Vilasinee HirunpanichB.Pharm(Hon), M.Sc In Pharm (Pharmacology)

Outline of diuretic drugs

Basic knowledge in anatomy and physiology

Classification of diuretics

Classification of Diuretics

Loop Diuretics Thiazides Diuretics K+-sparing diuretics Osmotic DiureticsCarbonic anhydrase

inhibitors

1. Loop diuretics (high ceiling diuretics)

block Na+-K+-2Cl- cotransport in the thick ascending limb of the loop of Henle

high efficacy: 25% of filtrated solute is reabsorbed

Structure of loop diuretics

Mechanism of action of Loop of Henle

pharmacokinetic

Rapidly absorbedEliminate by renal secretionTorsemide (1h) is more rapidly than furosemide (Lasix) (2-3 h)

Duration 2-3 h (furosemide), 3-4 h(torsemide)

Adverse effects

1. Fluid and electrolytes imbalance

Hyponatremia, Hypokalemia and hypomagnesia

2. H+ loss metabolic alkalosis

3. Ototoxicityethacrynic most often

Adverse effects (cont)

4. Hyperuricemia5. Hyperglycemia6. Hypersensitivity to sulfonamide

skin rash7. Others: dehydration

Ototoxic drugs; aminoglycoside

digitalis glycosideNSAIDsprobenecidLitiumanticoagulant

Drug interaction

Clinical indications

1. Hypertension and CHF2. Acute pulmonary edema 3. Other edematous conditions

3. Mild hyperkalemia (simultaneous NaCl and water)

4. I-, Br- intoxication

2.Thiazide Diuretics

Thiazide diuretics

Sulfonamide and benzothiadiazide (thiazide) derivatives–Hydrochlorothiazide (HCTZ), indapamide, chlorthalidone, metolazone

Mechanism of action of thiazide diuretics

Mechanism of actions

Increase Na+, Cl-, K+, Mg2+ in urine….water retention

Some drug has vasodilator effect such as indapamide (Natrilix )

Pharmacokinetic

Chlorothiazide is less lipid soluble and must given in large dose

Indapamide is excreted primarily by the billiary system

Adverse effects

1.Fluid and electrolytes imbalanceHypokalemia Hyponatremia

Hypercalcemia2. hyperglycemia due toimpaired pancreatic release of

insulin3.hyperlipidemia

4.allergic reaction

5. Other: weakness, fatigability

Drug interactionDecrease the effect of

anticoagulanturicosuric

agentsulfonylureainsulin

Increase the effect of

digitalis glycoside

lithium

Decrease the effect of thiazideNSAIDsbile acid sequesteringprobencid

Clinical indications

Hypertension, CHF

hepatic cirrhosis

nephrolithiasis due to idiopathic hypercalcinuria

nephrogenic diabetes insipidus

Br- intoxicity

3. K+-sparing diuretics

K+ sparing diuretics

1. Aldosterone antagonists

2. Inhibitor of renal epithelium Na+ channel

Aldosterone antagonist

Structure similar to aldosterone hormone

Ex.spironolactone (synthesis

steriod), eplerenone (spironolactone

analog)

spironolactonespecific antagonist

prevent protein synthesis that required for Na+ and K+ transport

increase Na+ excretion and preserve of K+

Potentcy is low and depend on aldosterone level

pharmacokinetic

SpironolactoneOnset and duration of action are

determined by the kinetic of aldosterone response in target tissue.

Slow onset (48 hr)Canrenone is the active

metabolized which has very long t12.than parent drug.

Adverse effects

hyperkalemia…..life threateningEndocrine effects

-gynecomastia-hirsutism-deepening voice- decrease libido

Pts using salicylate because inhibiting canrenone

K+

administration

coadministration with thiazide or loop diuretic for edema (additive effect)

hyperaldosteronism

contraindication

Clinical use

2. Inhibitor of renal epithelium Na+ channel

Triamtereneamiloride

late distal tubules and collecting ducts

block Na+ channel in the luminal membrane

increase NaCl excretion and decrease K+ excretion

Mechanism of action of K+-sparing diuretic

Adverse effectanemia: triamterene, folic

antagonistkidney stone (triamterene is

poorly soluble)ARF (acute renal failure)(combination of triamterene and

indomethacin has been reported )

life-threatening:

hyperkalemia

contraindication

Renal failureother K+ sparing diureticACEIK+ supplementNSIADs

Co administration with other diuretic (additive effect)

prevent depletion of intracellular K+ store

Clinical Use

Osmotic diuretics

Properties 1. Freely filtered at the glomerulus2. No reabsorption at the renal tubule3. No pharmacological effectsGlycerine, Isosorbide, Mannitol,

Urea site of action: Proximal tubule and

descending limb of Henle’s loop

Structure of osmotic diuretics

Mechanism of action

Limit water reabsorption

act as increase urine volume.

increase renal blood flow

Pharmacokinetic

Poorly absorbed so they must be given parenterally

Mannitol is excreted by glomerular filtration within 30-60 min

Adverse effects

1. Extracellular volume expansion

Rapidly distributed in the extracellular compartment and extract water from the intracellular compartment

2. Dehydration 3. Nausea, vomiting, headache

Clinical Indications

1. To increase urine volume 2. Reduction of intracranial and

intraocular pressureextract water from the eye and brainGlycerine: control intraocular

pressure, pre/post operative ocular surgery

Mannitol, urea: reduce cerebral edema before/after neuro-surgery

5. Carbonic anhydrase inhibitors

Inhibit carbonic anhydrase enzyme at proximal tubule

SO2NH2 (sulfonamide) group is essential for activity.

Acetazolamide (Diamox), dichlorophenamide, ethoxalamide, methazolamide

Structure of carbonic anhydrase inhibitors

Mechanism of action of carbonic anhydrase inhibitors

1. increase the excretion of HCO3-

(Urine alkalinization, pH 8)Increase Na+, K+, secretion2. Metabolic acidosis3. eye; decrease formation of

aqueous humor4. Paresthesia, Drowsiness,

Somnolence

Pharmacokinetic

Well absorbed after oral administration

The effect of increased of HCO3-

is apparent within 30 min.Maximal effect within 2 hPersist for 12 h after single doseExcrete by tubular secretion

Adverse effects

1. Hypersensitivitysulfonamide derivative (fever, rashes,

bone marrow suppression)2. Renal stoneCa2+ salt are relatively insoluble at

alkaline pH.3. Metabolic acidosis and urine

alkalinization4. Renal potassium wasting 5. Others: drowsiness, paresthesia

Clinical indications1. Glaucoma (decrease intraocular

pressure)Dorzolamide, brinzolamide

(topically use)2. Urinary alkalinizationincrease the secretion of uric

acid, weak acid drugs(aspirin)3. Metabolic acidosis4. Acute mountain sickness (24 h

before ascent)

Loop diuretic& thiazide (different position)

K+sparing diuretic& loop diuretic or thiazide (decrease ADR)

Moduretic (amiloride + HCTZ)Dyazide (triamterene+HCTZ)

Diuretic combination