Download University number : 42904352 Diuretics Introduction: In this journal, I

University number : 42904352
Diuretics
Introduction:
In this journal, I well talk about diuretics and what I understand and
learn from medicinal chemistry lecture and show therapeutic
application , then I well explain the classifications and the different
between them , and structure activity relation(SAR) for one class
(thiazide) , finally the side effect.
Body:
diuretic is chemicals that increase the rate of urine formation by
increasing the urine flow rate , diuretic usage leads to increased
excretion of electrolytes especially sodium and chloride ions and water
from body without affecting protein and vitamin, glucose ,amino acid
reabsorption .and the therapeutic use in treatment of different
edematous conditions , resulting from a variety of causes ( congestive
heart failure ,nephrotic syndrome , and chronic liver disease)and in
management hypertension ,also is used as adjunctive therapy in the
treatment of a wide range of clinical conditions, including hypercalcemia
, acute mountain sickness , glaucoma and primary hyperaldosterism. He
has 4 chemicals classes the carbonic anhydrase inhibitors ,thiazide and
thiazide like derivatives, High ceiling loop diuretic, and potassium
sparing .all this chemicals classes work in part from kidney. the
carbonic anhydrase inhibitors (CA inhibitors) in site 1 proximal
convoluted tubule ,and High ciling loop diuretics in site 2 thick
ascending henle's loop, thiazide in the site 3 distal tubule , finally
potassium sparing in the site 4 connecting tubule and collecting duct.
CA inhibitors infrequently used as diuretics because of their low efficacy
and the early development of tolerance . this is due primarily to two
factors .first there is a marked reduction in the filtered load of
bicarbonate because CA inhibitors produce both a reduction in plasma
concentration of bicarbonate and a 20% reduction in the GFR. When
there is less bicarbonate present in the luminal fluid , there is less
bicarbonate reabsorption to inhibit. Second, the metabolic acidosis
created by these diuretics provides a sufficient amount of non-CA
generated intracellular hydrogen ions to exchange for the luminal fluid
sodium . sodium reabsorption at site 1 progressively returns to normal
and the diuresis disappears. But they played , an important role in the
development of other classes of diuretics (thiazide)that are currently
largely used. there are two groups of CA inhibitors: simple heterocyclic
sulfonamides (like acetazolamide ),and another group is
metadisulfamoylbenzene(like chloraminophenamide) .
And the thiazide is development from chloraminophenamide . When
chloraminophenamide was treated with an acylating reagent ,cyclization
occurred, with the result of formation 1,2,4-thiadiazine-1,1-dioxide
(thiazide derivatives )and when chloraminophenamide was treated with
aldehyde or ketone , in place of the acylating reagent ,this produces the
corresponding( hydrothiazide derivatives). Structure Activity Relation
(SAR) for thiazide
chlorthiazide
hydrochlorothiazide
in position 3 is an extremely important site of molecular modification .
in fact , substituents at position 3 play an important role in determining
the potency , duration of action , and other pharmacokinetic properties
of the derivatives . and loss of double bond between C3-C4 increase the
potency approximately of 3-10 folds , this mean that in general
,hydrothiazide derivatives are more potent than thiazide s in an activity.
Direct substitution for the 4,5,8 position result activity decrease .
substitution at position6 with a deactivation group such as cl, Br,CF3
,CHCl3 electron withdrawing group is essential for the activity .the
unsubstituted sulfonamide group in position 7 is a prerequisite for the
activity . substitution of the sulfone group in position 1 with another
similar electrophilic group (carboxyl , carbamoyl) can produce an activity
increase. The thiazide derivatives like (chlorthiazide) ,and the
hydrothiazide derivatives like (hydrochlorothiazide) .the site 2 diuretics
High ceiling loop diuretics have a tremendous efficacy because they
inhibit the Na/K/CL co transport system located on luminal membrane of
cell of the thick ascending limb of henle's loop importantly , the
carboxylate moieties of furosemide and bumetanide are thought to be
responsible for their competing with Cl- for the Cl binding site on the
Na/k/2cl co –transport system . because site 2 such high capacity site for
Na reabsorption up to (20-25% ) of the filtered load of Na that normally
is absorbed in this nephron segment may be excreted in the urine .on
the other hand this inhibition destroys the hypertonicity of the medullar
interstitium preventing the reabsorption of water at the descending limb
of henle's loop .the loop diuretics include products :5-sulfamoyl-2aminobenzoic acid derivatives (anthranilic acid)like (furosemide) , and 5sulfamoyl-3- aminobenzoic acid derivatives (metanilic acid) like
(bumetanide). The potassium sparing a negative feature of all previous
diuretic classes is that they induce an increase in the renal excretion rate
of potassium . potassium sparing diuretics increase sodium and chloride
secretion without causing an increase in potassium excretion .the
potassium sparing diuretics include : spirolactones (spironolactone ,
canrenone),2,,4,7 triamion-6-arylpteridine(trimetren).the spironolactone
is a structural similar of progesterone . progesterone was observed to
possess an antialdosteronic activity , inhibiting the antinatriuretic and
kaluretic activity .the adverse effects of diuretics typical sulfonamide
associated hypersensitivity reaction such as urticarial , drug fever , blood
dyscrasias , and interstitial nephritis . this is usually a crossed
hypersensitivity , with agents of diuretics, containing sulfonamide group
, all diuretics cause hypokalemia except potassium sparing cause
hyperkalemia. and the CA inhibitors and potassium sparing cause
metabolic acidosis. Also the another adverse effects of thiazide and loop
diuretics is reduction in GFR .
Conclusion :
Diuretics is very important in treatment hypertension , edema , and
other adjunct therapy and primary target of diuretics is the kidney also
the diuretics have 4 classes CA inhibitors , thiazides, loop diuretics ,
potassium sparing. In severe renal failure , because of impairment blood
supply and therefore glomerular filtration , we cannot used thiazides &
other diuretics with exception of high ceiling diuretics because they have
vasodilation effect so improve blood flow.