eating disorders, especially bulimics, in attempts at weight loss. The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect. That is, the reduction in blood pressure is not due to decreased blood volume resulting from increased urine production, but occurs through other mechanisms and at lower doses than that required to produce diuresis. Indapamide was specifically designed with this in mind, and has a larger therapeutic window for hypertension (without pronounced diuresis) than most other diuretics.
References
Burgers Medicinal chemistry-6th edition volume-3 pg no:55-142 Text Book of Organic Medicinal & Pharmaceutical Chemistry(Wilson & Gisvolds)-10th edition pg no:553-579 Foyes principles of medicinal chemistry pg no: Essentials of medical pharmacology5th edition-KD Tripathi pg no:525-542 Sites:-Medicap,wikepedia,Science direct.com