Pharmacology of Diuretics

1. Course Title:
Pharmacology for Advance Practice
Course Code: MSN SC 701
Dr. Aqsa Mushtaq
PharmD, RPh, PhD Pharmacology
Department of Pharmacology
DCOP, DUHS.

2. Pharmacology Course Objectives
Units Topics
Unit-II Drugs influencing pain, inflammation, and infection
1. Describe the therapeutic option available for pain
a. Non Inflammatory analgesics e.g. acetaminophen
b. Inflammatory disorders e.g. Aspirin
1. Describe the therapeutic option available for bacterial infections
a. Penicilllin e.g. amoxicillin
b. Cephalosporine e.g. cefimax
1. Describe therapeutic options available for viral infections e.g. Acyclovir (zovirax)
2. Describe the therapeutic options available for fungal infections e.g. Amphotericin B (Fungizone)
Unit-IV Drugs influencing hematologic disorders
a. Anticoagulant therapy e.g. heparin and warfarin
b. Antiplatelet e.g. Aspirin
c. Thrombolytic agents e.g. Streptokinase

3. Unit-V Drugs influencing Cardiovascular disorders
1. Describe therapeutic options available for congestive heart failure
a. Cardioglycosides e.g. digoxin
b. Phosphodiesterase e.g. aminone
1. Describe therapeutic options available for CHD (angina)
a. Nitrates e.g. nitroglycerin
b. Beta blockers e.g. Atenolol
1. Describe therapeutic options available for hypertension
a. Antihypertensive drugs
- ACE inhibitors
- Diuretics
- Angiotension II Blockers
- B-blockers
Unit-VIII Drugs influencing renal disorders
1. Describe therapeutic options available for renal dysfunctions
a. Carbonic anhydrase inhibitors e.g. acetazolamide
b. Loop diuretics e.g. furosemide
c. Thiazide diuretics e.g. hydrochlorothiazide
d. Osmotic diuretic e.g. mnnitol
1. Describe therapeutic options available for renal failure
a. Angiotensin Converting enzymes e.g. Captopril
Unit-IX Describe therapeutic options available for Cancer
a. Alkylating agents e.g.
b. Antimetabolites e.g. methotrexate

4. Evaluation Criteria
1. Presentation (Case Study + Clinical Drug trial Article) = 10%
2. Quizzes = 20%
3. Final DUHS Examination = 70%

5. Recommended Book
Lehne's Pharmacology for Nursing Care 10th Edition by Jacqueline Burchum
DNSc APRN BC
Focus on Nursing Pharmacology 5th Edition by Amy M. Karch RN MS
Katzung & Trevor's Pharmacology Examination and Board Review, 8th
Edition by Anthony Trevor, Bertram Katzung

6. Objectives of today’s Lecture
After completion of this lecture you will be able to know
1. Therapeutic options available for renal dysfunctions
a. Carbonic anhydrase inhibitors e.g. acetazolamide
b. Loop diuretics e.g. furosemide
c. Thiazide diuretics e.g. hydrochlorothiazide
d. Osmotic diuretic e.g. mannitol

7. DIURETICS
The kidney is a complex organ with 3 main functions:
1- Maintain the acid-base balance.
2- Elimination of waste materials & return of useful metabolites to the blood.
3- Maintenance of an adequate electrolyte balance which in turn governs the amount of
fluid retained in the body.
** Malfunction of one or more of these regulatory processes may result in the retention of
excessive fluid by various tissues (edema).
** Edema is an important manifestation of many conditions such as pregnancy &
congestive heart failure.

8. Action of Diuretics:
It increase the urinary output of water and sodium “ prevention or
correction of edema” through one of the following mechanisms:
1- Increasing the glomerular filtration rate .
2- Decreasing the rate at which sodium is reabsorbed from the
glomerular filtrate by the renal tubules, therefore water is excreted along
with sodium .
3- Promoting the excretion of sodium & therefore water by the kidney.
Uses:
Congestive heart failure, hypertension, edema.

9. Terminology
• Natriuresis- Increased sodium excretion
• Kaliuresis- Increased Potassium excretion
• Diuretics- Drugs which cause a net loss of Na+ and water in urine.
(Exception- Osmotic diuretics (Mannitol) don't cause natriuresis but
produce diuresis)

10. A "diuretic" is an agent that increases urine volume,
While a "Natriuretic Agent" causes an increase in renal sodium excretion.
Because natriuretics almost always also increase water excretion, they
are usually called diuretics.
In simple words….
Drugs inducing a state of increased urine flow are called diuretics.

11. The nephron-
the functional
unit of the
kidneys

12. Body Fluid Compartments
12

13. Three Basic Renal Processes
1. Filtration
Filtration occurs at the glomerulus and is the first step in urine
formation. Virtually all small molecules that are present in plasma
undergo filtration.
2. Reabsorption
More than 99% of the water, electrolytes, and nutrients that are
filtered at the glomerulus undergo reabsorption.
3. Active Secretion
The kidney has “pumps” for active secretion. These pumps transport
compounds from the plasma into the lumen of the nephron.

14. Schematic representation of a nephron and collecting duct
2. Leaky- Freely permeable to water, solutes
Active absorption of Sodium Chloride,
Sodium Bicarbonate Glucose Amino Acids
Organic Solutes Followed by passive
absorption of water
3. Descending limb- Permeable to water
Thick ascending limb – Impermeable to
water but Permeable to sodium by
Na+K+2Cl- Co transport About 25% of
filtered sodium is absorbed here
4. Active transport of sodium by NaCl
symport
Calcium excretion is regulated by
Parathyroid hormone regulated by thyroid
gland
5. Aldosterone- On membrane receptor and cause
sodium absorption by Na+/K+ Exchange

15. Classification of Diuretics
Carbonic
Anhydrase
Inhibitors
Loop
Diuretics
Thiazide
Diuretics
Potassium
Sparing
Diuretics
Osmotic
Diuretics

16. Schematic diagram
of a nephron showing
sites of sodium
absorption and
diuretic action
Acetazolamide

17. Classification of Diuretics
1. Carbonic Anhydrase Inhibitors
• Brinzolamide, Acetazolamide, Dorzolamide
2. Loop Diuretics
• Furosemide, Bumetanide, Torasemide, Ethacrynic acid
3. Thiazide Diuretics
• Hydrochlorothiazide, Clopamide, Benzthiazide, Chlorthalidone, Metolazone, Xipamide,
Indapamide
4. Potassium Sparing Diuretics
– Aldosterone Antagonist
• Spironolactone, Canrenone, Eplerone
– Direct Acting (Inhibition of renal epithelial Na+ channel)
• Triamterene, Amiloride (more potent)
5. Osmotic Diuretic
– Mannitol, Isosorbide

18. Carbonic Anhydrase
Inhibitors
• Predominant location of Carbonic
anhydrase (CA) enzyme is the luminal
membrane of the PCT ,
• where it catalyzes the dehydration of
H2CO3. By blocking carbonic
anhydrase, inhibitors block NaHCO3
reabsorption
• and cause diuresis.
Acetazolamide
Methazolamide
Dorzolamide
Brinzolamide

19. Pharmacokinetics
• The carbonic anhydrase inhibitors are well absorbed after oral administration
• An increase in urine pH from the HCO3-diuresis is apparent within 30 minutes,
maximal at 2 hours, and persists for 12 hours after a single dose
Acetazolamide (250 mg tablets)
• ACEMOX®
• AZM ®
• EVAMOX ®
• SETACAR ®

20. Clinical Indications
Glaucoma
• Most common indication for use of carbonic anhydrase inhibitors
by direct antagonist activity on the ciliary epithelial carbonic anhydrase
Urinary Alkalinization
• Uric acid, cystine, and other weak acids are most easily reabsorbed from acidic
urine
Metabolic Alkalosis
• Acetazolamide can be useful in correcting the alkalosis

21. Contraindications:
- Low serum level of sodium & potassium.
- Renal & hepatic dysfunction.
- Adrenal insufficiency .
- Hypersensitivity to thiazide diuretics.
Side effects
• anorexia, polyuria, drowsiness, confusion, & acidosis.

22. Loop Diuretics
• It inhibits the reabsorption
of sodium and chloride in
the ascending loop of
Henle resulting in the
excretion of sodium,
chloride & to a lesser
degree potassium &
bicarbonate ions.
• Also it decrease the
reabsorption of sodium &
chloride &
• increase the excretion of
potassium in the distal
tubule.

23. • Uses:
• - Edema associated with:
• -Congestive heart failure
• -Liver cirrhosis.
• -Nephrotic syndrome.
• - Acute pulmonary
edema.
• - Hypertension.
Contraindications:
- hepatic coma associated
with electrolyte depletion.
- Anuria
- Sever renal diseases .
- Hypersensitivity.
Side effects:
- Dehydration, hypovlemia.
- Hypokalemia,
hyperglycemia,
Hyponatremia
- Nausea, vomiting,
diarrhea, anorexia.
- Tinnitus, blurring of
vision, headache, orthostatic
hypotension, rashes &
photosensitivity.
Note: Because the drug potentates the effects of muscle
relaxants, it is recommended to discontinue oral
medication 1 week before surgery & the I.V. 2 days before
surgery

25. Nursing considerations:
1- When high doses are required, administer lasix by infusion.
2- Store in a light-resistant container.
3- Monitor serum electrolytes & for signs of hypokalemia.
4- Observe patient for signs of dehydration & circulatory collapse .
5- Monitor pulse & blood pressure.
6- Advise the patient to take medication in the morning to avoid
interruption of sleep.
7- Discuss the need for a diet high in potassium.

26. Thiazides
• Thiazides inhibit Na-Cl
reabsorption from the
luminal side of epithelial
cells in the DCT by
blocking the Na+/Cl-
transporter (NCC).
• Less intracellular
Na+enhances
Na+/Ca++exchanger.

27. Clinical Indications:
hypertension
heart failure
nephrolithiasis (renal stones)
due to idiopathic hypercalciuria
diabetes insipidus
Side effects:
- Hypokalemia ( cardiac arrhythmias).
- Hyponatremia ( nausea, vomiting , lethargy ,
epigastric distress).
- Dry mouth, diarrhea , easy fatigability .
- Skin rashes , muscle cramps.
- Hyperglycemia.
Contra-indications:
Excessive use of any diuretic is dangerous in hepatic
cirrhosis, borderline renal failure, or heart failure

29. Spironolactone
Amiloride
Pharmacodynamics:
These diuretics prevent K+ secretion
by antagonizing the effects of
aldosterone at the late distal and
cortical collecting tubules.
Inhibition may occur by Direct
pharmacologic antagonism of
mineralocorticoid receptors
(spironolactone, eplerenone)
or
By inhibition of Na+ influx through
ion channels in the luminal membrane
(amiloride, triamterene).

30. Pharmacokinetics
• Substantial inactivation of spironolactone occurs in the liver.
• Overall, spironolactone has a rather slow onset of action, requiring several days
before full therapeutic effect is achieved.
• Eplerenone is a spironolactone analog with greater selectivity for the aldosterone
receptor.

31. Clinical Indications:
• Potassium-sparing diuretics are most useful in states of mineralocorticoid excess
or hyperaldosteronism.
• In the setting of enhanced mineralocorticoid secretion and excessive delivery of
Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics
of either type may be used in this setting to blunt the K+ secretory response.

32. Conttraindications:
- Acute renal insufficiency.
- Progressive renal failure.
- Patients receiving potassium supplement.
- Hyperkalemia.
Side effects:
- Hyperkalemia, hyponatremia ( dry mouth , lethargy, thirst & easy fatigability).
- Vomiting , diarrhea, cramps.
- Menstrual irregularities, gynecomastia, hirsutism & deeping of voice , impotence.
- Skis rashes & breast carcinoma .

33. Nursing consideration:
- protect drug from light.
- Food may increase absorption of aldactone.
- Obtain serum electrolyte levels prior to starting therapy.
- Record vital signs, intake & output & body weight.
- Advise the client to avoid food high in potassium.

34. The renin–angiotensin–
aldosterone system for
reflex maintenance of
blood pressure control.

35. Osmotic Diuretics
Pharmacodynamics
• The proximal tubule and descending limb of Henle's loop are freely permeable
to water. Any osmotically active agent that is filtered by the glomerulus but not
reabsorbed causes water to be retained in these segments and promotes a water
diuresis.
Pharmacokinetics
• Osmotic diuretics are poorly absorbed, which means that they must be given
parenterally. If administered orally, mannitol causes osmotic diarrhea. Mannitol is
not metabolized and is excreted by glomerular filtration within 30-60 minutes.

36. Clinical Indications
• To increase urine volume
• Reduction of intracranial and intraocular pressure
Toxicity:
• Extracellular Volume Expansion
• Dehydration, Hyperkalemia and Hypernatremia
• Hyponatremia(in patients with diminished renal function)

37. Nursing considerations:
1- Mannitol should not be added to other I.V. solutions nor should it be mixed with
other medications .
2- If blood is to be administered at the sometime , add 20 mEq of sodium chloride to
each liter of mannitol to prevent pseudoagglutination.
3- Monitor & record vital signs .
4- Observe for signs of electrolyte imbalance or dehydration.
5- Observe for signs, & symptoms of pulmonary edema (dyspnea,cyanosis, frothy
sputum).
“ Slow the rate & notify the physician”.

38. Pharmacodynamics
• Mechanism of water reabsorption across
the membranes of collecting duct cells.
Aquaporins 3 and 4 (AQP3, 4) are normally
present in the basolateral membranes,
• but the luminal water channel, AQP2, is
inserted only in the presence of ADH or
similar antidiuretic peptides acting on the
vasopressin V2 receptor.
Antidiuretic hormone(ADH) Agonists
• Vasopressinand desmopressinare used in
the treatment of central diabetes insipidus.

39. Antidiuretic hormone(ADH) Antagonists
Pharmacodynamics
• Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting
tubule.
Pharmacokinetics
• Conivaptan and demeclocycline are orally active. Conivaptan and demeclocycline
have half-lives of 5-10 hours.
Clinical Indications
• Syndrome of inappropriate ADH secretion
• Other causes of elevated antidiuretic hormone (ADH)

40. Toxicity
• Nephrogenic diabetes insipidus
• Renal failure
• Demeclocycline should be avoided in patients with liver disease and in children
younger than 12 years