Diuretics

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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

Site of Action of 6 group of Diuretics

Renal Physiology & Pharmacology


Kidneys-the prim organ for excretion & maintain the homeostasis Remove water, electrolytes, products of metabolic waste & other materials form blood Possess endocrine functions, i.e.-secrete erythropoietin rennin & 1,2,5-hydroxy cholecalciferol Selective reabsorb water, The reddish brown organ weighed-300gms Location-Either side of the vertebral column electrolytes & needed Kidney embedded in perirenal fat & nutrients from the urine. fibrous capsule

Nephrons-the working unit of kidney

with each kidney containing 1.2millon nephrons

Two types Cortical nephrons-(80%-short) Juxtamedullary nephrons-(long) Glomerular filtration pressure-50mmof Hg

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

Fate of Luminal Fluid

SITE-1:-The convoluted & straight portions of the proximal tubules


The plasma in the peritubular capillaries has a low hydraulic pressure 7 a higher oncotic pressure than the luminal fiuid The Na-K-ATPase,catalyzes the counter transport of intracellular Na interstitium &K Proximal tubules 3Na interstitium Proximal tubule cells 2K+ A voltage oriented ve inside proximal tubule cells

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 Inhibitors

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

. .

..es proximal tubule reabsorbtion of CO

CLASSES

Simple heterocyclic sulphonamides


ACETAZOLAMIDE METHAZOLAMIDE BENZOLAMIDE ETHOXAZOLAMIDE

Meta bisulfamoyl benzene derivative


DICHLORPHENAMIDE CHLORAMINOPHENAMIDE

Simple Heterocyclic sulphonamides

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

Methazolamide5-acetylamino-3-methyl-1,3,4-thiadiazol-2sulfonamidemethylation of N in the thiadiazole ring


H5C2O S SO 2NH 2 N

Acetazolamide 5-acetylamino-1,3,4-thiadiazole-2sulfonamide high lipid/water partition co-efficient &low pKa value


H5C6 S O O H3C N
+

NH

SO 2NH 2 N

Ethoxazolamide

Benzolamide

Sulfamoyl group is attached must posses aromatic character

Meta- bisulfamayl Benzene Derivative

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

Dichlorphenamide4,5-dichloro 1-3-benzene disulfonamide Substitution at R2 position produce maximal activity


SO 2NH 2

H2NO 2S

Cl

NH2

Chloraminophenamide -

H2NO 2S

SO 2NH 2

Pharmacokinetics

Absorbed well from the gastrointestinal tract

Distributed to the sites of major importance for


CA inhibition

Metabolism by undergoing biotransformation


Excreted through the kidney

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

Treatment of glaucoma- CA is a functionally important


. enzyme in the formation of aqueous humor

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

Organomercurials 5-sulfamoyl-2-aminobenzoic Acid


Furosemide Azosemide

5-sulfamoyl-3-aminobenzoic Acid
Bumetanide Piretanide

4-amino-3-pyridinesulfonylureas
Torsemide Triflocin

Phenoxyacetic Acids
Ethacrynic Acid

Miscellaneous site 2 diuretics


Etozoline,MK-447,CRE 10904

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

CH 2-CH 2-CH 2-CH 3


N 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

4-AMINO-3-PYRIDINE SULFONYL UREAS


CH3

NH

Torsemide:1-isopropyl-3-(4-(3-methyl phenyl amino) pyridine)-3 sulfonyl)urea


NH HC CH3 CH3

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

USE Mild & moderate hypertension

Cl O H5C2 C

Cl

Ethacrynic acid 2,3-dichloro-4-(2-methylene1-oxobutyl)phenoxy OCH 2COOH Acetic acid SAR

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

PHARMACOKINETICS OF ETHACRYNIC ACID


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 &ethacrynic 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 C 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

SITE-3:-The distal convoluted tubule


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.

CLASSES Thaiazides/Benzothiadiazines Hydrothiazides Thiazide like diuretics


1. 2. 3. 4. 5. 6.

Substituted m-disulfamoyl benzene Salicylanilide Benzhydrazides Tetrahydroquinazolinones 1-oxoisoindolines Phthalimidines

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

7th position with sulfamoyl gives diuretic action

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

THIAZIDE LIKE DIURETICS


Cl NH O H2NO 2S O S O CH3

Mefruside-substitution m- disulfamoyl benzene

Cl

OH CH3 NH

Xipamide -salicylanilide

H2NO 2S

C O H3C

Cl CH3 NH H2NO 2S C O H3C N

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

SITE-4:-The connecting tubule

CA catalyses the formation of carbonic acid

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`

The driving force PC the deficit of


intracellular Na+ created by the Na+-K+ATPase

3Na PC
2K+ IN

IN
PC

Creates lumen negative transepithelial voltage


Cl moves paracellularly K+-potassium channels H+ -H+ATPase

Mineralocorticoids

Na reabsorbed K+ & H+ excreated

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

Spironolacton -Aldosterone antagonist Steroidal group


H3C

7-acetylothio-17 hydroxy-3-oxopregn4-ene-21-carboxilyic acid--lactones

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

H3C H3C H O S C O CH3


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

Absorbed incompletely & erracticaly


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

A specific aldrosterone antagonist


CH3

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

8-(dicyclopropyl methyl) -1,3-dipropylxanthine

N O H3CH 2CH 2C

O H3CH 2CH 2C N H N

8-Cyclopentyl1-3-dipropyl xanthine

O H3CH 2CH 2C

Osmotic Diuretics

Undergo passive filtration at glomerulus

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

Adverse Side Effects and Contraindications


Class Adverse Side Effects
hypokalemia metabolic alkalosis dehydration (hypovolemia), leading to hypotension hyponatremia hyperglycemia in diabetics hypercholesterolemia; hypertriglyceridemia increased low-density lipoproteins hyperuricemia (at low doses) azotemia (in renal disease

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

Carbonic anhydrase inhibitors

Hypokalemia metabolic acidosis

ANP Clearance Receptor Blocker & Neutral Endopeptidase Inhibitors ANP

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

Why thiazide diuretics are used for diabetes insipidus?


They reduce urine volume Thiazide diuretics alone or -blockers impair glucose metabolisms in hypertensive patients with abdominal obesity. The metabolic analogue of thiazide act on the pituitaryADH releases--anti diuretic effect Increase the cell permiability of the collecting duct & reabsorbtion of water A synthetic analogue-(immuno cyto chemical charaterization) 1-3-mercaptopropionic acid)-8-Darginin vasopressin monoacetate trihydrate acts the pituitary gland--ADH

DIURETIC SITE OF ACTION

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

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