Renal pharmacology final

RENAL PHARMACOLOGY3rd year medical students

By: Dr. Hazem Abo Shousha

Function of the kidneys

excretion of waste

products

urea creatinine

control of fluids

constitutes

volume electrolyte PH

Diuretics

Drugs that cause excess loss of Na+ ions and water in urine ⬆➠ urine volume

Classification Of Diuretics

According To Efficacy (Ceiling)

High

Loop Diuretics (20-25%)

Moderate

Thiazides (5-8%)

Low

K+ Sparing Diuretics (2-

3%)

Carbonic Anhydrase Inhibitors

(<5%)

According To Effect Of Serum

Potassium

K+ Loosing

Loop Diuretics Thiazides CAEI

K+ Sparing

Spironolactone Amiloride, Triametrine

According to site of action

Renal Handling of Na+

1

23

4 5

6Na+

60%

Na+

H+

Na+

K+

2Cl-

Na+ Cl-

Ca+2

20-30%

10%

Na+

K+

H+

2-3%

H2O

Ca+2

Ca+2

Osmotic diuretics (Mannitol) 1 2 6CAEI 1Loop Diuretics 3Thiazides Diuretics 4K+ sparing Diuretics 5 6

5%

Mannitol

A B

• Loop diuretics• Thiazides• CAEI

Uric Acid

AmilorideTriamtrene

DCT

Spironolactone

Routes of access of diuretics to site of action

• Mannitol: is # in renal failure as it can’t access to nephron remain in blood circulatory overload➞ ➞• Loop and thiazides: enter lumen through organic acid secretory system compete with uric acid secretion # Gout➞ ➞• Loop diuretics: their access to the lumen in renal failure is decreased due to accumulation of waste products in blood ➞

↓diuretics effect ↑ dose of diuretics in renal failure➞

THIAZIDES AND RELATED AGENTS The thiazides are the most widely used of the diuretic

drugs. They are sulfonamide derivatives

Members:

• Hydrochlorothiazide

• Chlorothiazide

• Indapamide

• Metolazone

• Chlorthalidone

Mechanism Of Action:

• The thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na+, apparently by inhibition of a Na+/Cl- co-transporter on the luminal membrane of the tubules

Effect of Thiazides

a. Increased excretion of Na+ and Cl- : Thiazide diuretics cause diuresis

with increased Na+ and Cl- excretion, they achieve a maximum

natriuresis of 5-10% of filtered Na+.

b. Loss of K+: Because thiazides increase the Na+ in the fitrate arriving

at the distal tubule, more K+ is also exchanged for Na+, resulting in

a continual loss of K+ from the body with prolonged use of these

drugs.

Effect of Thiazides

c. Decreased urinary calcium excretion: In the

DCT, lowering of intracellular Na+ by thiazide-

induced blockade of Na+ entry enhances

Na+/Ca2+ exchange in the basolateral

membrane, and increases overall reabsorption

of Ca2+.

Effect of Thiazides

Effect of Thiazides

d. Long term use: ↓ Na+ in vessel wall and Ca⊖ +2 influx → VD.

Effect of Thiazides

e. Less active in GFR <20 ml/min except Metalazone.

Effect of Thiazides

f. Paradoxically, they reduce polyuria and polydipsia in nephrogenic diabetes insipidus.

Effect of Thiazides

Therapeutic uses:

1. Hypertension

2. Congestive heart failure

3. Renal stones due to idiopathic hypercalciuria

4. Nephrogenic diabetes insipidus

Adverse effects:

1. Hypokalemia, metabolic alkalosis, hyperuricemia.

2. Impaired glucose tolerance .

3. Hyperlipidemia by increasing serum cholesterol and LDL.

4. Allergic reaction as they are related to sulphonamide.

5. Unmask secondary hypercalcemia as hyperparathyroidism.

6. Impotence ?? May be due to depleted blood volume.

LOOP (HIGH-CEILING DIURETICS)Bumetanide, furosemide, torsemide, and ethacrynic acid are four diuretics that have their major

action on the ascending limb of the loop of Henle.They are sulfonamide derivatives.

Pharmacokinetics:

• Bumetanide is more completely absorbed from GIT than furosemide.

Loop diuretics are administered orally or parenterally. Their duration

of action is relatively brief (up to 6 hours). They are secreted into

urine.

Mechanism of action:

• Loop diuretics inhibit the co-transport of Na+/ K+/2Cl- in the luminal membrane in the

ascending limb of the loop of Henle. Therefore, reabsorption of these ions is

decreased. The loop diuretics are the most efficacious of the diuretic drugs, because

the ascending limb accounts for the reabsorption of 25 to 30 percent of filtered

NaCl, and downstream sites are not able to compensate for this increased Na+ load.

a. Reduce the generation of concentrated urine in the collecting duct.

b. They also prevent affect vasoconstriction in response to the increased Na+ and Cl-, by

maintaining vasodilating PG production “temporary”. This will cause increase renal

blood flow and is beneficial in treatment of acute left ventricular failure and

hypertension.

c. If they given with saline they will increase the Ca+2 and Mg+2 excretion in urine so

useful in treating hypercalcemia.

Effect of Loop diuretics

Therapeutic uses:

1. Acute pulmonary edema.

2. Acute renal failure.

3. Anion overdose as bromide, fluoride and iodide.

4. Marked edema due to congestive heart failure, nephrotic syndrome, and

liver cirrhosis.

5. Hypercalcemia.

Adverse effects:

Alkalosis

Contraindication of Thiazides and Loop diuretics

1. Hypersensitivity to sulfonamides except (ethacrynic acid)

2. Overuse is dangerous in hepatic cirrhosis, borderline renal failure,

or congestive heart failure

POTASSIUM-SPARING DIURETICS Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption and K+

excretion. The major use of potassium-sparing agents is in the treatment of hypertension, most often in combination with a thiazide.

Aldosterone antagonists: Spironolactone & Eplerenone

• Spironolactone is a synthetic steroid that antagonizes aldosterone at

intracellular cytoplasmic receptor sites. As well as the new

Eplerenone they prevent aldosterone-induced transcription and gene

expression.

Pharmacokinetics:

• Spironolactone is has poor oral absorption and is strongly bound to

proteins. It is rapidly converted by liver to an active metabolite,

canrenone. The action of spironolactone is largely due to the effect of

canrenone

• They both have delayed onset of action “several days”

Therapeutic uses:

1. Primary hyperaldosteronism

2. Edema of liver cirrhosis.

3. Hypertension.

4. Heart failure.

5. In combination with Loop or Thiazide to avoid hypokalemia.

Adverse effects:

1. Hyperkalemia: especially if combined with other drugs that cause

hyperkalemia or if renal failure.

2. Metabolic acidosis

3. Gynecomastia, impotence (not with Eplerenone)

Triamterene and Amiloride

• Triamterene and Amiloride block Na+ transport channels, resulting in a decrease in

Na+/K+ exchange. Although they have a K+-sparing diuretic action similar to that of

spironolactone, their ability to block the Na+/K+-exchange site in the collecting tubule

does not depend on the presence of aldosterone. Like spironolactone, they are not

very efficacious diuretics.

• Several days are needed for full therapeutic effect.

Adverse effects:

• Amiloride: hyperkalemia

• Triametrene:

• Hyperkalemia

• Renal stones

• Interstitial nephritis

• If combined with indomethacin → acute renal failure

• Megaloplastosis

CARBONIC ANHYDRASE INHIBITORS Acetazolamide inhibits the enzyme carbonic anhydrase in the proximal tubular epithelial

cells. Carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their diuretic effect, because they are much less efficacious than the

thiazides or loop diuretics. They also are sulfonamide related.


• Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm) and

on the apical membrane of the proximal tubular epithelium. Carbonic anhydrase

catalyzes the reaction of CO2 and H2O, leading to H+ and HCO3- (bicarbonate). The

decreased ability to exchange Na+ for H+ in the presence of acetazolamide results

in a mild diuresis. Additionally, HCO3- is retained in the lumen, with marked

elevation in urinary pH. The loss of HCO3- causes a hyperchloremic metabolic

acidosis and decreased diuretic efficacy following several days of therapy.

Therapeutic uses: 1. Treatment of glaucoma: The most common use of acetazolamide. It decreases the

production of aqueous humor, topical carbonic anhydrase inhibitors, such as dorzolamide,

have the advantage of not causing any systemic effects.

2. Urinary alkalization to increase excretion of acidic agents e.g. uric acid and aspirin.

3. Metabolic alkalosis due to excessive use of diuretics in patients with severe heart failure

4. Other uses:

• Adjuvant in treatment of epilepsy

• To increase urinary phosphate excretion in hyperparathyroidism

Adverse effects:

1. Hyperchloremic metabolic acidosis.

2. Renal stone by phosphaturic effect.

3. Hypokalemia.

4. Drowsiness and paresthesia in large doses.

5. Hypersensitivity reaction.

OSMOTIC DIURETICS Mannitol osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be

retained and promotes a water diuresis.

Pharmacokinetics

• Mannitol is NOT absorbed by the GI tract.

• when administered orally, it causes osmotic diarrhea.

• For systemic effect, mannitol must be given I.V.

Mechanism of Action

Inhibition of Water Diffusion

• Free filtration in osmotically active concentration

• Osmotic pressure of non-re-absorbable solute prevents water reabsorption and increase urine

volume :

- Proximal tubule

- Thin limb of the loop of Henle

- Collecting ducts (less extend)

• Increased Na+ excretion (variable effect).

12

6

Therapeutic uses:

1. Treatment of acute renal failure

2. Reduction of pressure in extravascular fluid compartments:

1. Reduce cerebral edema during neurosurgery

2. Reduction of intra-ocular pressure before eye surgery for glaucoma

3. Increase poison elimination when given orally

Adverse Effects of Osmotic Diuretics:

1.Pulmonary edema

2.Dehydration

3.Hyponatremia

4.Headache ,nausea and vomiting

Thiazides

Hypertension

Mild heart failure

Nephrolithiasis

Loop Diuretics

Pulmonary edema

Peripheral edema

Hypertension

Acute renal failure

Potassium-sparing Diuretics

Hypokalemia due to other

diuretics

Post MI

Heart failure

Carbonic Anhydrase Inhibitors

Glaucoma

Edema with alkalosis

Acidic drug toxicity

Osmotic Diuretics

Acute renal failure

Reduce intracranial

pressure

Glaucoma

Important Drug Interactions

Diminished Diuretic Response

NSAIDS

Salt

Decongestants

Probenecid

Hyperkalemia Induced by K-Sparing

DiureticsACE Inhibitors

Beta-Blockers

K Supplements

K-Sparing Diuretics

Heparin

Enhanced Ototoxicity of Loop

Diuretic

Ototoxic Drugs

Major uses of diuretics

EDEMATOUS STATES

Heart Failure & Acute pulmonary edema (Unload the heart)

Kidney Disease (nephrotic syndrome, acute renal failure ……)

Hepatic Cirrhosis

Idiopathic edema

NON EDEMATOUS STATESHypertension

Nephrolithiasis

Hypercalcemia

Diabetes Insipidus

Glaucoma (Open Angle)

Increased Intracranial Pressure

URINARY TRACT INFECTION

Drugs Used in Treatment of UTI

I- Specific Urinary antiseptic

Nitrofurantoin

Methenamine

Nalidixic Acid

II- Non-Specific antimicrobial agents

Sulphonamide & Trimethoprim

Penicillins

Aminoglycosides

Cephalosporins

III- Flouroquinolones

Norfloxacin

Ciprofloxacin

Ofloxacin

URINARY ANTISEPTICSThese drugs do not achieve antibacterial levels in the circulation, but

because they are concentrated in the urine, microorganisms at that site can be effectively eradicated.

Nitrofurantoin Methenamine Nalidixic Acid

NITROFURANTOINnitrofurantoin is bactericidal for many gram-positive and gram-negative bacteria;

however, P aeruginosa and Proteus is inherently resistant.

Pharmacokinetics:

• Nitrofurantoin is well absorbed after ingestion.

• It is excreted so rapidly that no systemic antibacterial action is achieved.

• The drug is excreted into the urine by both glomerular filtration and tubular

secretion.

• In renal failure, urine levels are insufficient for antibacterial action, but high

blood levels may cause toxicity.


• Antibacterial activity appears to correlate with rapid intracellular conversion of

nitrofurantoin to highly reactive reduced form by bacterial reductases.

• Produce damage to bacterial DNA.

• It is desirable to keep urinary pH below 5.5, which greatly enhances drug

activity.

Therapeutic uses:

1. Acute lower non-complicated UTI, should not exceed 14 days.

2. For prophylaxis of recurrent UTI

3. Not recommended for treatment of pyelonephritis or prostatitis

Adverse effects:

1. Nausea, vomiting and diarrhea.

2. Brown discoloration of urine.

3. Hypersensitivity reactions :

• Chills, Fever and Leukopenia.

4. Hemolytic anemia in G6PD deficiency.

5. Neurotoxicity.

Methenamine Mandelate & Methenamine Hippurate

Below pH 5.5, methenamine releases formaldehyde, which is antibacterial, Mandelic acid or hippuric acid taken orally is excreted unchanged in the urine, in which these drugs are bactericidal

for some gram-negative bacteria when pH is less than 5.5.

Therapeutic uses:

• Not 1st line drug for UTI

• For chronic suppressive therapy especially in E.Coli.

Adverse effects:

1. gastrointestinal distress

2. higher doses:

a. Albuminuria

b. rashes may develop

Contraindications:

1. in patients with renal insufficiency, because mandelic acid may

precipitate.

2. Hepatic insufficiency due to accumulation of ammonia.

3. Sulfonamides, react with formaldehyde and must not be used

with methenamine. The combination increases the risk of

crystalluria.

PHENAZOPYRIDINE• Not an antiseptic• Urinary analgesic• Alleviates dysuria, frequency, burning and urgency• Azo dye – colors urine orange or red, the patient should be

informed.• G.I.T. upset is seen in up to 10% of patients and can be reduced by

administering the drug with food.• Over dosage may result in methemoglobinemia.

Drug treatment of UTI falls into several categories:

1- Lower Urinary Tract Infections:

• Initial treatment with an oral cephalosporin, e.g. cephalexin or ampicillin

is usually satisfactory therapy and should last for 5 days.

• Single dose therapy with amoxycillin 3 g/day by mouth may be sufficient

to cure uncomplicated lower urinary tract infection.

2- Upper Urinary Tract Infections:

• Acute pyelonephritis may be accompanied by septicemia and it is

advisable to start with gentamicin plus amoxycillin IV or alternatively

cefotaxime IV alone as infusion.

• This is an infection of the kidney substance and needs adequate blood

as well as urine drug concentrations.

3- Chemoprophylaxis:

• Chemoprophylaxis is sometimes undertaken in patients liable to

recurrent attacks or acute exacerbations of ineradicable infection. It may

prevent subclinical renal damage in girls who are found to have

asymptomatic bacteriuria on routine screening.

• Nitrofurantoin, nalidixic acid or trimethoprim are satisfactory. The drugs

are best given as a single oral dose at night.

General Principles of Management of

UTI

• Pretreatment urine culture is not required in first attack of

uncomplicated cystitis in young women (non pregnant) but should be

done in all other situations before any empirical treatment is started.

Post treatment culture is required to judge cure of infection.

General Principles of Management of UTI

• Choice of antibacterial therapy in UTI is based on:

• age of patient.

• Sex.

• pregnancy status.

• site of infection.

• first attack or recurrence.

• predisposing factors.


• uncomplicated infections of lower urinary tract and respond to short

courses of therapy

(1-3 days)

• while upper UTI require longer treatment

(7-14 days)

• complicated cases require longer duration of treatment

(14 - 21 days).


• Maintain high urine output (2 -2.5 L ̸ day)


• Urinary pH is adjusted according to antibacterial activity of the drug used.

Alkaline pH favors sulfonamides,

Quinolones

Penicillin

aminoglycosides.

Adequate alkalinization of urine is achieved by sodium bicarbonate, sodium citrate or

potassium citrate. Acidifying agents should not be used in infection caused by urease

producing organisms (proteus, coliform and staph albus).


Education

Renal pharmacology final