This presentation covers about the classification of diuretics, structures with mechanism of action and SAR and therapeutic uses of drugs according to PCI syllabus
1. MEDICINAL CHEMISTRY II
B. Pharmacy III/IV (First sem.) PCI syllabus
DR. K. PURNA NAGASREE
M.PHARM. (BITS, PILANI), PH.D., PDF (DST, WOSA)
EX BITS, PILANI FACULTY
6. CLASSIFICATION (CHEMICAL)
I. Mercurial diuretics (Mercurous chloride, Mersalyl)
II. Nonmercurial diuretics
a. Thiazide derivatives - Chlorthiazide*,
Hydrothiazides - Hydrochlorothiazide, Hydroflumethiazide, Cyclothiazide
b. CAse inhibitors - Acetazolamide*, Methazolamide, Dichlorphenamide.
c. Sulphonamide diuretics
e. Aldosterone inhibitors – Spironolactone
f. Pteridine derivatives and related compounds - Triamterene, Amiloride
g. sulphomoyl benzoic acid derivatives - Furosemide*, Bumetanide
h. Phenoxyacetic acid derivatives - Ethacrynic acid
i. Purine or Xanthine derivatives
j. Osmotic diuretics - Mannitol
8. Diuretics
a. Thiazides
i. Chlorthiazide
Chlorthiazide is a white crystalline powder
Soluble in dilute solutions of alkali hydroxides, slightly soluble in water
and in alcohol and sparingly soluble in acetone.
It is a prototype benzothiadiazine derivative
Used in the treatment of oedema associated With congestive heart
failure, renal, and hepatic disorders.
9. ii. Hydrochlorthiazide
Hydrochlorthiazide is a white crystalline powder, which is soluble in
acetone and dilute alkali hydroxide solutions, but sparingly soluble in
alcohol.
It is similar to chlorothiazide but It is ten times more potent.
Used in the treatment of oedema associated with congestive heart failure,
renal, and hepatic disorders.
10. iii. Hydroflumethiazide
Hydroflumethiazide is a white crystalline powder, practically insoluble in
water and ether, soluble in ethanol.
It is a potent oral thiazide diuretic
Used in the management of oedema associated with cardiac failure,
premenstrual tension, and hepatic cirrhosis.
11. iv. Cyclothiazide
It exists as white, odourless powder, soluble in alcohol or methanol but
insoluble in water, chloroform, or ether.
Used as both diuretic and antihypertensive.
12. SAR of thiazide diuretics
The 2nd position can tolerate the presence of small alkyl groups such as CH3
Substituents with hydrophobic character in the 3rd position increases saluretic
activity 1000 times. Substituents include -CH2Cl, -CHCl2, -CH2C6H5, - CH2S, -
CH2, -C6H5
The increase in saluretic activity - with the lipid solubility.
Saturation of double bond between the 3rd and 4th
position of nucleus increases the diuretic activity approximately 3-fold to 10-
fold. Example - Hydrochlorthiazide.
13. SAR of thiazide diuretics
Hydrogen atom at the 2nd position is more acidic due to the presence of
neighbouring electron withdrawing sulphone group.
A free sulphamoyl at 7th position is essential for activity.
The loss of sulphamoyl group eliminates the diuretic effect, but not the
antihypertensive action
Direct substitution of the 4th, 5th, or 8th position with an ethyl group
usually results in diminished diuretic activity.
14. SAR of thiazide diuretics
Substitution of the 6th position with an activating group is essential for
diuretic activity. The substituents include Cl, Br, and CF3 groups.
The acidic protons make the formation of water-soluble sodium salt that
can be used for intravenous administration of the diuretics.
17. Mode of action of thiazides and
hydro thiazides
The sites of action for these drugs are cortical diluting segment or DT.
Here they inhibit Na+ - Cl- symport at the luminal membrane.
The sodium-chloride symporter (also known as Na+-
Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-
Cl− cotransporter or TSC) is a cotransporter in the kidney which has the
function of reabsorbing sodium and chloride ions from the tubular
fluid into the cells of the distal convoluted tubule of the nephron.
19. Mode of action of
thiazides and
hydrothiazides:
The sites of action for these
drugs are cortical diluting
segment or DT. Here
they inhibit Na+ - Cl-
symport at the luminal
membrane.
21. Uses of thiazide diuretics
Treatment of hypertension
Adjunctive therapy in oedema associated with CHF, hepatic cirrhosis,
renal dysfunction, corticosteroid therapy
To treat nephrogenic diabetes insipidus
Prevents the formation and recurrence of calcium stones and
nephrolithiasis in hypercalciuric patients
22. b. Carbonic anhydrase inhibitors
i. Acetazolamide*
Acetazolamide is a white crystalline powder, soluble in dilute alkali hydroxide
solutions, slightly soluble in water and in alcohol.
It is a CAse inhibitor effective for the adjunctive treatment of oedema due to
congestive heart failure, drug induced oedema, chronic simple(open
angled)glaucoma, secondary glaucoma prior to surgery.
Acetazolamide is employed in the treatment petitmal epilepsy.
23. ii. Methazolamide
Methazolamide is available as white or yellow crystalline powder with a slight odour,
which is soluble in water, in alcohol or in acetone and dimethyl formamide.
It is a more potent CA inhibitor than the prototypic acetazolamide and it is seldom
used as a diuretic.
Methazolamide - improved penetration into the eye, - treatment of glaucoma.
It is employed in the treatment of drug-induced oedema, oedema caused by
congestive heart failure and petitmal epilepsy.
24. iii. Dichlorphenamide
It exists as white crystalline powder with a characteristic odour,
soluble in water, sodium hydroxide, alcohol, and ether.
Used as a diuretic and for the treatment of primary and secondary
glaucoma. It produces less acidotic refractoriness to diuretic action
than acetazolamide.
25. SAR of CAse Inhibitors
1. Heterocylic sulphonamides
The C-2 sulphamoyl group is important for activity.
The free sulphamolyl moiety is necessary to bind with Zn++ in the enzyme; hence,
substitution of sulphamoyl group gives inactive compound.
The moiety to which the sulphamoyl group is attached must be aromatic in character.
The heterocyclic sulphonamides with higher partition coefficient and lowest Pka
value have greatest CAse inhibitory and diuretic activities. Example- acetazolamide,
methazolamide.
N-alkylation with methyl group on ring N- of acetazolamide yields active compound
(methazolamide).
26.
27. SAR of CAse Inhibitors
2. m-Disulphamoyl benzene derivatives
m-Disulphamoyl benzene do not have diuretic activity.
• Substituted m-sulphamoyl benzene exhibits diuretic activity.
• The unsubstituted sulphamoyl moiety is essential for the activity; any substitution
leads to affect the potency of the compound.
• The sulphamoyl moiety can be replaced with similar electrophilic groups (e.g.
carboxyl, carbamoyl) that may increase the potency of the compound.
• Maximum diuretic activity is obtained when 4th is substituted by Cl, Br, CF3, or NO2
group.
• Substitution of amino group at 6th position increases aleuronic activity, but decreases
CAse inhibitor activity.
29. Mode of action of CAse Inhibitors
CAse is an enzyme that is present in the PT that catalyses the
reversible reaction
H2O + CO2 ↔ H2CO3
Carbonic acid spontaneously ionizes as H2CO3 - H++ HCO3
-
CAse inhibitors reversibly inhibits CAse resulting in the slowing of
hydration of CO2 and decrease the availability of H+ to exchange
with luminal Na+ through Na+ - H+ antiporter.
These are weak diuretics cause GI disturbances and fatigue and
replaced by thiazides ( hyperchloremic acidosis)
31. Uses of CAse inhibitor diuretics
Treatment of cystinuria, enhanced excretion of uric acid
Used in metabolic alkalosis
used to treat glaucoma
Used to treat epilepsy and acute altitude sickness
32. c. High ceiling /Loop diuretics
i. Frusemide or furosemide
Furosemide is a white crystalline powder, practically insoluble in water and in
methylene chloride, soluble in acetone and in dilute solutions of alkali hydroxides,
sparingly soluble in ethanol.
Sulphonamide diuretic. It is slightly more potent than the organomercurial agents, is
orally effective, and its diuretic action is independent of alterations in body acid-base
balance.
It is used for the treatment of oedema associated with renal disease, nephritic
syndrome, Cirrhosis of the liver, and congestive heart failure.
33. ii Bumetanide
Bumetanide is a white crystalline powder, practically insoluble in water, soluble in
acetone, alcohol, and dilute solutions of alkali hydroxides, slightly soluble in methylene
chloride.
It is a 3-aminobenzoic acid, a potent loop diuretic with efficacy and biochemical effects
similar to those of furosemide.
Used in chronic congestive heart failure, chronic renal failure, chronic hepatic disease,
and in the nephritic syndrome.
It is used in the treatment of renal insufficiency and for The control and management of
acute drug poisoning.
34. iii. Ethacrynic acid
It exists as a white crystalline powder that is odourless, soluble in alcohol,
ether, or chloroform and in water.
An aryloxyacetic acid derivative that is a potent, short-acting diuretic.
It is used in the treatment of oedema caused by congestive heart failure,
cirrhosis of the liver, and renal disease, including the nephritic syndrome.
(Phenoxyacetic acid derivatives)
35. SAR of
Loop
Diuretics
They are either 5-sulphamoyl-2-amino benzoic acid (Frusemide) or 5-sulphamoyl-3-
amino benzoic acid (Bumetanide)
The carbonyl group at C-1 provides optimal diuretic activity.
The substitution of activating group (X) in the position 4 by Cl, alkoxy, aniline, benzyl,
or benzoyl group increases the diuretic activity.
The presence of sulphamoyl group in the 5th position is essential for activity.
The two series of 5-sulphamoyl benzoic acid differ in the nature of the functional
group that substituted in 2nd and 3rd position.
36. SAR of
Loop
Diuretics The presence of furfuryl, benzyl, and thienyl methyl group at 2nd amino group gives
maximum diuretic activity.
The wide range of alkyl group can be substituted at 3rd amino group of 5-sulfamoyl-
3-amino benzoic acid without modifying the optimal diuretic activity.
A molecule with a weakly acidic group to direct the drug to the kidney and an
alkylating moiety to react with sulphydryl groups and lipophilic groups
seemed to provide the best combination of a diuretic in the class.
5-Sulphamoyl-3-amino benzoic acid derivatives
37. High ceiling or Loop diuretics
Mode of action: Na+ -K + 2Cl - co-transporters.
The Na-K-Cl cotransporter (NKCC) is a protein that aids in the active
transport of sodium, potassium, and chloride - from the urine -
reabsorbed into the blood.
NKCC with Sodium pump – positive lumen potential - Ca2+ and Mg2+
also reabsorbed
loop diuretics attach to the chloride-binding site of these proteins to
inhibit reabsorption of Na+ -K + 2Cl - and also Ca2+ and Mg2+.
38. Imbalance in water and electrolytes
Hyponatremia, Hypokalemia, hypocalcemia
Uses
Acute pulmonary oedema
Chronic congestive heart failure
40. Uses of loop diuretics
Acute pulmonary oedema
Chronic congestive heart failure
Treatment of hypertension – no response to thiazides and anti
hypertensives
Hypercalcemia
Treatment of hyperkalemia in combination with NaCl
Used in acute renal failure to increase urine flow and K+
Treatment of toxic ingestion of bromide, fluoride and iodide (with saline )
41. d. Potassium-sparing diuretics
i. Spiranolactone (Aldosterone antagonist)
Spironolactone is a white or yellowish-white powder, practically insoluble in water and
soluble in alcohol.
It is a synthetic steroid that acts as a competitive antagonist of the potent, endogenous
mineralocorticosteroid, aldosterone.
It has a slower onset of action than triamterene or amiloride, but its natriuretic effect is
slightly greater during long-term therapy.
It is indicated in the treatment of essential hypertension, oedema associated with
congestive heart failure, hepatic cirrhosis with ascites, the nephritic syndrome and
hypokalemia, and in the diagnosis of primary aldosteronism.
It is useful in the treatment of aldosterone secreting tumours, and high-renin
hypertension.
42. Spiranolactone (Aldosterone antagonist)
Mode of action
Aldosterone inhibitors inhibit the aldosterone action on mineralocorticoid
receptor, where aldosterone generates aldosterone-induced proteins
along with Na+ K+ ATPase and amiloride sensitive Na+ channels that
leads to the reabsorption of Na+.
Aldosterone inhibitors limit the reabsorption by binding with
mineralocorticoid receptor.
A metabolite of spironolactone, canrenone is also active.
44. ii. Triamterene (Pteridine derivative-
sodium channel blockers)
Triamterene is a yellow crystalline powder, very slightly soluble in water and
alcohol.
It is a pteridine with structural resemblance to folic acid. Replacement of phenyl group
with small basic heterocyclic nucleus such as thiazole and pyridine produces highly
active compounds.
2 and 7 phenyl isomers of triamterene were very potent K + blockers.
Triamterene may be used alone in the treatment of mild oedema associated with
congestive heart failure or cirrhosis of the liver with ascites.
It is used in the treatment of oedema associated with nephritic syndrome, cirrhosis of
liver and Congestive heart failure.
45. iii. Amiloride (Pteridine derivative -
sodium channel blockers)
Amiloride hydrochloride is a pale-yellow to greenish-yellow powder, slightly soluble
in water and in anhydrous ethanol.
It is a potassium-conserving drug with natriuretic diuretic and antihypertensive
activity.
It is an aminopyrazine, Considered an open chain analogue of triamterene.
It blocks the reabsorption of sodium ion and the secretion of potassium ion. Amiloride
is more potent than triamterene.
46. Potassium sparing diuretics (Pteridine derivatives MOA)
These drugs act on Na+ channel from the luminal side and block the
actions.
Thus, it reduces the lumen negative transepithelial potential
difference, which governs K+ and H+ secretion
47. Uses of Potassium sparing
diuretics Used in combination with loop diuretics and thiazides in treatment of
oedema and hypertension
Pseudo hyperaldosteronism (Liddle’s syndrome)
To treat oedema associated with secondary hyperaldosteronism
Spironolactone is diuretic of choice in patients with hepatic cirrhosis
Amiloride is used to treat lithium induced nephrogenic diabetes
48. e. Osmotic Diuretics
i. Mannitol
Osmotic diuretics are non electrolytes, which are freely filtered at the
glomerulus and are not significantly reabsorbed from the tubules
Presence of these agents in the urine causes an increase in the electrolytes and
volume flow.
Mannitol, urea, glycerol, and isosorbide are the four osmotic diuretics, which are
freely filtered through the glomerulus and are insignificantly reabsorbed from the
tubules
They mainly induce diuresis by inhibiting sodium and water reabsorption in the PTs
and the henle’s loop.
50. Uses of osmotic diuretics
Management of cerebral oedema
Diagnostic agent for kidney function (mannitol)
To increase urine volume in few patients with acute renal failure due to
ischemia, nephrotoxins, haemoglobinuria and myoglobinuria
To reduce intraocular pressure (glycerine and isosorbide)
To reduce CSF pressure and volume
To reduce intracranial pressure before and after neurosurgery
Nephritic syndrome is the name given to a collection of different signs and symptoms that occur as a result of inflammation in the kidneys. This inflammation causes the kidneys to work less effectively. It also causes protein and red blood cells to leak from the bloodstream into the urine. Renal insufficiency is poor function of the kidneys that may be due to a reduction in blood-flow to the kidneys caused by renal artery disease. Normally, the kidneys regulate body fluid and blood pressure, as well as regulate blood chemistry and remove organic waste. Chronic renal failure, or chronic kidney disease (CKD), is a slow and progressive decline of kidney function. It's usually a result of a complication from another serious medical condition such as diabetes, high blood pressure or cardiovascular disease. Cirrhosis is when scar tissue replaces healthy liver tissue. This stops the liver from working normally. Cirrhosis is a long-term (chronic) liver disease. The most common causes are hepatitis and other viruses, and alcohol abuse. Other medical problems can also cause it. Heart failure, sometimes known as congestive heart failure, occurs when your heart muscle doesn't pump blood as well as it should. Certain conditions, such as narrowed arteries in your heart (coronary artery disease) or high blood pressure, gradually leave your heart too weak or stiff to fill and pump efficiently.
Ascites - the accumulation of fluid in the peritoneal cavity, causing abdominal swelling. Primary aldosteronism is a hormonal disorder that leads to high blood pressure. It occurs when your adrenal glands produce too much of a hormone called aldosterone. Your adrenal glands produce a number of essential hormones, including aldosterone. aldosterone secreting tumours – could lead to hyperaldosteronism ie primary or secondary...
