Renal drugs

Diuretics agents
By Desalegn Chilo
(B.pharm, MSc )
 Diuretics
 Are chemicals that increase the rate of urine flow and
sodium excretion by acting on the kidney
 From a therapeutic point of view, diuretics are
considered to be substances that aid in removing
excess extracellular fluid and electrolytes.
 Are also used to adjust the volume and/or composition
of body fluids in a variety of clinical situations,
including :-
 Hypertension; heart failure; renal failure; nephrotic syndrome
and cirrhosis
 diuretics
• THIAZIDE DIURETICS • POTASSIUM-SPARING
– Chlorothiazide
DIURETICS
– Chlorthalidone
– Amiloride
– Hydrochlorothiazide (HCTZ)
– Eplerenone
– Indapamide
– Spironolactone
– Metolazone
– Triamterene
• LOOP DIURETICS • CARBONIC ANHYDRASE INHIBITORS
– Bumetanide – Acetazolamide
– Ethacrynic acid
• OSMOTIC DIURETICS
– Furosemide
– Mannitol; urea
– Torsemide
Tubule transport systems and sites of action of diuretics.
• Most diuretics act upon a single anatomic segment of
the nephron.
• The classification of diuretics was based
• Site of action (loop diuretics)
• Efficacy (high-ceiling diuretics), medium efficacy
diuretics ,weak diuretics
• Chemical structure (thiazide diuretics), similarity of action with
other diuretics (thiazide like diuretics)
• Effects on potassium excretion (potassium-sparing diuretics),
• Mechanism of action (carbonic anhydrase inhibitors, osmotic
diuretics)
 I. Carbonic Anhydrase (CA) Inhibitors diuretics:

• are unsubstituted sulfonamide derivatives and were

discovered when it was found that bacteriostatic
sulfonamides caused an alkaline diuresis and metabolic
acidosis
Example: Acetazolamide (250 mg),
 Dichlorphenamide (50 mg),
 Methazolamide (50 mg)
• Acetazolamide is the prototype of this class of agents
 Mechanism of Action
• Normally the carbonic anhydrase enzyme facilitates
the reaction between H2O + CO2 to form carbonic
acid.

CO2 + H2O CA H2 CO3 CA H+ + Hco3

• Inhibition of carbonic anhydrase reduces H+ ion

concentration in renal tubules.
• As a result, there is increased excretion of
bicarbonate, sodium, water, and potassium.
• Resorption of water is decreased and urine volume is
increased.
 These drugs inhibits both luminal and cytoplasmic
carbonic anhydrase
 Carbonic anhydrase is present in many nephron sites,
but the predominant location of this enzyme is the
luminal membrane of the proximal tubule cells where it
catalyzes the dehydration of H2CO3, a critical step in
the reabsorption of bicarbonate
 By blocking carbonic anhydrase, inhibitors block
sodium bicarbonate reabsorption and cause diuresis.
Carbonic anhydrase-mediated Na+-H + exchange
in proximal convoluted tubule
 Inhibition of cytoplasmic CA limits the formation of
intracellular protons and
 Inhibition of luminal CA delays luminal carbonic acid
dehydration
 Both of which indirectly inhibit luminal Na+ -H+
exchange.
• These results in increased delivery of Na+ and
H2CO3 nephron segments beyond the proximal
tubule.
 Effect on electrolyte excretion

 CA Inhibitors primarily cause;- increase in urinary HCO 3-,

K+, and water excretion.
– The fractional excretion of ;-
• Na+ -------5%, and
• K+ ---------70%, but
• Have little on the excretion of Ca2+ or Mg2+.

• 45% of the whole kidney HCO3- reabsorption is

inhibited.
 CA inhibitors are now rarely used as diuretics
 The diuretic efficacy is reduced with continued therapy
because;-

– Plasma [HCO3-] fall, reducing the amount of HCO3-

that appears in the urine. And thus the uncatalyzed
reaction between CO2 and water is sufficient to

achieve HCO3- reabsorption.

– In addition depletion leads to enhanced NaCl

reabsorption by the reminder of the nephron.
 Pharmacokinetics

 Well absorbed after oral administration.

 An increase in urine pH from the bicarbonate diuresis is
apparent within 30 minutes, maximal at 2 hours, and persists
for 12 hours after a single dose.
 Excretion of the drug is by secretion in the proximal tubule;

therefore, dosing must be reduced in renal insufficiency.

 Clinical Indications
a. Glaucoma፡ (Acetazolamide)
 decreases the production of aqueous humor and
reduces intraocular pressure in patients with chronic
open-angle glaucoma, probably by blocking carbonic
anhydrase in the ciliary body of the eye= decreases
the intraocular pressure
 The primary indication for CA inhibitors is open angle glaucoma.
 Drug such as dorzolamide and brinzolamide, (topical) have
the advantage of not causing systemic effects
 But CA inhibitors are less effective as compared to other class of
drugs and have short duration of action
b. Increased intracranial pressure
 The formation of cerebrospinal fluid by the choroid
plexus involves bicarbonate secretion into the
cerebrospinal fluid.
 Therefore; Production of CSF, is dependent on CA and
thus CA inhibitors may be used to decrease CNS
pressure.
c. Acute Mountain Sickness (AMS)
 AMS occurs when people ascend to high altitude

(usually >3500m) because of lack of oxygen.

 Headache, fatigue, undue breathlessness on exertion,
the sensation of the heart beating forcibly, loss of
appetite, nausea, vomiting, dizziness, ataxia, difficulty
sleeping and irregular breathing during sleep are the
common complaints.
 The only cure for mountain sickness is either
acclimatization or descent but acetazolamide can be
used either for prophylaxis or symptomatic treatment.
The proposed mechanism of action of CA inhibitors use in
AMS includes;-
 Increase kidney excretion of bicarbonate and lead to
decreased blood PH.
– The decreases of blood pH stimulates extra breathing,
which results in higher oxygen levels in the blood.
– The decrease in serum pH lowers hemoglobin's affinity for
oxygen, thereby increasing oxygen delivery to the tissues.
 Acetazolamide is effective for prophylaxis and the
recommended dose is 125mg BID for 3 days before ascent to
 3500m, and for two more following day
d. Epilepsy:
• as an adjuvant in the treatment of absence seizure when
primary drugs are not fully effective by increasing in the
efficacy of GABA-mediated inhibition.

e. Metabolic Alkalosis (an alkalosis caused by diuretic-induced

increases in H+ excretion).
f.Alkaline Diuresis
 By urine alkalinization which is beneficial as in the case of
acidic drug overdoses to facilitate excretion.
 Adverse Drug Reactions

Hypokalemia
 Increased delivery of Na+ in the late distal tubule and
collecting duct enhances the driving force for the
reabsorption of Na+ which is linked to secretion of K+ to
the lumen.

Metabolic acidosis
 Metabolic acidosis develops due to urinary loss of
bicarbonate.

Renal Stones : Kidney stone formation can occur due to

precipitation of calcium phosphate salts in alkaline urine.
• Allergic reactions
 Allergic reactions such as rash, fever, and interstitial
nephritis may occur in patients hypersensitive to
sulfonamides
 Other sulfonamide related ADR such as bone marrow
depression may rarely occur.
• CNS effects
 With large doses, many patients exhibit drowsiness
 Contraindication

Chronic Obstructive Pulmonary Disease (COPD) : -

 CA Inhibitors deplete bicarbonate required to buffer
CO2 and worsen respiratory acidosis.

Hepatic Cirrhosis: -
 Increased urine pH causes less NH3 binding and

increases serum NH3.

 Retention of ammonia and precipitation of hepatic
coma
 II. Loop Diuretics

• MOA: Bind to Na+/2Cl-/K+ cotransporter at the chloride

binding site and inhibit the luminal Na+/K+/2Cl- transporter
in the thick ascending limb of Henle's loop and reduce the
reabsorption of NaCl.
• other effect: Increase renal prostaglandins, resulting in the
dilation of blood vessels and reduced peripheral vascular
resistance.
• NSAIDs (eg, indomethacin) can interfere with the actions of
the loop diuretics by reducing prostaglandin synthesis in the
kidney
• Typical loop diuretic is Furosemide
Other drugs include: -
– Bumetanide,
– Torsemide,
– Ethacrynic acid
– Muzolimine,
– Azosemide,
– Piretanide
• loop diuretics are highly efficacious because;-

1. large solute load normally is reabsorbed by the thick

ascending limb (25% to 30% of filtered NaCl load).

2. There is minimal solute reabsorption beyond the thick

ascending limb… no Compensation
• Unlike thiazides, loop diuretics increase the Ca2+ and
Mg2+ content of urine
– by abolishing the transepithelial potential difference
• Furosemide has a CA inhibitor (weak) activity and
increase HCO3- excretion
 Pharmacokinetics

• Rapidly absorbed

• Eliminated by tubular secretion as well as by

glomerular filtration
• Diuretic response is extremely rapid following IV
• The duration of action for furosemide is usually 2–3
hours and that of torsemide is 4–6 hours.
• Half-life depends on renal function
 Therapeutic uses
• Treatment of Edematous conditions

• Acute pulmonary edema

– Loop diuretics increase systemic venous capacitance and
thereby decrease left ventricular filling pressure.
• Chronic congestive heart failure
– To reduce extracellular fluid volume and thus reduce
venous and pulmonary edema.
• Edema in renal failure and nephritic syndrome
• Edema of liver cirrhosis
• Treatment of hypertension
– Not recommended for routine use, reserved for
emergency case and when other antihypertensive
agents fail to respond.

• Treatment of Hypercalcemia in combination with

isotonic saline administration to prevent volume
depletion.
• Treatment of hyperkalemia
• Used in acute renal failure
– to increase the urine flow and K+ secretion

• Treatment of toxic ingestions of bromide, fluoride and

iodide (with simultaneous saline administration).
 ADR Of Loop Diuretics

Hyponatremia: (due to excessive use )

hypotension.
Hypokalemia due to
• increased delivery of Na+ to the late distal tubules and
collecting duct and also due to stimulation of rennin release.
Metabolic alkalosis
• due to increased delivery of Na+ to collecting tubule where
the reabsorption of Na+ enchases excretion of H+
• Stimulation or rennin release further increase H+ secretion
related Na+ Reabsorption
Hypomagnesemia and rarely hypocalcemia
• Hypocalcemia is rare because Ca++ is reabsorbed at DCT
under the influence of PTH.
Ototoxicity
• Manifestations include reversible hearing impairment &
deafness, tinnitus, and vertigo
• Especially common with ethacrynic acid
Hyperuricemia
• Occurs due to hypovolemia- associated enhancement
of uric acid reabsorption
• May precipitate gout

Other rare ADRs

• Include allergic reactions, leukopenia or
agranulocytosis ,thrombocytopenia pancreatitis.
 Drug Interactions

• Effect of loop diuretic reduced by NSAIDs

• Diuretic effect is reduced by probenecid
• Potentiate ototoxicity or nephrotoxicity of amphotericin B,
aminoglycosides
• Potentiate induction of arrhythmias by digitalis glycosides.
• Potentiate hypokalemia associated with amphotericin B,
mineralocorticoids, some synthetic penicillins, many others
(that induce hypokalemia)
• Potentate neuromuscular junction blockers.
 III. Thiazides
MOA: They block Na+/Cl- transporter in the distal
convoluted tubule
• Thiazides enhance Ca 2+
reabsorption in the distal
convoluted tubule therefore, are useful in the
treatment of kidney stones caused by hypercalciuria
• Examples:
• Chlorothiazide; Hydrochlorothiazide (HCT);
Methyclothiazide
• Chlorthalidone; Indapamide
• Like loop diuretics, the actions of thiazides can be inhibited
by NSAIDs under certain conditions.
• uric acid secretion may be reduced

• Small amount of NaCl (~5% of filtered load) is excreted as

large amount (up to 90%) is absorbed at earlier sites.
• Thus thiazides have only a medium diuretic efficacy.

• Thaizides also cause exertion of K+ and titrable acid due to

Na+ delivery to late distal and collecting tubules.
• Some thiazides have weak CA inhibitory activity and produce
HCO3- excretion
 Pharmacokinetics

• All thiazides and related drugs are well absorbed orally

and are administered only by this route
• They are secreted at proximal tubule by organic acid
secretary system.
• Most agents undergo little hepatic metabolism and are
excreted as such.
 Therapeutic uses of thiazides

• Treatment of mild to moderate hypertension: are

drugs of choice in the initial management of HTN.
• Hypercalciuria
– They prevent Ca++ loss which may be associated with
recurrent calcium stones in kidney.
– May also be useful in osteoporosis.
• Edema (maintenance therapy of mild to moderate
edema)
 ADRs of Thiazides

Fluid and Electrolyte imbalance

• Especially Hypokalemia, Hyponatremia, Hypochloremia,
Metabolic alkalosis, Hypomagnesemia, Hypercalcemia,
and Hyperuricemia.

GIT disturbances
• Anorexia, Nausea, Vomiting, Cramping, Diarrhea,
Constipation
CNS disturbances
• Vertigo, headache, paresthesias
Allergic reaction
• Thiazides are sulfonamides and can cause allergic
reactions similar to other sulfonamides.
Glucose intolerance
• Hyperglycemia occurs due to impaired insuline release
and diminished glucose utilization.
Hyperlipidemia
• May increase LDL cholesterol, total cholesterol, and
total triglycerides.
 Drug interaction

• Hypokalemia induced by thiazides potentiates digitalis

toxicity
• Probenecid reduces diuretic effect of thiazides, and
thiazides diminish its uricosuric action
• Amphotericin B and corticosteroids increase the risk of
hypokalemia induced by thiazide diuretics
 IV. Potassium Sparing Diuretics
Two classes of drugs
– Aldosterone Antagonists : -
• Spironolactone, Canrenone,, Potassium
canrenoate,
– Na+ channel Inhibitors: -
• Triamterene and Amiloride
• Both classes of drugs decrease potassium excretion
secondary to their inhibition of the lumen-negative
transepithelial potential difference
• Either mechanism produces poor diuresis when the
drugs used alone. (little solute reabsorption occurs )
However the diuretic activity increased if:
– sodium load in the body is high
– Aldosterone concentrations are high
– sodium load in tubule is high - secondary to diuresis
• Spironolactone competitively inhibits the binding of
aldosterone to its receptor and abolishes its effects.
• Its metabolite canrenone has also similar effects.
• Amiloride and triamterene inhibit the sodium channel in the
luminal membrane of the late distal tubule and collecting duct
 Clinical Uses

• Because of their mild diuretic effect, all potassium sparing

diuretics are not use alone either in the treatment of edema
or hypertension.
• Used in combination with loop and thiazide diuretics mainly to
avoid hypokalemia and also to enhance diuretic efficacy.
• Hyperaldosteronism
– Spironolactone is used in primary hyperaldosteronism
(hypersecretion) and also secondary hyperaldosteronism
resulting from congestive heart failure, nephritic syndrome,
hepatic cirrhosis, etc
 ADRs
Hyperkalemia
– is increased in renal disease, and if used together with
other drugs that decrease aldosterone activity (Beta
blockers, NSAIDs, ACE inhibitors).
– Oral K+ supplementation should be discontinued if K+
sparing diuretics are used.
Metabolic Acidosis: Due to decrease secretion of H+
 ADRs

Endocrine abnormalities
– Spironolactone may produce adrenal and sex hormone
effects with long term use due to its steroidal
structure.
• Gynecomastia, impotence, decreased libido, hirsutism,
deepening of the voice, and menstrual irregularities.
GI effects

– Spironolactone also may induce diarrhea, gastritis,

gastric bleeding, and peptic ulcers; it is
contraindicated
 Pharmacokinetics

• Spironlacotone has good oral bioavalability(75%).

• It is highly bound to plasma proteins and is extensively

metabolized
• Its metabolites are active, the most important of which
is Canrenone (responsible for ½ - 2/3 of the activity)
• It has a short half-life (approximately 1.4 hours).
However canrenone, has a half-life of approximately
16.5 hours, which prolongs its pharmacological effects.
 Drug interactions

• Dangerous hyperkalemia with KCl supplements

• Risk of hyperkalemia increases with Beta blockers,
NSAIDs, ACE inhibitors
• Salicylates, block spironolacton action by inhibiting
secretion of canrenone
• Spironolactone may increase plasma digoxin level.
 Osmotic Diuretics

• The prototype osmotic agent is mannitol.

• Other drugs include: -
– Glycerin, Isosorbide, and urea.
• are freely filtered at the glomerulus
• undergo limited re-absorption by the renal tubule
and increase tubular tonicity
• prevent passive water re-absorption both in the
proximal tubule and the thin descending loop of
Henle (the major site of action).
 V. Osmotic Diuretics
• osmotic diuretics increase the urinary excretion of nearly
all electrolytes including Na+, K+, Ca2+, Mg2+, Cl-,
HCO3-, and phosphate.
• Na+ reabsorption may be slightly reduced due to
– increased rate of urine flow or
– luminal retention of water opposes Na+ reabsorption.
 Pharmacokinetics

• Manitol and urea are poorly absorbed and are not

effective orally. Thus must be given intravenously
• Glycerin and isosorbide can be given orally
• Eliminated renaly via glomerular filtration, except
gylcerin.
 Clinical Uses

Reduction of intracranial and intraocular pressure

• Osmotic agents encourage movement of water from CSF
and Aqueous humor by increasing osmotic pressure of
the plasma
• Used to control IOP and ICP both preoperatively and
postoperatively
Acute Renal failure
• Osmotic agents are used in acute renal failure where
kidney is incapable of forming urine. They maintain GFR
and urine flow
 ADRs

ECF fluid volume expansion

• Extract water form intracellular compartment and
increase ECF volume. Thus they produce pulmonary
edema and aggravate congestive heart failure
• Initial osmotic agents may cause hyponatremia which
could explain common side effects such as headache,
nausea and vomiting.
Dehydration and Hypernatremia
• Excessive use leads to free water loss, severe
dehydration and hypernatremia.
 Contraindications

• Pulmonary edema,
• acute left ventricular failure, CHF
• Cerebral hemorrhage
• Acute tubular necrosis