Diuretics April 2025 and it's various classes

Diuretics
Prof. Baba Sulemana Mohammed
Department of Pharmacology & Toxicology
School of Pharmacy & Pharmaceutical Sciences
University for Development Studies, Tamale

Physiology of the Renal System
► The nephron is the functional unit of the kidney and
regulates fluid and electrolytes.
Urine formation:
1. Glomerular filtration rate = 180L/day
2. Tubular re-absorption (around 98% of filtrate)
3. Tubular secretion
4. Daily urine output = 1.5 L/day
• How may we increase urine output?
↑ Glomerular filtration Vs ↓Tubular reabsorption (the most
important clinically)
If you increase the glomerular filtration  increase tubular
reabsorption (so you can not use glomerular filtration)

• Diuretics mostly exert their effect directly on the
kidneys leading to electrolyte excretion and
consequently to osmotic excretion of water, which
increases the 24-hr urine volume (ie. more than the
1.5 L/day) .
• Uses of Diuretics
1. To maintain urine volume ( e.g.: renal failure)
2. To mobilize edema fluid (e.g.: heart failure, liver
failure, nephrotic syndrome)
3. To control high blood pressure.

►Percentage of reabsorption in each segment:
– Proximal convoluted tubule - 60-70%
– Thick portion of the ascending limb of the loop of
Henle - 25%
– Distal convoluted tubule - 5-10%
– Cortical collecting tubule - 5% (Aldosterone and
ADH)

Classification of Diuretics
► Is best done according to their site of action in the nephron
1) Diuretics that inhibit transport in the Proximal
Convoluted Tubule (Osmotic diuretics, Carbonic Anhydrase
Inhibitors)
2) Diuretics that inhibit transport in the Medullary
Ascending Limb of the Loop of Henle (Loop diuretics)
3) Diuretics that inhibit transport in the Distal Convoluted
Tubule(Thiazides : Indapamide , Metolazone)
4) Diuretics that inhibit transport in the Cortical Collecting
Tubule (Potassium sparing diuretics)

MANNITOL
• Osmotic Diuretics, M

A. Diuretics that inhibit transport in the Proximal
Convoluted Tubule
1. Osmotic Diuretics (e.g.: Mannitol – sugar alcohol/ polysaccha)
Mechanism of action:
- are hydrophilic compounds that are easily filtered through the glomerulus
with little re-absorption and thus increase urinary output via osmosis.
Given parenterally. If given orally they will cause osmotic diarrhea.
Indications:
- to decrease intracranial pressure in neurological condition
- to decrease intraocular pressure in acute glaucoma
- to maintain high urine flow in acute renal failure during shock
Adverse Reactions:
- Early extracellular water expansion may complicate heart failure and
produce pulmonary edema
- Dehydration
- Hypernatremia due to loss more of water than sodium (increase in concentration)
Contraindication:
1- heart failure
2- chronic renal failure

2. Carbonic Anhydrase Inhibitors (Acetazolamide (Oral);
Dorzolamide (Ocular); Brinzolamide (Ocular)
Mechanism of action: Simply inhibit reabsorption of sodium and
bicarbonate.
•Inhibition of HCO3 reabsorption  metabolic acidosis.
•HCO3 depletion  enhance reabsorp of Na and Cl away from the proximal 
hyperchloremea.

Clinical uses
1. As a diuretic (weak) : because depletion of HCO-
3  prevents
reabsorption of Na+
and Cl-
2. In glaucoma :
• The ciliary process absorbs HCO-
3 from the blood.
• ↑HCO-
3  ↑aqueous humor (H20 formation).
• Carbonic anhydrase inhibitors prevent formation of H2O from HCO-
3
3. Urinary alkalinization: to increase renal excretion of weak acids
e.g. cystine and uric acid.
4. In metabolic alkalosis (by causing acidosis).
5. Epilepsy : because acidosis results in ↓seizures.
6. Acute mountain sickness.
7. Benign intracranial hypertension
Dorzolamide and brinzolamide are mixed with β
blockers (Timolol) to treat glaucoma (as topical
drops)

Acetazolamide
►Side Effects:
– Sedation and drowsiness;
– Hypersensitivity reaction (because it contains
sulphur)
– Acidosis (because of decreased absorption of
HCO3
-
)
– Renal stone (because of alkaline urine eg calcium
phosphate, calcium oxalate salt)
– Hyperchloremia, hyponatremia and hypokalemia

B. Diuretics Acting on the Thick Ascending Loop of
Henle (loop diuretics) High ceiling (most efficacious)
► E.g. Furosemide (LasixR
), Torsemide, Bumetanide
Ethacrynic acid.
Mechanism of Action:
1. Simply inhibit the coupled Na/K/2Cl co-transporter in the
loop of Henle. Also, they have potent pulmonary
vasodilating effects (via prostaglandins).
2. They eliminate more water than Na.
3. They induce the synthesis of prostaglandins in kidney
( NSAIDs interfere with this action).
They are the best diuretics for 2 reasons:
1- they act on thick ascending limb which has large capacity of
reabsorption.
2- action of these drugs is not limited by acidosis

In loop diuretics and thiazides
:
The body senses the loss of Na
in the tubule.
This leads to compensatory
mechanism (the body will try
to reabsorb Na as much as
possible)
So the body will
increase synthesis of
aldosterone leading to :
1- increase Na
absorption
2- hypokalemia
3- alkalosis

Side effects:
– Ototoxicity (the hair cells in the ear contain the Na/K/2Cl co-transporter)
– Hypokalemic metabolic alkalosis (lost of H+
with K+
); hypocalcemia and
hypomagnesemia; hypochloremia;
– Hypovolemia;
– Hyperuricemia (the drugs are secreted in proximal convoluted tubule and
they compete with uric acid for the protein transporter)
– Hypersensitivity reactions (contain sulfur)
Therapeutic Uses:
a) Oedema (in heart failure, liver cirrhosis, nephrotic syndrome)
b) Acute renal failure
c) Hyperkalemia
d) Hypercalcemia

Contraindications
a. Exaggerated response leading to adverse reactions-
hypersensitivity
b. Compromised kidney function- insufficient delivery to site
of action
 agents act on lumen, decreased kidney function decreases access
of agent to renal tubule, due to decreased GFR and/or renal
blood flow
c. Cardiac glycoside sensitivity changes with K+
 decreased Plasma K+ increases sensitivity to cardiac glycosides
(Digitalis)
d. Exacerbates existing low volume or salt conditions

C. Diuretics that Inhibit Transport in the Distal Convoluted
Tubule (e.g.: Thiazides and Thiazide-like substances
(Indapamide; Metolazone)
Mechanism of action:
– Inhibit Na+
transport via inhibition of Na+
/Cl-
co-
transporter.
– They have natriuretic action (eliminate sodium)
Side effects:
– No ototoxicity;
– Hypercalcemia due to ↑PTH,
– More hyponatremia; hypokalemia
– Hyperglycemia (due to both impaired pancreatic release of insulin and
diminished utilization of glucose)
– Hyperlipidemia
– Hyperurecemia

Therapeutic uses:
a) Hypertension - Drugs of Choice (eg Hydrochlorthiazide; Bendrofluazide,
Indapamide)
b) Refractory oedema (doesn’t respond well to ordinary treatment)
Eg. Metolazone combined with the loop diuretics
c) Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria
d) Hypocalcaemia.
e) Nephrogenic Diabetes Insipidus.
1. Thiazides will cause mild hypovolemia  more proximal reabsorption and less
water to aldosterone sites,
2. Also they express more transporters at the distal tubule
 Indapamide is a potent vasodilator

D. Diuretics that inhibit transport in the Cortical Collecting Tubule (potassium sparing diuretics).
Classification of Potassium Sparing Diuretics:
1. Directly acting on mineralocorticoid receptors
(Aldosterone Antagonists eg spironolactone
(AldactoneR
))
– Normally Aldosterone increases synthesis of Na
channel proteins and Na+
/ K+
-ATPases
– Spironolactone (a synthetic steroid) and its
metabolite, canrenone
• Competitively antagonise Aldosterone
• Full diuretic effect occurs after continuous administration
(a delayed onset of action) (Why? )

Classification of Potassium Sparing Diuretics contd.
2. Indirect acting on mineralocorticoid
receptor (via inhibition of Na+
influx through
ENaC) (e.g. Amiloride, Triamterene)
– Act on cortical collecting tubule cells (from
luminal membrane)
– Inhibit Na+
entry into the cell whereby K+
secretion
is diminished.

Diuretics April 2025 and it's various classes

K+
sparing Diuretics:
Therapeutic uses:
– In states of primary aldosteronism (e.g. Conn’s
syndrome, ectopic ACTH production), of secondary
aldosteronism (e.g. heart failure, hepatic cirrhosis,
nephrotic syndrome)
– To overcome the hypokalemic action of diuretics
– Hirsutism (the condensation and elongation of
female facial hair) because it is an antiandrogenic
drug.

Side effects:
1. Hyperkalemia (some times it’s useful otherwise it’s an adverse
effect).
2. Hyperchloremic metabolic acidosis
3. Antiandrognic effects (e.g. gynecomastia: breast enlargement in
males, impotence) by spironolactone.
4. Triametrene causes kidney stones.
►Diuretics Combination preparations
these are anti-hypertensive drugs:
DyazideR
= Triametrene 50 mg + Hydrochlorothiazide HCT 25 mg
AldactazideR
= Spironolactone 25 mg + HCT 25 mg
ModureticR
= Amiloride 5 mg + HCT 50 mg
► Note : HCT to decrease hypertension and K sparing diuretics to
overcome the hypokalemic effect of HCT
► Contraindications: Oral K administration and using of ACE inhibitors

Vasopressin (ADH)
• A nonapeptide from the pituitary, promotes
reabsorption of water
– Mediated by V2 receptor subtype
– ADH binds to V2 to cause fusion of vesicles
(contain type 2 aquaporins) with luminal cell
membrane = influx of water

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Editor's Notes