by

Dr.GAYE HAFEZ
Pharmacology
2022

DIURETICS
 • The basic urine-forming unit of the kidney is
Anatomy of kidney the nephron.
• The nephron consists of a filtering
apparatus, the glomerulus, connected to a
long tubule portion that reabsorbs
substances the body must conserve, and
leaves behind and/or secretes substances
that must be eliminated.
• The nephron can be divided into 4 major
anatomical and functional regions:
– The proximal tubule
– The loop of Henle (which consists of the
proximal straight tubule, the
intermediate tubule, the thick ascending
limb)
– The distal convoluted tubule
– The collecting duct
• Normally ~65% of filtered Na+ is reabsorbed in the proximal tubule; this
part of the tubule is highly permeable to water.

• Approximately 25% of filtered Na+ is reabsorbed in the loop of Henle.

• The distal convoluted tubule actively transports NaCl and is impermeable

to water.

• The fine control of ultrafiltrate composition and volume takes place in the
collecting duct.

• The transport that occurs in a specific segment of the nephron is primarily

determined by the transporters present in the epithelial cells and the
whether they are located on the luminal or basolateral membrane.
• The kidney filters the extracellular fluid volume across the renal glomeruli an
average of 12 times a day, and the renal nephrons precisely regulate the fluid
volume of the body and its electrolyte content via processes of secretion and
reabsorption.
• Hypertension
• Heart failure may disrupt this balance.
• Renal failure
• Nephrotic syndrome
• Cirrhosis

• Diuretics increase the rate of urine flow and Na+ excretion and are used to
adjust the volume or composition of body fluids in these disorders.
• Precise regulation of body fluid osmolality is also essential. It is controlled by a
finely tuned homeostatic mechanism that operates by adjusting both the rate of
water intake and the rate of solute-free water excretion by the kidneys—that is,
water balance.
• Abnormalities in this homeostatic system can result from genetic diseases,
acquired diseases, or drugs and may cause serious and potentially life-
threatening deviations in plasma osmolality.
Principles of blood pressure
regulation and its
modification by drugs
Diuretic
Natriuretic
Aquaretic
 RENAL TUBULE TRANSPORT MECHANISMS

• Proximal Tubule
• Renal Autacoids
• Loop Of Henle o adenosine
• Distal Convoluted Tubule o prostaglandins
• Collecting Tubule System o peptides
Osmosis: diffusion of water from high to low concentration of water
• PROXIMAL: Almost all the glucose, bicarbonate, amino acids, and
other metabolites are reabsorbed. Approximately two-thirds of the
Na+ is also reabsorbed. Water follows passively from the lumen to
the blood to maintain osmolar equality.

If not for the extensive reabsorption of solutes

and water in the proximal tubule, the
mammalian organism would rapidly become
dehydrated and lose its normal osmolarity.
 • https://www.youtube.com/watch?v=C_SG017I3nQ
• https://www.youtube.com/watch?v=NzdvoGZquIk

Renal excretion= Filtration- Reabsorption+ Secretion

 Although continued diuretic administration
causes a sustained net deficit in total-body Na+,
Principles of diuretic action the time course of natriuresis is finite because
renal compensatory mechanisms bring
• increase the rate of urine flow Na+ excretion in line with Na+ intake, a
• increase the rate of Na+ excretion phenomenon known as diuretic braking.
(natriuresis) and of an These compensatory mechanisms include:
accompanying anion, usually Cl− • activation of the sympathetic nervous system
• activation of the renin-angiotensin-
• Most clinical applications of aldosterone axis
diuretics are directed toward • decreased arterial blood pressure (which
reducing extracellular fluid volume reduces pressure natriuresis)
by decreasing total-body NaCl • renal epithelial cell hypertrophy
content.
• increased renal epithelial transporter
expression
• alterations in natriuretic hormones such as
ANP.
 DRUGS THAT ALTER SODIUM &
WATER BALANCE

• Dietary sodium restriction

• Diuretics
• Low-dose diuretic therapy is safe, inexpensive, and effective in
preventing stroke, myocardial infarction, and congestive heart
failure, all of which can cause mortality.

Urine output Fluid overload BP

Inhibitors of Carbonic Anhydrase
• Carbonic anhydrase (CA) is found
in the luminal and basolateral
membranes of proximal tubular
epithelial cells, as well as in the
cytoplasm.
• Carbonic anhydrase plays a role in
NaHCO3 reabsorption and acid
secretion.
 Acetazolamide (Diazomid®)
Dichlorphenamide
Methazolamide

• Carbonic anhydrase inhibitors potently inhibit both the membrane-

bound and cytoplasmic forms of carbonic anhydrase, and can cause
nearly complete abolition of NaHCO3 reabsorption in the proximal
tubule.

Proksimal tübüllerde karbonik anhidraz

enzimini inhibe ederek sodyum ve hidrojen
iyonunun değişim kapasitesini azaltır.
Bikarbonatın geri emilimini engeller.
Böylece sodyum bikarbonat diürezine ve
vücuttaki total bikarbonat depolarının
azalmasına sebep olur.
HCO3 lümen içinde kalır ve idrar pHsı
belirgin olarak yükselir.
• Effects on Urinary Excretion
• Other Actions: Carbonic anhydrase in the ciliary processes of the eye
mediates formation of HCO-3 in aqueous humor. Inhibition of
carbonic anhydrase decreases the rate of formation of aqueous
humor and consequently reduces intraocular pressure.

aqueous humor: intraocular fluid

Gözün ön ve arka odacıklarını dolduran sulu sıvı
Therapeutic Uses
Dorzolamide (drop)

• Open-angle glaucoma Brinzolamide (drop)

• Preoperatively in acute-angle closure glaucoma to lower intraocular
pressure before surgery
• Glaucoma Acetazolamide, oral
• Absence seizures Acetazolamide
• High-altitude illness or mountain sickness Acetazolamide
• Familial periodic paralysis Dichlorphenamide

• Finally, carbonic anhydrase inhibitors can be useful for correcting

metabolic alkalosis, especially one caused by diuretic-induced
increases in H+ excretion.
Toxicity, Adverse Effects, Contraindications, Drug Interactions

• Bone marrow depression, skin toxicity, sulfonamide-like renal

lesions, and allergic reactions
• With large doses, many patients exhibit drowsiness and paresthesias

• contraindicated • contraindicated in patients with

in patients with hyperchloremic acidosis or severe
hepatic cirrhosis COPD
 Osmotic Diuretics
• Osmotic diuretics are freely
filtered at the glomerulus,
undergo limited reabsorption by
the renal tubule, result in some
degree of diuresis.

• They inhibit water reabsorption in

the proximal convoluted tubule
and the thin descending loop of
Henle and collecting duct, regions
of the kidney that are highly • Osmotic diuretics increase urinary excretion of
nearly all electrolytes, including Na+, K+, Ca2+,
permeable to water. Mg2+, Cl−, HCO-3, and phosphate.
Mannitol
Glycerin
Urea
• Osmotic diuretics are used to effect increased water excretion
rather than Na+ excretion, they are not useful for treating conditions
in which Na+ retention occurs.

• They are used to maintain urine flow following acute toxic

ingestion of substances capable of producing acute renal failure.
 Therapeutic Uses Mannitol, IV
Osmotic diuretics are used to
control intraocular pressure
To reduce cerebral edema
during acute attacks of
and brain mass before and
glaucoma and for short-term
Treatment of dialysis after neurosurgery and to
reductions in intraocular
disequilibrium syndrome control intracranial pressure
pressure both preoperatively
in patients with traumatic
and postoperatively in
brain injury
patients who require ocular
surgery.

For the enhancement of

urinary excretion of For the diagnosis of bronchial
To prevent acute kidney
salicylates, barbiturates, hyperreactivity (by oral
injury (?)
bromides, and lithium inhalation)
following overdose

For antihemolytic urologic irrigation during

transurethral procedures
 Toxicity, Adverse Effects, Contraindications, and Drug Interactions
• Loss of water in excess of • Hypernatremia
electrolytes can cause
hypernatremia and dehydration.
• In patients with heart failure or
pulmonary congestion, it may
cause frank pulmonary edema.
• Hyponatremia with high dose

• In patients who are anuric

owing to severe renal
disease
• Both mannitol and urea are
contraindicated in patients
with active cranial bleeding.
 Inhibitors of Na+-K+-2Cl− Symport:
Loop Diuretics, High-Ceiling Diuretics
• inhibit activity of the Na+-K+-2Cl− symporter
in the thick ascending limb of the loop of
Henle
• the highest efficacy in mobilizing Na+ and Cl−
from the body.
Furosemid (Lasix®, oral, IM/IV)
Bumetanide
Ethacrynic acid
Torsemide (Sutril Neo®)

LASIX=lasts six hours

• Inhibitors of this symporter block its
function.
• Loop diuretics increase urinary Na+ and
Cl− excretion profoundly (i.e., up to 25%
of the filtered Na+ load) and markely
increase Ca2+ and Mg2+ excretion.
• Acutely, loop diuretics increase uric acid
excretion; their chronic administration
results in reduced uric acid excretion.
• High doses of inhibitors of Na+-K+-
2Cl− symport can inhibit electrolyte
transport in many tissues. This effect is
clinically important in the inner ear and
can result in ototoxicity, particularly
in patients with preexisting hearing
impairment.
 the treatment of acute pulmonary edema

treatment of chronic CHF when diminution of extracellular fluid

volume is desirable to minimize venous and pulmonary congestion

Therapeutic not considered first-line diuretics for the treatment of hypertension

Uses
treatment of edema and ascites of liver cirrhosis

In patients with a drug overdose, loop diuretics can be used to induce

forced diuresis to facilitate more rapid renal elimination of the
offending drug

Loop diuretics, combined with isotonic saline administration to prevent

volume depletion, are used to treat hypercalcemia. With saline, useful for
the treatment of life-threatening hyponatremia
Toxicity, Adverse Effects, Contraindications, Drug Interactions
• Serious depletion of total-body Na+ : hyponatremia
• Extracellular fluid volume depletion associated with hypotension, reduced GFR, circulatory
collapse, thromboembolic episodes, and, in patients with liver disease, hepatic
encephalopathy.
• Hypochloremic alkalosis
• If dietary K+ intake is not sufficient, hypokalemia may develop, and this may induce cardiac
arrhythmias, particularly in patients taking cardiac glycosides.
• Increased Mg2+ and Ca2+ excretion may result in hypomagnesemia (a risk factor for cardiac
arrhythmias) and hypocalcemia (rarely leading to tetany)
• Loop diuretics should be avoided in postmenopausal osteopenic women, in whom
increased Ca2+ excretion may have deleterious effects on bone metabolism.
• Loop diuretics can cause ototoxicity that manifests as tinnitus, hearing impairment,
deafness, vertigo, and a sense of fullness in the ears. -mostly reversible
• Loop diuretics also can cause hyperuricemia
• Skin rashes, photosensitivity, paresthesias, bone marrow depression, and GI disturbances.

Contrandications: Severe Na+ and volume depletion, hypersensitivity to

sulfonamides (for sulfonamide-based loop diuretics), and anuria unresponsive to a
trial dose of loop diuretic.
 Drug interactions may occur when loop diuretics are coadministered with the
following:
• Aminoglycosides, carboplatin, paclitaxel, and others (synergism of ototoxicity)
• Anticoagulants (increased anticoagulant activity)
• Digitalis glycosides (increased digitalis-induced arrhythmias)
• Lithium (increased plasma levels of Li+)
• Propranolol (increased plasma levels of propranolol)
• Sulfonylureas (hyperglycemia)
• Cisplatin (increased risk of diuretic-induced ototoxicity)
• NSAIDs (blunted diuretic response and salicylate toxicity with high doses of
salicylates)
• Probenesid (blunted diuretic response)
• Thiazide diuretics (synergism of diuretic activity of both drugs, leading to
profound diuresis)
• Amphotericin B (increased potential for nephrotoxicity and intensification of
electrolyte imbalance)
 Inhibitors of Na+-Cl− Symport:
Thiazide-Type and Thiazide-Like Diuretics
• They act mainly in the distal tubule to
decrease the reabsorption of Na+
apparently by inhibition of a Na+/Cl-
cotransporter on the luminal membrane
of the distal convoluted tubule.
• These drugs increase the concentration
of Na+ and Cl- in the tubular fluid.
Chlorthalidone
Hydrochlorothiazide
Indapamide
Chlorothiazide
Metolazone

Thiazide-like diuretics
Ion transport in the distal tubule
❖ Thiazide diuretics

Sodium-water retention: su-tuz tutulumu

Actions:

Reduced
Decreased peripheral
urinary vascular
Loss of
calcium resistance
Mg2+
excretion
Loss of
K+
Increased
excretion
of Na+ and
Cl-
Therapeutic uses:

• Thiazide diuretics are used for the treatment of edema associated

with diseases of the heart (CHF), liver (hepatic cirrhosis), and kidney
(nephrotic syndrome, chronic renal failure, and acute
glomerulonephritis).
• Additive or synergistic effects when combined with other classes of
antihypertensive agents

Hypertension (combination therapies)

Heart failure
Hypercalciuria
Diabetes insipidus
Toxicity, Adverse Effects, Drug Interactions
Contraindications
• Volume depletion
• Hyperglycemia
• Hypersensitivity
fatal ventricular arrhythmia
• Hyperlipidemia

thiazide diuretic–induced K+ depletion

quinidine, dofetilide, arsenic trioxide

thiazide
 Chlorthalidone
Thiazide-like analogs: Indapamide
Metolazone

Indapamide (Fludex®)

• Similar with hydrochlorothiazide

• long duration of action
• In combination therapies:
• At low doses, it shows significant atenolol+ chlorthalidone
antihypertensive action with minimal (Tenoretic®)
diuretic effects
• In combination therapies:
Amlodipin+indapamide (Natrixam®)
Perindopril+indapamide (Coveryl Plus®)
 Inhibitors of Renal Epithelial Na+ Channels:
K+-Sparing Diuretics
• act in the collecting tubule to inhibit Na+
reabsorption and K+ excretion.
• block Na+ transport channels, resulting
in a decrease in Na+/K+ exchange.
• It is extremely important that patients
who are treated with any potassium-
sparing diuretic be closely monitored for
potassium levels.

Triamterene (Triamseril®)
Amiloride (Moduretic®)
 Antagonists of Mineralocorticoid Receptors:
Aldosterone Antagonists, K+-Sparing Diuretics
• Mineralocorticoids cause salt and water retention and increase
K+ and H+ excretion by binding to specific MRs.
• Aldosterone binds to MRs.

Spironolactone (Aldactone®)
Eplerenone may have
Eplerenone (Inspra®) less endocrine effects than spironolactone.

antagonizes aldosterone at intracellular

cytoplasmic receptor sites.
• In most edematous states, blood levels of aldosterone are high, which
is instrumental in retaining Na+.
• When spironolactone is given to a patient with elevated circulating
levels of aldosterone, the drug antagonizes the activity of the
hormone, resulting in retention of K+ and excretion of Na+.
 Therapeutic uses ADEs
• gastric upsets and can cause peptic ulcers
• Diuretic
• gynecomastia in males
• Resistant hypertension • menstrual irregularities in females
• Secondary hyperaldosteronism • It is most effectively employed in mild
edematous states
• Heart failure • hyperkalemia, nausea, lethargy, and
mental confusion

❑Spironolactone is the diuretic of

choice in patients with hepatic
cirrhosis.
 Inhibitors of Sodium-Glucose Symport:
SGLT2 Inhibitors, Gliflozins
• For DM
• SGLT2 inhibitors are also efficacious diuretics (new info)

• In type 2 diabetes, gliflozins also protect against declining

renal function, end-stage kidney disease, death due to
kidney disease, and acute kidney injury

• Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin

 Inhibitors of the Nonspecific Cation Channel:
Natriuretic Peptides
• A human recombinant BNP, nesiritide produced by the ventricular
myocardium, is available for clinical use.
 Adenosine Receptor Antagonists

• There are four adenosine receptor subtypes (A1, A2A, A2B, and A3).

• A1, A2A, and A2B receptors regulate aspects of renal physiology.

• The A1 receptor is expressed in the proximal tubule and stimulates

reabsorption of Na+. Consequently, antagonists of A1 receptors cause
diuresis/natriuresis, yet are K+ sparing.
 Kidney Function in Disease

Edematous states:
• In many diseases, the amount
Idiopathic
of sodium chloride Heart failure
edema
reabsorbed by the kidney
tubules is abnormally high.
This leads to the retention of
water, an increase in blood
volume, and expansion of the Premenstrual Hepatic
extravascular fluid edema ascites
compartment, resulting in
edema of the tissues.
Nephrotic
syndrome
 Kidney Function in Disease

• Nonedematous states

Hypertension
Diabetes
insipidus

Nephrolithiasis Hypercalcemia
 Strategies

• Interrelationships among renal function, Na+ intake, water

homeostasis, distribution of extracellular fluid volume, and mean
arterial blood pressure and suggests three fundamental strategies
for mobilizing edema fluid:

• Correction of the underlying disease

• Restriction of Na+ intake
• Administration of diuretics
Some related terms
Summary
Question:

• A group of college students is planning a mountain climbing trip to

the Andes. Which of the following drugs would be appropriate for
them to take to prevent mountain sickness?

A. A thiazide diuretic
B. An anticholinergic
C. A carbonic anhydrase inhibitor
D. A loop diuretic
E. A beta-blocker
Question:

• An alcoholic male has developed hepatic cirrhosis. To control the

ascites and edema, he is prescribed which one of the following?

A. Hydrochlorothiazide
B. Acetazolamide
C. Spironolactone
D. Furosemide
E. Chlorthalidone
Question:

• A 55-year-old male with kidney stones has been placed on a diuretic

to decrease calcium excretion. However, after a few weeks, he
develops an attack of gout. Which diuretic was he taking?
A. Furosemide
B. Hydrochlorothiazide
C. Spironolactone
D. Triamterene
Loop diuretics increase urinary Na+ and Cl− excretion
profoundly (i.e., up to 25% of the filtered Na+ load) and
markedly increase Ca2+ and Mg2+ excretion.
Acutely, loop diuretics increase uric acid excretion; their
chronic administration results in reduced uric acid
excretion.
Question:

• Which of the following drugs is contraindicated in a patient with

hyperkalemia?

A. Acetazolamide
B. Chlorothiazide
C. Ethacrynic acid
D. Chlorthalidone
E. Spironolactone
Case
A 43-year-old man has a blood pressure of 138/88 taken during his annual
examination. He has no other health problems and his blood laboratory
results are in the normal range. He is modestly overweight and has a family
history of cardiovascular disease.

• What, if any, are the therapeutic options for this patient?

• A year later at his next annual examination, the patient’s blood pressure
is 142/91. What, if any, are the therapeutic options for this patient?
• What are the considerations in choosing an appropriate antihypertensive
drug therapy for this patient?
• He is prescribed hydrochlorothiazide (12.5 mg daily). What is the
mechanism of action of this drug in reducing blood pressure?
Case

• A 68-year-old woman is being treated with 25 mg of

hydrochlorothiazide for her hypertension. During her most recent
checkup, her blood pressure was 161/93 and she was also diagnosed
with type 2 diabetes.

• What changes should be made in her treatment?

• This patient is prescribed enalapril in addition to her
hydrochlorothiazide. What adverse effects are possible that the
patient should be counseled to be aware of?
Answer

What changes should be made in her treatment?

This patient has stage 2 hypertension and an important comorbidity, type 2
diabetes mellitus. The risk of cardiovascular disease, disability, and death in
hypertensive patients is increased markedly by concomitant cigarette smoking,
diabetes, or elevated low-density lipoprotein; the coexistence of hypertension with
these risk factors increases cardiovascular morbidity and mortality to a degree
that is compounded by each additional risk factor. Because the purpose of treating
hypertension is to decrease cardiovascular risk, other dietary and pharmacological
interventions may be required to treat these comorbid conditions. ACE
inhibitors/AT1-receptor antagonists should be first-line drugs in the treatment of
diabetics with hypertension in view of these drugs’ well-established benefits in
slowing the development and progression of diabetic glomerulopathy.
Case

A 31-year-old woman is being treated for mild hypertension with

valsartan and hydrochlorothiazide. She is in good health and becomes
pregnant.

• Are the drugs she is taking for her hypertension safe in pregnancy?
• What changes in her drug therapy should be made?
Answer

What changes in her drug therapy should be made?

This woman had chronic hypertension prior to her pregnancy, but is
considered low risk because she had mild hypertension with no evidence
of organ damage. To minimize risk to the fetus, she should not receive an
antihypertensive drug unless her systolic blood pressure exceeds 160 mm
Hg or her diastolic pressure exceeds 110 mm Hg. If her blood pressure
exceeds these values, methyldopa is the drug of choice because of its
record of safety and efficacy. Hydralazine and a β-adrenergic blocker such
as labetalol can also be used.
Monet