DRUG USE IN RENAL AND URINARY

TRACT DISORDERS

Dr. dr. IGA Artini, M.Sc.

Department of Pharmacology
Faculty of Medicine Udayana University
 LEARNING OUTCOMES

Describe the alteration of drug pharmacokinetic and

pharmacodynamic due to renal disorders

Describe drug-induced renal diseases

Describe pharmacological properties of diuretics and urinary antiseptics

 KIDNEY
Elimination of waste product;
maintaining water, electrolyte and acid base balance
Site of drug action, target for drug toxicity, elimination of drug

Glomerular filtration
Unbound drug, MW < 30 kD

RENAL DRUG Tubular secretion

CLEARANCE
Active transport via transporter

Tubular reabsorption
Lipophylic, pKa, MW
PATHOPHYSIOLOGICAL CHANGES
IN RENAL DISEASE

• GFR decrease
• Functional nephron mass
decrease • Metabolic load
• Proteinuria • Malnutrition
• Uremia • Anemia
• Platelet dysfunction • Diabetes mellitus
• Oedem, ascites • Hypertension
• High free fatty acid • Infection
• Naussea, vomiting • UT Stone
 PHARMACOKINETIC CHANGES IN
RENAL DISORDERS

Drug malabsorption, increase bioavailability

ABSORPTION (drugs undergo FPE), Tmax ↑, gastric pH increase
(absorption of Fe, ketoconazole, etc. decrease)

Decrease serum protein (malnutrition, proteinuria),

decrease the binding of acidic drugs to albumin
DISTRIBUTION
(uremia, high FFA), increase Vd water soluble drugs
(oedema/ascites)

Non-renal clearance might be altered

METABOLISM Activity of drug-metabolizing enzyme impaired
 Effect of Renal Disorders
on Drug Excretion

Drugs eliminated mainly by renal in unchanged form

may be accumulated

Functional nephron mass and GFR ↓  decrease excretion of

unbound drugs, MW<60,000 D

Organic acid ↑  inhibit excretion of acidic drug due to competition

 Excretion of weak acid drug in urine vs. time
in acidic and alkaline urine

Alkaline urine
% drugs
excreted

Acidic urine

TIME
 Acidic drugs eg. phenobarbital, phenytoin,
salicylic acid, warfarin, NSAID, sulfonamide, theophylline etc.

Basic drugs eg. Quinidin, lidocain

Drugs eliminated mainly by renal excretion in unchanged form

eg. Nitrofurantoin, penicillin, cephalosporin, aminoglycoside,
diuretic, tetracyclin, sulfonamide, ACEI, digoxin,
ethambuthol, atenolol, disopyramide

Drugs excreted mainly by glomerular filtration

eg. Ampicilin, aminoglycoside, digoxin

Drugs excreted mainly by tubular secretion

eg. Beta lactam, anticancer, diuretics, NSAID, ACEI, OAD,
Cimetidin, procainamide, anthracycline, digoxin
Pharmacologic Activity of Selected Drug Metabolites
 PHARMACODYNAMIC CHANGES
IN RENAL DISORDERS

• Changes in tissue response to drug

 increase sensitivity of certain drugs
(CNS drugs, digitalis, anticoagulants, antiplatelet,
nephrotoxic agents)
 decrease sensitivity of drugs
(diuretics, uricosurics)

2004-2005
 DRUG-INDUCED RENAL DISEASE

IMMUNE-MEDIATED NEPHROTOXICITY
• Glomerulonephritis, allergic interstitiil nephritis, lupus nephritis
• Sulfonamide, penicillin, amfotericin B, aminoglycoside, INH,
rifampicin, phenytoin, etc.

NON IMMUNOLOGIC NEPHROTOXICITY

• Blood flow regulation, intrarenal drug metabolism, tubular transport
process, urine concentration, acidification abilities
• Direct (heavy metals, x-ray contrast, analgesics, etc.)
• Indirect eg. calcification, bleeding, obstruction
(calciferol, diuretics, uricosurics, cytotoxic, anticoagulant, etc.)
 Pathophysiology of
drug-induced renal disease

1. PRE RENAL
 Dehydration, CHF
 contrast, ACEI, ARB,
immunosuppressant
2. INTRINSIC RENAL
 GN, interstitiil nephritis,
ATN, nephrotic synd.
 Penicillin, sulfonamide,
rifampicin, PPI, NSAID,
antiepileptic
3. POST RENAL
 Ureter stone, prostate,
precipitation
 Acyclovir, cotrimoxazole
 Drug-induced
renal disease

1. Glomerular injury
2. Vascular injury
3. Tubular/Tubulointerstisiil injury
 Risk Factor for
Drug-Induced Renal Disease
Patient-specific factor
Female, old age, volume depletion, metabolic perturbation,
immune response gene, gene mutation in hepatic and
renal metabolic system, gene mutation in renal transport protein

Kidney-specific factor
High blood flow, increase toxin concentration in medulla and interstitium,
biotransformation to ROS, high metabolic rate of tubular cells,
proximal tubular uptake of toxins

Drug- specific factor

Prolonged dosing period and toxin exposure, direct nephrotoxic effect,
combination of drugs, competition for transporters,
insoluble compound and metabolite
 Basic Principle for Drug Use
in Renal Disorders

Use drugs only if absolutely required

Drug selection

Dosage adjustment

Drug monitoring

Multiple health problems and require multiple medications

 be aware of drug interaction
 SELECTION OF DRUGS
Alteration of drug efficacy

Increase risk of untoward effect

Nephrotoxic drug  risk if use vs risk if not use

Frequent monitoring on drug response

and adverse drug reaction
Dosage Adjustment
in Renal Disorders
Required if drug elimination by kidney > 30%,
active metabolite, GFR < 30 mL/min,
nephrotoxic drugs

Caution for narrow TI drugs

Loading dose don’t have to be adjusted in renal failure

except digoxin and aminoglycoside (low Vd and narrow safety margin)

Maintenance dose must be adjusted in renal failure

 lengthen drug interval
 dose reduction (based on GFR)
 Drugs with Narrow Therapeutic Index

Cleared predominantly by liver

• Adriamycin, azathioprin, vincristin, cyclophosphamide,

cyclosporin, heparin, warfarin, lignocaine, meperidine,
metoprolol, morphine, oxprenolol, phenytoin, prazosin,
propranolol, theophylline

Cleared predominantly by kidney

• Amikacin, colistin, digoxin, gentamycin, kanamycin, lithium,

streptomycin, tobramycin, vancomycin, 5-fluorocytocin
2004-2005
 Supplemental dose post HD

Needed for drugs that removed on HD in a large quantity

Drugs with MW < 500 D, water soluble uncharge, low protein

binding, Vd < 1 L/kg

Aminoglycosides, cephalosporines, pennicilins, sulfonamide,

trimethoprim, ofloxacin, ciprofloxacin, metronidazole, flucytosine,
INH, pyrazinamide, ethambuthol, acyclovir, ganciclovir,
zidovudin, didanosine
PRESCRIBING IN RENAL DISORDERS
CNS DRUGS
• Antianxiety, hypnotics, antipsychotics  risk of CNS depressant

ANALGESICS, ANTIINFLAMMATORY DRUGS

• Mostly NSAID (and COX-2 inhibitors) are nephrotoxic
• Might worsen hyperkalemia, oedema, and hypertension
• Might also decrease antihypertension effect of β blocker, ACEI and ARB
• Acetaminophen relatively safe
• Opiate might be fatal due to retension of active metabolite
• Corticosteroid  worsen Na retention
• Tramadol  prolonged interval

GI DRUGS
• Ranitidine eliminated by kidney and liver  dosage adjustment
• PPI  no adjustment
• Avoid antacids (contain Mg and Al) and sucralfate
 CARDIOVASCULAR DRUGS
DIURETICS

• ACEI and ARB cause GFR decrease, serum creatinine increase,

serum potassium increase
• CCB, clonidine, alpha blocker eliminated by liver  no adjustment
• Digoxin : need dosage adjustment
• β blocker hydrophylic (atenolol, bisoprolol, nadolol, acebutolol)
eliminated by kidney  dosage adjustment
• Metoprolol, propranolol, labetalol metabolized by hepar  no
adjusment
• Diuretics highly bound to protein  not filtrated, but secreted by
OATP in tubules
• Avoid K-sparing diuretic due to risk of hyperkalemia
• Etacrynic acid, furosemide, bumetamide  risk of ototoxicity
 ANTIMICROBIAL DRUGS

• Mostly have wide therapeutic index except aminoglycosides and

vancomycin  dosage adjustment only if GFR<20 mL/min
• Avoid aminoglycosides due to nephrotoxic and ototoxic effect
• Avoid tetracycline  worsen uremic state and increase BUN (due
to its antianabolic effect)
• OAT : avoid streptomycin and ethambuthol due to risk of
vestibular toxic and optic neuritis
• Avoid amfotericin B
• Antiviral : acyclovir and ganciclovir eliminated by kidney 
dosage adjustment
INSULIN & ORAL ANTIDIABETIC DRUGS

• Insulin requirement decrease due to renal disorders

• Avoid chlorpropamide  prolong half life
• Glibenclamide, gliburide cause prolong
hypoglycemia due to active metabolite accumulation
• Metformin contraindicated in renal failure  risk of
lactic acidosis
• Glipizide : choice in renal failure (short duration,
eliminated by liver, no active metabolite)
 DIURETICS

CARBONIC ANHYDRASE INHIBITORS

LOOP DIURETICS

THIAZIDES AND THIAZIDE-LIKE DIURETICS

POTASSIUM SPARING DIURETICS

OSMOTIC DIURETICS

08/03/2010 Ngatidjan, AGONISTANTAG-2010

 Site of action of
diuretics in the
segment of
nephron

2004-2005
 CARBONIC
ANHYDRASE
INHIBITORS
Azetazolamide
Dorzolamide
Methazolamide
Dichlorphenamide

• 60-70% of filtered Na+ is

reabsorbed in the PCT
• Highly permeable to water 
reabsorption is isotonic.
• HCO3- is poorly reabsorbed in
luminal side  require CA
enzyme

• Bind to carbonic anhydrase enzyme  inhibit NaHCO3 reabsorption in PCT  bicarbonate loss
• Cause potassium wasting, metabolic acidosis, hypercalciuria, hyperamonemia, hypersensitivity
• Not in use as diuretic anymore  Indications for glaucoma, urine alkalinization,
metabolic alkalosis, acute mountain sickness
2004-2005
 LOOP DIURETICS
Furosemide
Bumetanide
Torsemide
Ethacrynic acid

• 20-30% is reabsorbed in TAL

• TAL has large reabsorptive capacity;
impermeable to water
• TAL and DCT  diluting segments
• Contribute to formation of
hypertonicity of medulla interstitium

• Strong, but brief diuresis (within 1 hr, lasts ~ 4hrs)

• Used for moderate to severe fluid retention and hypertension
• Most potent diuretics available
• Act by inhibiting the Na+/K+/2Cl- symporter in the thick ascending limb loop of Henle
 inhibit reabsorption of Na+, K+, Cl-, as well as Ca2+ and Mg2+ in TAL
• Metabolic alkalosis, hypokalemia, hyponatremia, hypotension, ototoxicity, allergy
2004-2005
 Clinical application and drug interaction

Acute pulmonary edema, other edematous state (CHF, nephrotic

syndrome, CH), hypercalcemia, acute renal failure, hypertension,
drug overdose (forced diuresis)

Drug Effect
Aminoglycoside, cisplatin Increase risk of ototoxic
Anticoagulant Increase anticoagulant effect
Cardiac glycoside, Increase risk of arrhythmia
antiarrhythmia
Sulfonylurea Increase risk of hyperglycemia
Propranolol Increase propranolol level in plasma
NSAID, probenecid Decrease diuretic response
Thiazide Synergistic effect
08/03/2010 Ngatidjan, AGONISTANTAG-2010
 THIAZIDES

• 5-8% Na+ reabsorption; no K+

recycle; no Ca2+ and Mg2+
reabsorption
• PTH promote Ca 2+
reabsorption
•TAL and distal tubule are
diluting segments; impermeable
to water
• Not contribute to formation of
medulla hypertonicity

• Medium potency diuretics; sulfonamides (caution for sulfonamide cross-allergy)

• Act by inhibiting the Na+/Cl- symporter in the distal convoluted tubule
• Indication: edema, hypertension, nephrolithiasis (hypercalciuria) treatment,
• nephrogenic diabetes insipidus, Br- intoxication
• Depletion of EFV, hypotension, metabolic alkalosis, hypokalemic, hyponatremia,
• hypomagnesemia, hypercalcemia, ototoxicity, allergy
2004-2005
 Drug interaction involving Thiazides

Drug Effect
Anticoagulants Decrease anticoagulant effect
Urikosurics Decrease urikosuric effect
Sulfonylureas Decrease sulfonylurea effect
Insulin Decrease insulin effect
Anesthetic Increase anesthetic effect
Cardiac glycoside Increase cardiac glycoside effect
Lithium Increase lithium effect
Loop diuretics Increase loop diuretic effect
NSAID Decrease thiazide efect
Corticosteroid Increase risk of hypokalemia
Amfotericin
Quinidine Increase risk of torsade de pointes and ventricular
fibrilation
 Potassium Sparing
Diuretics

Na+ channel inhibitors

• Amiloride
• Triamterene
Aldosterone antagonists
- Spironolactone
- Eplerenone

• Na+ reabsorption 2-5% (final site)

• Final adjustment composition and volume ultrafiltrate;
• Vasopressin (ADH) alter water permeability
• In medulla portion of CD, interstitial fluid is hypertonic
 concentrate urine
• Aldosterone promotes reabsorption of Na+ in
exchange for K+ and H  (transcriptionally upregulates
the Na+/K+ pump and sodium channels)

 Act on the distal portion of the distal tubule and collecting tubule (Na+ is exchanged for K+)
 Aldosterone antagonist  Competitively inhibit the binding of aldosterone to mineralocorticoid receptor
 MR-spironolactone complex  can not induce AIP (aldosterone-induced protein) synthesis
 Na channel inhibitors  directly inhibit Na channel  inhibit reabsorption of Na
2004-2005
 Na+ channel inhibitors

Quick onset
Mild increase of NaCl excretion
Decrease excretion of K+, H+, Ca2+, Mg2+ and uric acid

Uses: Treatment of hypokalemia (coadministered with other

diuretics), lithium-induced nephrogenic DI
Side effects: Hyperkalemia (life-threatening), metabolic
acidosis

Contraindicated in hyperkalemia
Drug interaction with other K+ sparing diuretics, ACEI, K+
supplement, NSAID
08/03/2010 Ngatidjan, AGONISTANTAG-2010
 Aldosterone antagonists

• Not require access to tubular lumen

• Spironolactone has affinity to progesterone and androgen
receptor  side effects gynecomastia, impotency, irregular
menstruation, decrease libido
• Eplerenone low affinity to progesterone and androgen
receptor
• Combination with thiazide or loop diuretics in edema and
hypertension, hyperaldosteronism

08/03/2010 Ngatidjan, AGONISTANTAG-2010

 Osmotic Diuretics

– Glycerin, mannitol, urea

– Small non-reabsorbable molecules
– Inhibit passive reabsorption of water
– Filtered by glomerulus
– Increase osmolality of plasma and tubular fluid
– Predominantly increase water excretion without significantly
increasing Na+ excretion => limited use

– Can cause electrolyte imbalance also

– Used to reduce of intracranial pressure or reduce cerebral
edema (does not cross blood-brain barrier => water is pulled
out of the brain into the blood), control IOP (glaukoma)
– Mannitol and urea only given IV

2004-2005
 Compensatory mechanism for prolonged diuretics used

Compensatory mechanism include activation of SNS, activation of RAA axis,

increased expression of renal epithelial transporters and alteration in ANP
URINARY ANTISEPTICS
 Oral drugs which have antibacterial activity in urine,
rapidly excreted via urine, minimal or no systemic
effect
 Act by acidifying urine, inhibiting DNA synthesis,
releasing antibacterial substance
 Chronic urinary tract infection
 Nitrofurantoin, nalidixic acid,
methenamine
 SE : GI disturbance, allergic reaction,
hemolytic anemia, glucosuria
THANK YOU