1. Introduction to Renal Pharmacology
Diuresis. Conceptual image of the effect of diuretics on the kidney. A diurectic is any drug that encourages the excretion of urine. Common diuretics include caffeine and alcohol. Medically, diuretics can be used to treat heart failure, cirrhosis of the liver and hypertension (high blood pressure). The diuretic alleviates the symptoms of these disease by causing sodium and water loss through urine.
Dr. Kaukab Azim

2. Drug List Carbonic Anhydrase Inhibitors
Thiazide Diuretics and Congeners
Loop Diuretics
Acetazolamide
Dorzolamide
Hydrochlorthiazide
Indapamide
Furosemide
Ethcrynic Acid
Potassium Sparing Diuretics
Osmotic Diuretics
ADH Antagonists
Triamterene
Amiloride
Spironolactone
Mannitol
Conivaptan
Tolvaptan

3. In the next few slides we will revisit some useful physiological concepts
For each nephron unit, the glomerular filtration rate (GFR) is a function of the: a) hydrostatic pressure in the glomerulus b) hydrostatic pressure in the proximal tubule c) mean oncotic pressure in the glomerulus d) mean oncotic pressure in the proximal tubule (this is negligible as no proteins are filtered into nephron under normal physiological conditions) e) ultrafiltration coefficient (Kf)

4. The proximal Tubule
About 65% of the solutes are reabsorbed by the proximal tubule(since this tubule is highly permeable to water the reabsorption is isotonic)
Na+ is transported across the proximal tubule by:
Symports that reabsorb Na+ with other organic nutrients like amino acids and glucose.
Antiports that reabsorb Na+ while secreting H+ into the tubular lumen.
The energy for these secondary active transport systems is furnished by the Na+/K+ pump in the basolateral membrane.

5. An organic acid is an organic compound with acidic properties
An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group -COOH. Sulfonic acids, containing the group -SO2OH, are relatively stronger acids. The relative stability of the conjugate base of the acid determines its acidity. Other groups can also confer acidity, usually weakly: -OH, -SH, the enol group, and the phenol group. In biological systems, organic compounds containing only these groups are not generally referred to as organic acids.
A few common examples include:
Lactic acid
Acetic acid, formic acid, citric acid, oxalic acid, uric acid

6. The loop of Henle
The thin descending limb is permeable to water, yet its permeability to NaCl and other solutes is low.
The thin and thick ascending limbs are impermeable to water and urea.
The thick ascending limb (TAL) actively reabsorbs NaCl through a Na+/K+/2Cl symport (about 25% of the Na+ filtered load is reabsorbed) so diluting the tubular fluid.
This symport is capable of establishing about 200 milliosmole concentration gradient between the tubular lumen and the interstitial fluid and so is the most important cause of the high renal medullary osmolarity.

7. Figure and text from Guyton
The thick ascending limb also has a sodiumhydrogen
counter-transport mechanism in its luminal
cell membrane that mediates sodium reabsorption and
hydrogen secretion in this segment.
The thick segment of the ascending loop of Henle is
virtually impermeable to water. Therefore, most of the
water delivered to this segment remains in the tubule,
despite reabsorption of large amounts of solute. The
tubular fluid in the ascending limb becomes very dilute
as it flows toward the distal tubule, a feature that is
important in allowing the kidneys to dilute or concentrate
the urine under different conditions, as we
discuss much more fully in Chapter 28.

8. The Macula Densa
TAL makes contact with the afferent and efferent arterioles via macula densa which senses the concentration of Na+ in the tubule.
If the amount of sodium is increased macula densa stimulates the formation and release of ATP (and/or adenosine) which causes contraction of mesangial cells and afferent arterioles through purinergic receptor activation, so decreasing GFR (tubuloglomerular feedback)
If the amount of sodium is decreased macula densa stimulates renin release which increases the synthesis of angiotensin II. Angiotensin II constricts the efferent arterioles more than the afferent, so increasing GFR.
[these mechanisms are specifically directed toward stabilizing GFR]

9. The Distal Tubule The early distal tubule
This tubule also actively reabsorbs NaCl through a Na+/Cl- symport (about 5-10% of the Na+ filtered load is reabsorbed) but is impermeable to water.
The TAL and the early distal tubule are parts of the ‘diluting segment’ of the nephron which regulates the diluting ability of the kidney.
The late distal tubule and the cortical collecting tubule
Water permeability here depends on ADH. With high levels of ADH these tubules are highly permeable to water thus causing large amount of water to be reabsorbed into the hypertonic interstitium.

11. Principal and Intercalated Cells
Luminal membranes of principal cells of these nephron segments have Na+ channels that allow Na+ entry down the electrochemical gradient created by the Na+/K+ pump (normally 2-3% of filtered Na+ load is reabsorbed through these channels). The permeability of these channels is modulated by aldosterone.
The intercalated cells of these nephron segments avidly secrete H+ by an active H+-ATPase pump. This pump plays a key role in the acid-base regulation of body fluids.

12. The Medullary Collecting Duct
Water reabsorption here depends on:
ADH
The osmolarity of the medullary interstitium established by the countercurrent mechanism.
This high osmolarity contributes to the high concentrating ability of the kidney.

13. Name the hormones secreted by the kidneys?
3 of them
So what will you treat in chronic renal failure?
Renin
1,25, dihydroxy Vit D (Calcium, phosphate absorption from the gut)
Erythropoeitin
Urea, uric acid and creatinine are not themselves toxic but are markers of other toxic substances
Water and electrolyte balance
Acid base balance.
What do western people eat? A lot of red meat. The get fixed acids e.g. HCl and sulphuric acid
What will you eliminate from the diet of patients with renal failure?
The proximal convoluted tuble cells are the most metabolically active cells. All the proximal and distal tubles lie in the cortex. The cortex is the most metabolically active part of the kidneys.
The cortex extracts most of the oxygen, and even though the medullary regions consume less oxygen, they are more susceptible to ischemia.
The organic secretory system that is the middle third of proximal tubule is saturable. It secretes uric acid and antibiotics, and also diuretics. That is why we get hyperurecemia when we use diuretics because they compete with uric acid for secretion into tubular lumen. Probenecid interferes with the secretion of penicillins. There is also an organic base secretory system.
Are there any waste products that are going to accumulate in the body? Name 2 that you will clinically measure?

14. Clinical Condition in which Diuretics are used
Edematous States
Non-edematous States
Hypertension
Hypercalcemia
Diabetes insipidus
Heart Failure
Hepatic Ascites
Increased portal pressure
hypoalbuminemia
Secondary Aldosteronism
Nephrotic Syndrome
Premenstrual edema
From Lippincott
Heart Failure
Hepatic Ascites
Increased portal pressure and hypoalbuminemia
Secondary Aldosteronism
Nephrotic Syndrome
Premenstrual edema

15. Site and Mechanism of Action of Diuretics
Name
Site of Action
Mechanism of Action
Relative efficacy
Carbonic Anhydrase Inhibitor
Proximal tubule
Inhibit NaHCO3 reabsorption 2
Loop Diuretics
Thick ascending limb of the loop of Henle
Block the Na+K+/2Cl- symporter 15
Thiazide Diuretics
Early distal tubule
Block the Na+/Cl- symporter 5
Potassium Sparing Diuretics
Late distal tubule and cortical collecting duct
Block Na+ channels 1
Osmotic Diuretics
Thin descending limb of the loop of Henle and proximal tubule
Increase osmolarity of tubular fluid 6

16. Carbonic Anhydrase Inhibitors
Chemistry
- Acetazolamide, dorzolamide (All compounds are sulfonamides).
Mechanism of action
Inhibition of membrane-bound carbonic anhydrase (CA) in the cells of proximal tubule which leads to blockade of the reaction H2CO3 = H2O + CO2 that normally occurs in the proximal tubule lumen
Inhibition of cytoplasmic CA in the cells of proximal tubule which leads to blockade of the reaction: H2 O + CO2 = H2 CO3 that normally occurs in the cytoplasm
The final effect is a nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (but NaHCO3 reabsorption by mechanisms independent from carbonic anhydrase still occur in other parts of the nephron).

19. Acetazolamide Decreased Urinary secretion Increased Urinary secretionK+
Renal effects
- Increased renal excretion of: Na+, K+, HCO3-
- Decreased renal excretion of: NH4+, H+.
- Urine pH: alkaline.
- Acid-base balance: metabolic acidosis (acidosis is associated with
hyperchloremia because Cl tend to exit from cells when H+ is high, in
order to maintain electroneutrality) .
- Efficacy of diuretic: low (the maximum increase in Na+ excretion
Is about 5% of the filtered Na+ load. Moreover, as metabolic acidosis
develops, the filtered load of HCO3- decreases, and therefore the
diuretic effect undergoes a complete tolerance in 2-3 days)
HCO3-
Volume of Urine
Please see notes below

20. Pharmacokinetics Oral bioavailability: .100%.
Urinary excretion: .90% by tubular secretion.
Administration: acetazolamide PO, dorzolamide topical (eye drops)

21. Adverse effects Paresthesias (frequent), drowsiness
Nephrolithiasis (due to precipitation of calcium phosphate salts inalkaline urine)
Hyperchloremic metabolic acidosis
Hyperuricemia
Hypokalemia (the main mechanism is the same as that of thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion).
Sulfa-type allergic reactions

22. Contraindications and Precautions
Therapeutic Uses
Edema
Glaucoma (50-60% reduction in aqueous humor production)
Epilepsy (direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission)
High altitude sickness
Metabolic alkalosis
Contraindications and Precautions
Hepatic cirrhosis (alkalinization of urine decreases urinary trapping of NH 4+)
Chronic obstructive pulmonary disease (the risk of metabolic acidosis is increased)
Hypersensitivity to sulfa drugs.
Hypokalemic states
Mechanism of Action: Carbonic anhydrase is an enzyme responsible for forming hydrogen and bicarbonate ions from carbon dioxide and water. By inhibiting this enzyme, acetazolamide reduces the availability of these ions for active transport. Hydrogen ion concentrations in the renal tubule lumen are reduced by acetazolamide, leading to an alkaline urine and an increased excretion of bicarbonate, sodium, potassium, and water. A reduction in plasma bicarbonate results in metabolic acidosis, which rapidly reverses the diuretic effect. Reduced intraocular pressure (IOP) is the result of a 50—60% reduction in aqueous humor production by acetazolamide and is likely due to decreased bicarbonate ion concentrations in ocular fluid. The anticonvulsant activity of acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission. The successful treatment of altitude sickness involves production of respiratory and metabolic acidosis, which increases ventilation and binding of oxygen to hemoglobin. This occurs because the drug decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension.
Other effects
- The blockade of CA on the ciliary body epithelium decreases the
production of the aqueous humor, which is rich in HCO3-.
- The blockade of CA in the choroid plexus decreases the production of
cerebrospinal fluid.
Please see notes below

23. Adverse effects Paresthesias (frequent), drowsiness
Nephrolithiasis (due to precipitation of calcium phosphate salts in alkaline urine)
Hyperchloremic metabolic acidosis
Hyperuricemia
Hypokalemia (the main mechanism is the same as that of thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion).
Sulfa-type allergic reactions

24. Loop Diuretics Chemistry
Furosemide, bumetanide, and torsemide are sulfonamides. Ethacrynic acid is not a sulfonamide
Mechanism of action
Inhibition of electroneutral Na+/K+/2Cl- cotransport located on the luminal surface of the thick ascending limb of Henle's loop, which leads to:
a decreased lumen-positive potential which normally drives divalent cation reabsorption.
a decreased hypertonicity of the medulla and therefore a decreased ability of the kidney to concentrate the urine.
an inhibition of macula densa sensitivity (by inhibiting Na+ and Cl- transport into macula densa, the macula densa is no longer able to sense salt concentration in the tubular fluid. Therefore it initiates two responses that can increase GFR:
It inhibits the tubuloglomerular feed back
It stimulates renin release from the adjacent juxtaglomerular cells.
Loop diuretics that are sulfonamide compounds also cause a slight inhibition of carbonic anhydrase.

26. Pharmacology of Loop Diuretics
Renal effects
Increased renal excretion of: Na+,Cl-, K+, H+, Ca++, (sulfonamides also increase the excretion of HCO3).
Acid-base balance: metabolic alkalosis.
The diluting and concentrating capacity of the kidney are decreased.
Efficacy of diuretic effect: high (the maximum increase in Na+ excretion is 20-25% of the filtered Na+ load. Moreover the diuretic effect remains even when the GFR is less than 30 mL/min).
Duration of diuretic effect: 2-6 hours.
Vascular effects
Vasodilation, mainly in the venous bed.
Redistribution of blood flow within the renal cortex. (these effects are due, at least in part, to drug induced induction of prostaglandin synthesis and stimulation of prostaglandin release)
Pharmacokinetics
Absorption, and biotransformation are drug-related.
Kidney excretion occurs by active secretion by the proximal tubule.
Administration: PO, IM, IV.

27. Therapeutic uses of Loop Diuretics
Acute pulmonary edema (given IV).
Heart failure.
Edema (associated with chronic renal failure or nephrotic syndrome).
Ascites (associated with hepatic cirrhosis or right-sided heart failure).
Hypertension (when associated with renal insufficiency or heart failure).
Hypercalcemia.
(Addition of a thiazide can cause a dramatic synergistic effect when a patient become refractory to a loop diuretic alone )

28. Furosemide Decreased Urinary secretion Increased Urinary secretion Na+K+
Ca2+
Volume of Urine

29. Adverse Effects Ototoxicity Hyperuricemia Hypotension Hypokalemia
Hypomagnesemia
Adverse Effects

30. Remember the one’s in the red box

31. The most commonly used diuretics
Thiazide Diuretics
The most commonly used diuretics

32. Pharmacology of Thiazide (and congeners)
Chemistry
Thiazides are benzothiadiazine derivatives
Other compounds (congeners) are not thiazides but are pharmacologically similar to thiazides.
All compounds are sulfonamides.
Mechanism of action
Inhibition of electroneutral Na+/Cl- cotransport located on the luminal surface of early distal convolute tubule
Slight inhibition of carbonic anhydrase.

34. Renal effects Increased renal excretion of: Na+, K+, H+, Cl-, HCO3-,.
Decreased renal excretion of: Ca++, NH4+, urates.
Urine pH: alkaline (due to inhibition of carbonic anhydrase).
Acid-base balance: metabolic alkalosis.
Kidney diluting capacity: decreased.
Efficacy of diuretic effect: moderate (the maximum increase in Na+ excretion is 5-10% of the filtered Na+ load. Moreover, with the exception of indapamide and metolazone, the diuretic effect disappears if the glomerular filtration rate is less than 30 mL/min).
Duration of diuretic effect: variable (6-48 hours).

35. Hydrochlorothiazide Decreased Urinary secretion Increased UrinaryK+
Ca2+
Volume of Urine

36. Other effects Vascular effects
Arteriolar vasodilation (after chronic administration) that occurs at lower dosages than are required for diuresis
Pharmacokinetics
Absorption, distribution and biotransformation are drug-related.
Kidney excretion occurs by glomerular filtration and active secretion by the proximal tubule.
Administration: PO, IM, IV.

37. Contraindications and Precautions
Therapeutic Uses
Hypertension (first choice diuretics).
- Edema associated with diseases of:
a) the heart (i.e. heart failure)
b) the liver (i.e. hepatic cirrhosis)
c) the kidney (i.e. nephrotic syndrome).
- Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.)
- Calcium nephrolithiasis, idiopathic hypercalciuria.
- Meniere’s disease (they can prevent the endolymphatic fluid buildup)
- Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)
Goodman and Gilman’s
THERAPEUTIC USES
Thiazide diuretics are used to treat edema associated with heart
(congestive heart failure), liver (cirrhosis), and renal (nephrotic syndrome, chronic renal failure,
and acute glomerulonephritis) disease. With the possible exceptions of metolazone and indapamide,
most thiazide diuretics are ineffective when the GFR is <30–40 mL/min.
Thiazide diuretics decrease blood pressure in hypertensive patients and are used widely for the
treatment of hypertension, either alone or in combination with other antihypertensive drugs (see
Chapter 32). In this regard, thiazide diuretics are inexpensive, as efficacious as other classes of
antihypertensive agents, and well tolerated. Thiazides can be administered once daily, do not
require dose titration, and have few contraindications; moreover, they have additive or synergistic
effects when combined with antihypertensive agents. Although thiazides may marginally increase
the risk of sudden death and renal cell carcinoma, they generally are safe and reduce cardiovascular
morbidity and mortality in hypertensive patients. Because adverse effects of thiazides
increase progressively in severity at doses higher than maximally effective antihypertensive doses,
only low doses should be prescribed for hypertension. A common dose for hypertension is 25
mg/day of hydrochlorothiazide or the equivalent of another thiazide. Many experts view thiazide
diuretics as the best initial therapy for uncomplicated hypertension. Concern regarding the risk of
diabetes should not cause clinicians to avoid thiazides in nondiabetic hypertensives.
Thiazide diuretics, which reduce urinary excretion of Ca2+, sometimes are employed to treat
calcium nephrolithiasis and may be useful for the treatment of osteoporosis (see Chapter 61). Thiazide
diuretics also are a mainstay for treatment of nephrogenic diabetes insipidus, reducing urine
volume by up to 50%. The mechanism of this paradoxical effect remains unknown. Since other
halides are excreted by renal processes similar to those for Cl–, thiazide diuretics may be useful for
the management of Br– intoxication.
Contraindications and Precautions
Absolute
Anuria
Sulfonamide hypersensitivity, thiazide diuretic hypersensitivity
Precautions
Hyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure

38. Adverse Effects Hypokalemia Hyperuricemia Hypercalcemia Hyperlipidemia
Hyperglycemia
Adverse Effects

40. Potassium Sparing Diuretics
Chemistry
Triamterene and amiloride are organic bases.
Spironolactone is a steroid drug.
Mechanism of action
Spironolactone blocks aldosterone receptors in the late distal tubule and cortical collecting tubule (the synthesis of Na+/K+ ATPase in the basolateral membrane, as well as the synthesis of protein Na+ channels in the luminal membrane are impaired).
Triamterene and amiloride directly block Na+ channels in the luminal membrane of late distal tubule and cortical collecting tubule.

42. Triamterene Decreased Urinary secretion Increased Urinary secretionK+
Volume of Urine

43. Absolute contraindications
Hyperkalemia
Renal failure
Precautions
Gout
Pregnancy
Acid base imbalance
Therapeutic uses
Most commonly used in combination with other diuretics
There are other uses that we will discuss in 3rd semester
Ascites
Edema
Hyperaldosteronism
Hypertension
Hypokalemia
Premenstrual syndrome

44. PHARMACOLOGY OF ANTIDIURETIC HORMONE ANTAGONISTS
Drugs
- Conivaptan, tolvaptan
Mechanism of action
Competitive antagonists at vasopressin receptors (conivaptan at V1a and V2, tolvaptan at V2)
Renal effects
Increased water diuresis (these drugs are also called aquaretics)
Water diuresis increases more than salt diuresis (in this way hyponatremia is relieved).
Increased renal excretion of: Na+, K+, Ca++
Urine osmolality: decreased

45. Other effects Other effects Conivaptan is a strong inhibitor of CYP3A4
Pharmacokinetics
Half lives: Conivaptan 5-10 hrs, tolvaptan < 12 hrs
Administration: Conivaptan IV. Tolvaptan PO.
Adverse effect
Infusion-site reactions (with conivaptan)
Nephrogenic diabetes insipidus
Postural hypotension (if hypovolemia develops)
Hypokalemia (. 9%)
Therapeutic uses
Syndrome of inappropriate ADH secretion (when water restriction failed to correct the disorder)
Chronic euvolemic hyponatremia

46. (An IV osmotic diuretic) Contraindications and Precautions
Mannitol
(An IV osmotic diuretic)
Therapeutic Uses
Cerebral edema (To reduce raised intracranial pressure)
Oliguria in renal failure
Acute attack of Glaucoma
Contraindications and Precautions
Absolute
Heart Failure, dehydration, intracranial bleeding
Precautions
Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation
For the prevention or treatment of acute renal failure (oliguria): NOTE: Data supporting the routine use of mannitol in the treatment or prevention of acute renal failure are lacking. However, mannitol may be useful in the prevention of acute renal failure for select situations if administered prior to the insult to the kidney.[31937] [31943] NOTE: In patients with marked oliguria, or those believed to have inadequate renal function, an initial test dose of 0.2 g/kg IV over 3—5 minutes should be given to produce a urine output of at least 30—50 ml/hr for 2—3 hours; this dose may be repeated if there is no improvement in urine output. If urine output does not increase after a second test dose, mannitol should not be used. •for the treatment of acute renal failure (oliguria): Intravenous dosage: Adults: After the initial test dose is given, and if the patient has a urine output of 30—50 ml/hr for 2 hours, 20—100 g IV infusion can be administered in a 24 hour period as mannitol 15% or 20%; most patients respond to 100 g IV, although doses of 200 g IV may be necessary in some patients. Adjust the rate to maintain a urinary output of 30—50 ml/hr. Elderly: See adult dosage. In general, dose selection should be cautious, usually starting at the low end of the dosing range. Children†: Safety and efficacy have not been established; however, following an initial test dose, the therapeutic dose is usually 0.5—2 g/kg IV infusion over 30—60 minutes.[31937] Maintenance dose is 0.25—0.5 g/kg IV every 4—6 hours. •for the treatment of post-operative acute renal failure (oliguria) after cardiac surgery: Intravenous dosage: Adults: Initially, 0.3—0.4 ml/kg/hr continuous IV of mannitol 20% plus furosemide 2 mg/ml in combination with 2—3 mcg/kg/min of dopamine; once diuresis occurs, the mannitol-furosemide solution can be titrated to desired urine output. In a clinical trial of 100 oliguric (< 30 ml/hr urine output) or anuric (< 17 ml/hr urine output) post-op cardiac surgery patients with adequate cardiac output, 40 patients were give intermittent loop diuretics plus IV fluids and 60 patients were given a continuous IV infusion of 20% mannitol plus 2 mg/ml furosemide solution at a rate of 0.3—0.4 ml/kg/hr in combination with renal doses of dopamine (2—3 mcg/kg/min). Diuresis occurred in 10% of patients receiving the diuretics and in 93% of patients receiving the mannitol-furosemide and dopamine infusions; only 6.7% of patients in the mannitol-furosemide plus dopamine group required dialysis compared with 90% of patients in the diuretics group. In a subset of patients that received the mannitol-furosemide and dopamine infusions within 6 hours of acute renal failure onset, the return to normal or baseline renal function occurred quicker (after 1 week vs. after 3 weeks).[31931] •for the prevention of acute renal failure (oliguria): Intravenous dosage: Adults: After the initial test dose, give the balance of 50 grams IV infusion administered as a 20% mannitol solution over 1 hour; then, administer 5% mannitol via continuous IV infusion at a rate sufficient to maintain urine output at 50 ml/hr. Sodium chloride, calcium gluconate, magnesium, and potassium may need to be given. Monitor serum osmolarity, serum electrolytes, urine output, and fluid status.[31946] •for the prevention of acute renal failure (oliguria) during cardiovascular or other types of surgery: Intravenous dosage: Adults: 50—100 g IV infusion as mannitol 5%, 10%, or 15% either before or after the surgery; the concentration will depend on the fluid requirements of the patient. •for the prevention of acute renal failure (oliguria) in patients undergoing renal transplantation: Intravenous dosage: Adults and Children†: 250 ml of mannitol 20% solution administered via IV infusion in combination with moderate hydration (i.e., 2.5 L) just before arterial clamp removal. In a study of 131 patients undergoing cadaveric renal transplantation, mannitol plus moderate hydration, vs. hydration only, decreased the incidence of acute renal failure in patients taking cyclosporine (19% vs. 54% for mannitol plus hydration vs. hydration only, respectively, P<0.01) or azathioprine (18% vs. 44% for mannitol plus hydration vs. hydration only , respectively, P<0.05). Other anecdotal data from these same authors indicate that the incidence of renal failure is reduced from 40% to <10% with moderate hydration and mannitol infusions.[31932] •for the prevention of acute renal failure (oliguria) in patients with rhabdomyolysis: Intravenous dosage: Adults: 0.5 g/kg IV infusion of 20% mannitol over 15 minutes followed by a continuous IV infusion of 0.1 g/kg/hr. Give 100 mEq of sodium bicarbonate in 1000 ml of 0.45% normal saline in combination with the initial mannitol bolus; a continuous IV infusion of 100 mEq sodium bicarbonate in 1000 ml 0.45% normal saline should then be administered at a rate of 2—10 ml/kg/hr. The mannitol infusion should be adjusted and additional IV boluses given as needed to maintain a urine output of 200 ml/hr. Serum electrolytes, serum osmolarity, urine output, urine pH, and serum pH should be monitored.[31934] [31942] Another author recommends 200 g/day IV as a continuous infusion of 20% mannitol. The mannitol infusion should be given in combination with IV fluids containing sodium bicarbonate.[31933] The evidence regarding the effectiveness of mannitol in the prevention of rhabdomyolysis-induced acute renal failure is conflicting. •for the prevention of acute renal failure (oliguria) in patients with hemolytic transfusion reactions: Intravenous dosage: Adults: 20 g IV infusion over 5 minutes. This dose can be repeated if no diuresis occurs. Once urine flow is 30—50 ml/hr, IV fluids containing a maximum of 50—75 mEq Na+/L should be given at a rate equal to the desired urine output until oral intake is adequate. For the treatment of cerebral edema or increased intracranial pressure: Intravenous dosage: Adults: Initially, 1—2 g/kg IV, followed by 0.25—1 g/kg IV every 4 hours. Some clinicians recommend a lower initial dose (e.g., 0.25—1 g/kg). An osmotic gradient between the blood and CSF of approximately 10 mOsm will reduce intracranial pressure. One study indicates that either of the 3 doses of 0.25 g/kg, 0.5 g/kg, or 1 g/kg given IV every 8 hours results in similar reductions in intracranial pressure.[31936] However, recent data indicate that early use of high doses of mannitol of 1.4 g/kg IV may be more beneficial than lower doses in controlling intracranial pressure. Improvements in outcomes in comatose patients with severe head trauma were seen; however, more data is needed to identify patients who will benefit the most from high-dose mannitol.[31479] In nonemergent situations, doses are administered over 20—30 minutes to avoid transient increases in cerebral blood flow. When an immediate reduction in ICP is needed, mannitol can be administered over 3—5 minutes. Doses of mannitol are usually held if the serum osmolarity exceeds 320 mOsm/kg as this osmolarity is associated with an increased risk of renal failure.[31479] Elderly: See adult dosage. In general, dose selection should be cautious, usually starting at the low end of the dosing range. Children†: Safety and efficacy have not been established; however, for acute elevations, 0.25 g/kg IV infusion over 15 minutes is recommended; a dose of 0.5 g/kg IV may be necessary in some patients.[31975] For prophylaxis, 0.25—1 g/kg IV infusion over 30 minutes followed by 0.25—0.5 g/kg IV q4h. Maintain serum osmolarity < 320 mOsm/kg.[31935] For the reduction of increased intraocular pressure: Intravenous dosage: Adults: 1.5—2 g/kg IV of 15% or 20% mannitol infused over as short of a time period as 30 minutes in order to obtain a prompt and maximal effect. When used pre-operatively, the dose should be administered 60—90 minutes before surgery to achieve maximal reduction of intraocular pressure. Elderly: See adult dosage. In general, dose selection should be cautious, usually starting at the low end of the dosing range. Children†: Safety and efficacy have not been established; however, 1—2 g/kg IV administered as a 15—20% solution over 30—60 minutes has been used. When used pre-operatively, the dose should be administered 60—90 minutes before surgery to achieve maximal reduction of intraocular pressure. For toxin excretion enhancement (e.g., urinary excretion of salicylates, barbiturates, bromides, lithium): Intravenous dosage: Adults: 50—200 g IV infusion as a 5—25% solution, administered at a rate adjusted to maintain a urine output of 100—500 ml/hour. Total maximum dose is 200 g IV. One author recommends a test dose of 12.5—25 g IV infusion as mannitol 20—25% over 3—5 minutes. The balance of 50 g IV infusion of 20% mannitol can be administered over 1 hour. Then, a continuous IV infusion of 5% mannitol can be administered at a rate sufficient to maintain urine output at 150—500 ml/hr. This author also recommends that 45 mEq of sodium chloride, 24 mEq of sodium acetate, 1 g magnesium sulfate, and 20 mEq of potassium acetate be added to each liter of mannitol solution.[31940] Monitor serum electrolytes, serum osmolarity, and fluid status. Elderly: See adult dosage. In general, dose selection should be cautious, usually starting at the low end of the dosing range. Children†: Administer as a 5—10% IV infusion up to a maximum dosage of 2 g/kg IV. Monitor serum electrolytes, serum osmolarity, and fluid status. For antihemolytic urologic irrigation for transurethral prostatic resection or other transurethral surgical procedures: Bladder instillation: Adults: Irrigate the bladder with 2.5—5% solution. Maximum Dosage Limits The total dosage, concentration, and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement, and urinary output. While the usual adult dosage ranges from 20 to 100 g IV in a 24 hour period, there is no absolute maximum dosage; however doses in excess of 200 g/day IV or 400 g/48 hours IV have been associated with acute renal failure. In patients with increased intracranial pressure or cerebral edema, the plasma osmolality should not exceed 320 mOsm/kg. Patients with Hepatic Impairment Dosing Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with Renal Impairment Dosing Although the half-life of mannitol is increased in renal failure, no specific dosage adjustments are needed. However, mannitol is contraindicated in patients with well-established anuria, and should also be discontinued in patients with progressive renal dysfunction following mannitol administration. †non-FDA-approved indication