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Diuretics
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PH 1.24 Diuretics

 1.24.1. Explain the physiology of urine formation.

 1.24.2. Classify diuretics based on the efficacy and site of
action.
 1.24.3. Explain mechanism of action, uses, adverse effects,
drug interactions and contraindications of thiazide diuretics.
 1.24.4. Explain mechanism of action, uses, adverse effects and
drug interactions of loop diuretics.
 1.24.5. Explain mechanism of action, uses and adverse effects
of carbonic anhydrase inhibitors.
 1.24.6. Explain mechanism of action, uses, and adverse effects
of potassium sparing diuretics.
 1.24.7. Explain mechanism of action, uses, adverse effects and
contraindication of osmotic diuretics.
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Introduction

“Diuretic” - an agent that increases urine volume

“Natriuretic” - causes an increase in renal sodium (Na+)excretion

Diuretics
Drugs that increase the excretion of sodium and water
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 Normal - 180L/day
filtered
 99% of glomerular
filtrate is
reabsorbed
 1.5 L urine is
produced in 24
hours
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Relative actions of diuretics

Sodium absorption at various sites

PCT - 65 to 70%
Asc LH - 20-25%
DT – 8 to 9%
CD – 1-2%
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Carbonic anhydrase
inhibitors
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-NaHCO3 reabsorption
in PT is dependent on
Carbonic anhydrase (CA)
- NaCl reabsorption
Most relevant to diuretic action: 9
NaHCO3 and NaCl
Carbonic
anhydrase
inhibitors

Block NaHCO3 reabsorption

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Carbonic anhydrase inhibitors

Acetazolamide
Carbonic anhydrase plays a key role in NaHCO3 reabsorption
• Inhibition of the enzyme
• Na+-H+ exchange is prevented
• Na+ excreted along with bicarbonate
• Excretion of Na+, K+, HCO3- and water
• Well absorbed orally
• Excretion is by secretion in PT- dose reduced in renal failure
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Uses

• Not commonly used to treat edema

• Glaucoma – decreases aqueous humour formation and reduces

intraocular pressure

• Acute mountain sickness - symptomatic relief & prophylaxis

• To alkalinize the urine – enhance renal excretion of acidic drugs

• As adjuvant in epilepsy
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Adverse effects
• Metabolic acidosis
• Hypokalemia
• Headache, drowsiness, tingling and numbness in hands and feet
• Hypersensitivity reactions
• Contraindicated in cirrhotics - may induce or worsen hepatic
encephalopathy
• Carbonic anhydrase inhibitors may accumulate in patients with
renal insufficiency
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Loop diuretics
 Loop 14
diuretics

Block Na + /K + /2Cl -
cotransporter
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Loop diuretics(High ceiling diuretics)

Furosemide, Bumetanide, Torasemide

Large amount of NaCl is reabsorbed in this segment – so loop

diuretics are highly efficacious

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Pharmacokinetics

• Rapidly absorbed orally

• Eliminated by glomerular filtration and tubular secretion

• Duration – 3-6 hours Onset of action

IV 2-5 min
• Severe CHF – BA markedly reduced
IM 10-20 min
• Effective even in relatively severe renal failure Oral 20-40 min
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Loop diuretics(High ceiling diuretics)

 Have weak carbonic anhydrase inhibitory action

 Decrease renal excretion of uric acid
 Acute changes in renal & systemic hemodynamics

PG’s

LVF
Pulmonary
edema
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Uses

1. Edema of cardiac, hepatic or renal origin

2. Acute pulmonary edema – IV Furosemide

• increase systemic venous capacitance and thereby decrease

left ventricular filling pressure

• Relieves pulmonary congestion , relieves the load on the heart

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Uses

3. Cerebral edema – combined with osmotic diuretics

4. Hypertension with renal impairment, CHF, resistant cases,

hypertensive emergencies

5. Along with blood transfusion

6. Hypercalcaemia of malignancy

• Medical emergency

• I.V Furosemide with normal saline

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Adverse effects

• Hypokalemia – fatigue, muscular cramps, cardiac arrhythmias

• High dietary K+ intake
• Supplement of KCl
• Concurrent use of K+ sparing diuretic
• Acute saline depletion –haemoconcentration –risk of peripheral
venous thrombosis
• Dilutional hyponatremia- CHF
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Adverse effects
• Hypocalcemia, hypomagnesemia (arrhythmias)

• Loss of K+, H+ – hypokalemic metabolic alkalosis

• Hyperuricemia

• Hyperglycemia, hyperlipidemia

• Ototoxicity –alterations in the electrolyte composition of endolymph

• Skin rashes, photosensitivity

• Nausea, vomiting, diarrhoea, Giddiness, paresthesias

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Adverse effects

Caution :

Hepatic cirrhosis- precipitate mental disturbances & hepatic coma

Overzealous use of any diuretic is dangerous in hepatic cirrhosis,

borderline renal failure, or heart failure.
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Drug interactions

• Enhance digitalis toxicity

Diuretic induced • ↑ risk of polymorphic ventricular
Hypokalemia tachycardia
• Reduce sulfonylurea action

• competitively inhibits tubular

Probenecid secretion of diuretics
• Diuretics diminish uricosuric action
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Drug interactions

• inhibit PG synthesis – no intrarenal

hemodynamic changes – diminish
NSAIDs the action of diuretics

• Enhance ototoxicity and

nephrotoxicity of loop diuretics
Aminoglycosides

Serum lithium level rises due to enhanced reabsorption of Li+ in PT

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Thiazide diuretics
 Thiazide
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diuretics

Na+ and Cl– cotransporter

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Thiazide diuretics

• Hydrochlorothiazide, indapamide, chlorthalidone

• Inhibit Na+-Cl- symport in early distal tubule
• Moderately efficacious
• Tend to reduce GFR – not effective in pt with low GFR
• Decrease Ca2+ excretion and increase Mg2+ excretion
• Decrease urea excretion
• Extrarenal action – reduction in BP, decreased insulin release
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Pharmacokinetics

• Administered orally

• Duration of action varies

• All thiazides are secreted by the organic acid secretory system in

the proximal tubule and compete with the secretion of uric acid
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Uses
1. Hypertension

• Used in mild to moderate HTN

2. Edema

• Mild to moderate (maintenance therapy)

• More effective in cardiac edema

3. Nephrogenic Diabetes insipidus

4. Nephrolithiasis due to idiopathic hypercalciuria

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Adverse effects

• Hypokalemia

• Hyperuricemia

• Hyponatremia, Hypercalcemia

• Hyperglycemia, Hyperlipidemia

• Metabolic alkalosis

• Weakness, fatigability, and paresthesias

• Allergic reactions – photosensitivity, hemolytic anemia

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Potassium sparing
diuretics
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Epithelial Na + Aldosterone ??
channel

Regulates Na +
absorption &
K + secretion
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Inhibitors of
renal
epithelial
Aldosterone
Na +
antagonist
Channel

 Collecting tubule is the most important site of K + secretion by the

kidney
 The site at which virtually all diuretic-induced changes in K + balance
occur
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Potassium sparing diuretics

• Aldosterone antagonists – Spironolactone, Eplerenone

• Inhibitors of renal epithelial Na channels – Amiloride, Triamterene

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Aldosterone antagonist
• Mineralocorticoids: Bind to specific mineralocorticoid receptors

• Cause retention of salt and water

• ⇪excretion of K+ and H+

• Mineralocorticoid receptor (MR) antagonists

• Inhibition of Na+ retaining actions of aldosterone & se K+

secreting stimulation

• Mild saluretic effect

• Antagonize K+ loss induced by other diuretics

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Uses

1. Used in combination with thiazide/loop diuretics to treat edema and

hypertension

• Prevent hypokalemia

• Increased mobilization of edema fluid

2. Primary hyperaldosteronism (Conn’s syndrome), Oedematous

conditions associated with secondary hyperaldosteronism

3. Congestive heart failure (Eplerenone)

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Adverse effects

• Hyperkalemia( risk increased in renal insufficiency)

• Hormonal side effects- gynaecomastia, menstrual irregularities,

erectile dysfunction

• Metabolic acidosis

• Drowsiness , ataxia, mental confusion , epigastric distress

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Drug interactions

↑ hyperkalemia • If combined with K+ supplements &

Angiotensin Converting Enzyme
Inhibitors

↑ eplerenone conc • CYP-3A4 inhibitors( e.g:ketoconazole)

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Inhibitors of renal epithelial
Na + channels.
• Inhibit luminal Na+ channels at distal part of distal tubule &
collecting duct  inhibiting Na+ reabsorption & K+ excretion.

• Adverse effects- Hyperkalemia (risk increased in renal

insufficiency)

• D/I:

• K+ supplements, ACEIs,/ARBs → dangerous hyperkalemia

• Use : with Thiazides & loop diuretics treats hypertension, as they

check hypokalemia side effects of these diuretics.
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Inhibitors of renal epithelial
Na + channels.

Amiloride –
• Cystic fibrosis (aerosolized)
• Lithium induced nephrogenic diabetes insipidus
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Osmotic diuretics
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Osmotic diuretics

• Freely filterable by the glomerulus

• No tubular reabsorption
• Pharmacologically inert
• Increase the osmolarity of the tubular
fluid
• Inhibit passive reabsorption of water
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Mechanism of action

 Retains fluid isoosmotically in PT and

descending LH dilutes luminal fluid and
prevents NaCl reabsorption
 Inhibits transport processes in ascending LH
 Expand ECF fluid volume increases GFR and
inhibits renin release
 Increases renal blood flowcorticomedullary
osmotic gradient is dissipatedpassive salt
absorption reduced.
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Mannitol
 Not absorbed orally – osmotic diarrhoea
 Given parenterally – not metabolized
 Expands ECF volume – increases GFR & renal
blood flow – decreases medullary tonicity
 Osmotic effect in the tubules
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• Acute impending renal failure (shock, severe trauma,

cardiovascular surgery, massive hemolysis) – to
maintain GFR and urine flow
• Acute attack of glaucoma
• Pre and postoperatively in ocular surgery
• Reduce cerebral edema and brain mass before and
after neurosurgery.
• Counteract low osmolarity of plasma due to rapid
hemodialysis
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Headache, nausea, vomiting

Contraindications
 Acute renal failure - Extracellular fluid volume expansion
can cause pulmonary edema or heart failure
 Anuria, Acute tubular necrosis
 Cerebral hemorrhage
 Acute LVF, Pulmonary edema
Other osmotic diuretics
 Isosorbide, Glycerol – orally effective
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Classification of diuretics

High efficacy diuretics (High ceiling diuretics, Loop diuretics)

 Furosemide, Bumetanide, Torasemide

Medium efficacy diuretics

 Thiazides – Hydrochlorothiazide, Benzthiazide, Hydroflumethiazide

 Thiazide like diuretics – chlorthalidone, indapamide, metolazone

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Classification of diuretics

Weak or adjunctive diuretics

 Potassium sparing diuretics –

 Aldosterone anatagonist -Spironolactone, Eplerenone

 Inhibitors of renal epithelial Na + - Amiloride, Triamterene

 Carbonic anhydrase inhibitors – Acetazolamide

 Osmotic diuretics – Mannitol, glycerol

 High efficacy • Inhibitors of Na+-K+-2Cl- 51
cotransport

Medium efficacy • Inhibitors of Na+-Cl- symport

• Carbonic anhydrase
inhibitors
• Inhibitors of renal epithelial
Low efficacy Na+ channels
• Aldosterone antagonist
• Osmotic diuretics
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Further reading

 Diuretic braking/ resistance

 Positive and negative free water
clearance
 Which thiazide can be given in case of low
GFR?
 Combination of diuretics
 Aquaretic
 Thiazides in Diabetes insipidus
 Individual drugs
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Questions

 Labelled diagrammatic representation of

nephron and indicate the site of action of
different groups of diuretics.
 Classification of diuretics.
 Mech of action, uses and adverse effect of
any group.
 Mannitol –short note.
 As a part of other chapters –CHF,
Hypertension, glaucoma.