Diuretics

DIURETIC S SUMOLLY ANAK DAVID

DEFINITION  Anything

that promotes the formation of urine by the kidney.

 Diuretics

are drugs that increase the excretion of solutes (mainly NaCl) and water.

 The

primary goal of diuretic therapy is to reduce ECF volume in order to lower blood pressure or rid the body of excess interstitial fluid (edema).

FUNCTION OF THE NEPHRONS 1. Proximal Tubules  Reabsorption

of :

Almost all filtered organic  Glucose, amino acid  Sodium chloride  NaHco3 (carbonic anhydrase dependent)  Highly permeable to H20 

 Secretion 

of:

H+ (via Na+/H+ exchanger)

2. Thin Descending Limb of Loop Of Henle  Highly

permeable to H20  Not permeable to NaCl, urea

3. Thin ascending Limb of Loop Of Henle  Permeable

to NaCl: passive reabsorption of NaCl  Impermeable to H20

4. Thick Ascending Limb of Loop Of Henle  permeable

to NaCl, K+,Mg2+, Ca2+  Not permeable to H20, urea

5. Distal Convuluted Tubule  Actively

transport NaCl  Impermeable to H20

6. Collecting Duct  Reabsorption

of:

Na+ (aldosterone dependent)  H2o (ADH dependent) 

 Secretion

H+  K+ 

of:

REGULATION OF RENAL FUNCTION BY SELECTED HORMONES

MAJOR DIURETIC CLASSES ♠ thiazide diuretics: ♪ hydrochlorothiazide, chlorothiazide ♠ loop diuretics: ♪ furosemide, torsemide, indapamide ♠ K+ sparing diuretics: ♪ amiloride, triamterene, ♪ spironolactone,eplerenone ♠ osmotic diuretics: ♪ mannitol, urea ♠ carbonic anhydrase inhibitors: ♪ acetazolamide

SITE OF ACTION OF DIURETICS

LOOP DIURETIC BUMETANIDE, INDAPAMIDE, FRUSEMIDE, TOLBUTAMIDE Mechanism of action: ♣ inhibit the Na+/ K+/ 2Cl- cotransport system in the thick ascending limb of Henle's loop . ♣ Inhibiting the kidney's ability to reabsorb sodium, thus enhancing the loss of sodium in the urine. And when sodium is lost in the urine, water goes with it. ♣ This type of diuretic is called a high-ceiling diuretic or a loop diuretic.

THERAPEUTIC EFFECT  Hypertension,

CHF (in the presence of renal insufficiency or for immediate effect). ARF, CRF, ascites, and nephrotic syndrome  Acute Pulmonary Edema, other edema conditions  To enhance urinary excretion of chemical toxins  Hypercalcemia (loop diuretic cause increase in Mg2+ & Ca2+ excretion)

ADVERSE EFFECT

PHARMACOKINETIC/ DYNAMIC Bumetanide (Bumex®)

Furosemide (Lasix®)

Torsemide (Demadex®)

1

40

20

85% (1)

60% (1.5 )

85% (1)

Met.; Renal (60 - 90 min)

Mainly Renal (1 hr; 9 hrs in ESRD)

Hepatic Met. (3 hrs; 7 hrs in cirrhosis)

Onset of action, min (po / iv)

40 / 5

40 / 5

40 / 10

Duration (po) (hrs)

4

6

6

0.5 - 2.0 mg qd -bid

20 - 80 mg qd - bid

10 - 40 mg qd - bid

Equivalent Dose, mg

Bioavailability (po/iv dose ratio) Elimination Route (half-life)

Usual Adult Oral Dosage

THIAZIDE DIURETIC HYDROCHLOROTHIAZIDE, CHLORTALIDONE, CHLOROTHIAZIDE Mechanism of action: ♣ Thiazide diuretics are secreted into the tubular fluid by proximal tubule cells. These agents act in the distal convoluted tubule and block a Na+, Cl- symporter that is associated with the luminal membrane. ♣ ↑ plasma urate concentration: -compete with the urate for secretion by the organic acid secretory system at the proximal tubules ♣ ↓ GFR ( direct effetc on renal vasculature) ♣ ↓ ca2+ secretion due to direct effect at the early portion of the distal tubules  hypercalcemia

THERAPEUTIC EFFECTS treat edema associated with a variety of pathophysiologic conditions including congestive heart failure, cirrhosis, renal insufficiency and the nephrotic syndrome,  therapy of hypertension  Decrease ca2+ excretion 

PHARMACOKINETIC Only 10% of chlorothiazide is absorbed  Efficacies of thiazides are the same but potencies are different 

Agent

Dose (mg/day)

CTZ

500-2000

HCTZ

25-200

Not metabolised  Eliminated by secretion at proximal tubules 

ADVERSE EFFECTS

POTASIUM SPARING DIURETICS ALDOSTERONE VS, NA+ CHANNEL VS Blocking the exchange of sodium for potassium, resulting in excretion of sodium and potassium but relatively little loss of potassium… ♣ Aldosterone antagonist: ◙ eg: spironolactone, eplerenone ◙ competitive inhibitor of aldosterone at the mineralocorticoid receptors ◙ act at the distal portion of distal tubule & the collecting duct ♣ Aldosterone effect: ↑ Na+, H2o reabsorption, ↑ K+ secretion & Ca2+ excretion

ADVERSE EFFECT

POTASSIUM SPARING DIURETIC

ADVERSE EFFECT

THERAPEUTIC USES 

Use in combination with loop & thiazide diuretic  Enhances

natriuresis caused by other diuretics  Prevents hypokalemia 

Block aldosterone  Tx

of primary hyperaldosteronism  Tx of edema of liver cirrhosis  Tx of hypertension  Tx for heart failure

CONTRAINDICATION/ DRUG INTERACTION Hypersensitivity  Anuria  Hyperkalemia  Pregnancy (spironolactone) 



Increased risk of hyperkalemia  Other

K sparing diuretic  Potassium supplements/ diets (bananas, nuts, salt)  ACEis/ ARBs

OSMOTIC DIURETICS MANNITOL, UREA 

Mechanism of action:  Freely filterable but non reabsorbable solutes 

↑ tubular osmolarity, causes water to be retained in the segment & promotes water diuresis

Act mainly at the proximal tubule to reduce the reabsorption of H20 & solutes including NaCl  Marked increased in delivery of Na+ & H2o out of the loop of Henle  ↑ osmolarity of extracellular fluid-extraction of H20 from intracellular compartments  Expansion of extracellular fluid volume  ↓ blood viscocity  Inhibition of renin release  ↑ in urinary excretion of all elctrolytes 

( Na+, K+, Ca2+, Mg2+, Cl-, HCO3, PO4)



Toxicity and Adverse Effects : Expansion

of extracellular volume Lead to pulmonary edema in pt with heart failure or pulmonary congestion Extraction of H2o from cell Increased ECFV & hyponatremia (Headache , nausea , vomiting) Loss of H2o in excess of electrolytes dehydration

THERAPEUTIC USES  Osmotic

diuretics maintain renal blood flow in patients with acute renal failure.  These agents can also be used to treat increases in intraocular pressure in glaucoma as well as reduce cerebral edema  ↑ elimination of toxic agents via the urine

CARBONIC ANHYDRASE INHIBITORS ACETAZOLAMIDE 





Mechanism of action: interfere with the reabsorption of HCO3 which is reabsorbed in the proximal tubule and requires the activity of carbonic anhydrase Toxicity and Adverse Effects: Metabolic acidosis as a result of HCO3- loss, sedation and paresthesia. Also, because of the structural similarity to sulfonamides, carbonic anhydrase inhibitors can cause bone marrow depression and allergic reactions Therapeutic uses: Carbonic anhydrase inhibitors are not used for their diuretic properties. Rather these agents are used to reduce intraocular pressure in the treatment of glaucoma. This is because these agents inhibit intraocular carbonic anhydrase and thus the formation of aqueous humor. Also used to treat epilepsy & motion sickness.

DOSAGE OF DIURETICS (ADULTS) Diuretics

Route

Dose

Furosemide

p.o, iv, im

20-80 mg/day divided q 6-12H

HCTZ

p.o

25-100mg/day in 1 or 2 doses

CTZ (deleted)

p.o

500mg-2gm in 1 or 2 doses

iv

100-500mg/day

Spironolactone p.o

25-400mg/day in 1-2 divided doses

Acetazolamide p.o

250mg od-qid

INTERACTIONS Interacting drugs Potential interactions ACEIs / K+ sparing ↑ hyperkalemia => cardiac problem diuretics (monitor serum potassium closely) Aminoglycosides/ Loop diuretics

Ototoxicity & nephrotoxicity (monitor serum creatinine)

Digoxin/ thiazide & Hypokalemia=> increased digoxin binding loop diuretics and toxicity (monitor K+ and cardiac function) B-blockers/ thiazide Hyperglycemia, hyperlipidemia, diuretics hyperuricemia Steroids/ thiazide & ↑ risk of hypokalemia loop diuretics (monitor serum potassium closely) CBZ/ thiazide diuretics

Increased risk of hyponatremia (monitor Na+)

REFERENCE Michael T. Piascik. 2002. The Pharmacodynamics of Diuretic Drugs.  Anderson et al. Handbook of Clinical Drug Data. 10th edition.  British National Formulary. 50th edition. 2005.  Lance et al. Drug information Handbook. 17th Edition. 2008-2009.  www. Uptodate.com  Nasr Anaizi. 1997-2002 the Drug Monitor  Brater, D. C. DIURETIC THERAPY. 339 (6) 387-395.  Katzung, B.G. 2004. basic & clinical pharmacology. 9th ed. Diuretic Agents. 