Drug Usage in Patients with Renal FailureArini SetiawatiDept. Pharmacology & TherapeuticsMedical Faculty, Univ. of Indonesia

Drugs : - elim. by hepatic metabolism to inactive metabolites and / or by renal excretion of parent drug and / or active / toxic metabolites In renal failure :- For drugs eliminated completely / partially (> 33%) by the kidneys, and renally excreted active/toxic metabolites need dosage adjustment- Clinically significant removal by hemodialysis need supplemental dose

Renal Failure (RF) :Drug pharmacokinetics & pharmacodynamics frequently altered risk of ADR

Multiple medical problems polypharmacy drug interactions

Drug absorption in RF :N, V, D, bowel edema drug malabsorption, worsened by NSAIDs

gastric salivary urea ammonia ureases gastric pHabs. of Fe, ketoconazole, itraconazole, etc.

Plasma protein binding in RFUremia FFA

MalnutritionProteinuria Nefrotic syndr. free drug intensity of drug effect extent of drug distribution rate of elimination total plasma conc. protein binding free drug, esp. acidic drugs to albumin (penic., phenobarb., phenytoin, salic., warfarin, NSAIDs, sulfa, theoph.) serum protein free drug

Drug distribution in RFEdema or ascites Vd of water-sol. drugs

Vol. contraction Vd of aminoglyc.Muscle wasting Vd of digoxin plasma conc.

Drug biotransformation in RF (1)Drugs metabolized completely by the liver to inactive metabolites normal dosage

Phase II metabolism = conjugation (glucuronidation, sulfation, acetylation) : normal normal dosage

Drug biotransformation in RF (2)Phase I metabolism :- microsomal oxidation : normal or accelerated (accum. of inducers)- reduction (cortisol)- peptide hydrolysis (insulin, glucagon, PTH)- ester hydrolysis (diflunisal, procaine)due to nonhepatic (esp. renal) metabolism slowed

Drug excretionMost important organ : kidneysExcretion : unchanged form & metabolitesExcretion of unchanged & active forms : renal elimination3 processes : - glomerular filtration- active secretion in proximal renal tubule- reabsorption along the renal tubulesRenal function :- mature at the age of 2 years (< 2 yrs: normal Ccr < 0.7 mg/dL)- after the age of 40 : 1% / year

Renal excretion in RFRenal clearance (ClR) =fu GFR + active tubular secretion - active & passive tubular reabsorptionfu = fraction of unbound drug (to plasma protein)

In Renal Failure : renal excretion

drug doses or interval of drug adm.

Drugs mainly eliminated by renal excretion Penicillins Ethambutol Cephalosporins Diuretics Aminoglycosides ACE inhibitors Tetracyclines (Avoid !) Digoxin Sulfonamides Atenolol Nitrofurantoin DisopyramideThese drugs are excreted by the kidneys in unchanged form will accum. in RF intensity of pharmacol. effect & toxicity dosage

Glomerular filtration in RF only unbound drugs with MW < 60.000 are filtered by functional nephronsRF functional nephron mass GFReg. ampicillinaminoglycosidesdigoxin- ampicillin : large margin of safety GFR biliary excretion dosage only if GFR < 20 ml / min.- aminoglycosides digoxin dosage in all degrees of RFexcreted mainly by glom. filtr. low therap. ratio

Active tubular secretionFrom bloodstream to the lumen of proximal renal tubuleMembrane transporters : - P-gp : for organic cations & neutral compounds - MRP : for organic anions & conjugated metabolites Competition among organic acids, and among organic bases Example : penicillin + probenecid for gonorrhea

Active tubular secretion in RF Dysfunction of tubular secretion excretion of drugs Organic acids accum. in RF (eg. conjugates, FFA) inhibit secretion of penicillins, cephalosporins, sulfa, nitrofurantoin, thiazides, furosemide, etc. Organic bases competition usually not important clinically.

Tubular reabsorption mostly occurs by nonionic passive diffusion of lipid soluble drugs along the renal tubulesthe degree of ionisation depends on the pH of the luminal fluid - acidic drugs : pKa 3.0 7.5- basic drugs : pKa 6.0 12.0 E.g. in cases of phenobarbital or salicylate toxicity : alkalinize the tubular urine with NaHCO3 ionisation excretionmembrane transporters at distal renal tubule :for active reabs. from the tubular lumenback into the systemic circulation, of compounds required

can be affected by urinary pH

Renal excretion of metabolites in RF accum. of toxic metabolites ADReg. of meperidine seizuresof nitrofurantoin periph. neuropathyof morphine excess respir. depr.

End-stage renal disease (ESRD)ESRD - glom. filtration almost none - tubular secretion of acidic drugs (competition with accum. organic acids) requires dialysisDrugs - excreted by glomerular filtration at least partially dialyzable - excreted by tubular secretion may / may not be dialyzable

Drug removal during Hemodialysis (HD)Dialysate is aqueous only water soluble drugs are dialyzableMostly by diffusion through membrane poresOnly unbound drug is diffusibleDiffusivity as MW - MW > 1000 Daltons (very few drugs) :negligible diffusive clearance- Small solutes : flow-dep. clearance- Larger mols. : diffusion rateCharged drugs are less dialyzable, because :- charged repulsion at the membrane surface- drug binding to the membrane

Supplemental dose after HDRequired if signif. drug removal occurs during HDDrugs : - MW < 500 Daltons - water soluble, uncharged - minimal protein binding - Vd < 1 l/kgHD clearance is clinically significant if total body clearance by 30-50 %Suppl. dose = (desired conc. conc. postHD) x Vd

significant removal

Peritoneal Dialysis (PD) :- very inefficient in removing drugs little evidence of significant drug removal during chronic PD- eg. 1 HD treatment removes ~ 2/3 of body stores of aminoglycosides24-hours CAPD removes only 25-30 % of the drug.

Drugs requiring supplemental doses after each HD session Aminoglycosides MetronidazoleCephalosporins (most) FlucytosinePenicillins (most) Ethambutol, INHVancomycin PyrazinamideSulfonamides, TMP Aciclovir, GanciclovirOfloxacin, ciprofloxacin Zidovudine, Didanosine

Renal function for drug dosing Drug elimination by the kidney is assumed directly proportional to GFR, and ClCr is traditionally used to approximate GFR.Cockcroft & Gault formula : (140 - age) x ideal BW (kg)- For men : ClCr (ml/min) = 72 x CCr (mg/dl) - For women : 0.85 x ClCr for men- For acute renal failure : ClCr < 10 ml/min should be assumed for drug dosage adjustment

Dosage Adjustment : DLLoading dose (DL)to achieve therapeutic conc. directly DL = Desired therap. conc. (peak) x Vd (mg/kg) (mg/l) (l/kg)

No adjustment, except :- digoxin : 50-75 % of usual DL- AGs : 75-80 % of usual DL

bec. Vd & narrow margin of safety

Dosage Adjustment of DM (maint. dose)2 methods :Interval extention ( l ) with normal DM- may prod. odd interval dosing errors & compliance- not for drugs with narrow margin of safety(large plasma level fluctuation)- potentially lead to periods of subtherapeutic drug concs.- encouraged for drugs with conc.-dependentkilling (eg. AG)

Dosage Adjustment of DM (2)2. DM reduction (D) with normal interval- more constant drug levels - desired for drugs with narrow margin of safety (digitalis, antiarrhythmias, and anticonvulsants)- risks toxicity due to higher trough levels (eg. AG)

3. Combination of I & D for convenience,without jeopardizing efficacy & safety

Dosage Adjustment of DM (3)G = 1 f (1 GFRF / GFRN)f = ClR / ClT

G = Giusti-Hayton correction factorGFRF = GFR in RFGFRN = normal GFR

ClR = renal clearance of drugClT = total clearance of drug

Dosage Adjustment of DM (4)DMF = DMN x G DMF = DM in RF; IF = IN x 1/G DMN = normal DMI = dosing interval

For small GFR in ESRD (ClCr < 10 ml/min) :use Clinulin or Cliohexolnot ClCr (some Cr tub.secr.)

Dosage Adjustment example Gentamicin : f = 1RF with GFR = 33 ml/min.Normal GFR = 100 ml/min.Normal dosage = 7 mg/kg od in 60 kg patient to achieve Cmax = 20 mg/ml = 10 x MIC of Ps.aerug.

G = 1 1 (1- 33/100) = 1/3 DM in RF :- 420 mg every 3 x 1 day = 3 days or- 1/3 x 420 mg = 140 mg once daily or- 2/3 x 420 mg = 280 mg every 2 x 1 day = 2 days (choose the most convenient) as an example of dosage adjustment but for AG, choose the 1st

Pharmacodynamics in RFUremia :- CNS sensitivities to benzodiazepines and opiates- pressor effects of catecholamine- bradycardia by b-blockers- hypokalemia arrhythmia by digitalis- hyperkalemia AV block by digitalis, quinidine, procainamide, phenothiazines, TCADs

Other Pharmacologic Problems in RF (1)UTIs : require adeq. AB conc. in renal parenchyma or urine* AG enter urine only by glom. filtration not effective* Penic, Cephalosp.SA, TMP * Require normal doses adeq. urin. levels(modest serum levels no clin. conseq.)

enter urine by tub. secr. effective

Other Pharmacologic Problems in RF (2)2. Renal cyst infection :* Cotrimoxazole Chloramph, FQ

* Penic, Cephalosp, AG can penetrate cyst walls effectivepoor penetration not effective

Other Pharmacologic Problems in RF (3)3. Muscle paralysisRF accum. of NM blockers & prolonged effect, worsened by accum. of AG respir. dysfunction

4.Creatinine - a base also actively secreted by renal tubule basic drugs (cimetidine, TMP) compete for tubular secr. Clcr & Ccr

Other Pharmacologic Problems in RF (4)5. Metabolic loadsAcidAspirin, acetazolamideAlkalineAntacidsMgAntacids, laxativesKK-penic, K-sparing diuretics, ACEINaAmpicillin, piperacillin, ticarcillinUreaGlucocorticoids, tetracyclines (antianabolics), hyperalimentation, proteinH2ONSAIDs, carbamazepine

Special Drugs & CircumstancesNSAIDs nephrotoxic : - inhib. of renal PG renal vasocontr. ARF - hypersensitivity interstitial nephritis - long-term use renal papillary necrosis* High-risk pts : - elderly - compromised RBF & vol. depletion + UTI avoid use* If use is necess., esp. contin. use close monit. of ClCr & regular urinalysis

2. Analgesics* acetaminophen safe, but not always effective* opiates for more severe pain, but retention of active metabolites prolonged analgesia & respir. depr.* analgesic nephropathy avoided by using single analgesic (not mixture of > 1 analgesic, esp. combined with caffeine or codeine)

3. Cardiovascular DrugsACEI & ARB * Pre-existing - renal dis. due to atherosclerosis (compromized renal perfusion)- periph., cerebral, coron. vasc. dis.* Usually revers. on drug withdrawal* Accum. In renal dysf. dosage* Check renal function 3-4 days after starting therapy ensure no GFR or serum K renal dysf.

CCBs elim. by hepatic metabolism used in usual dosages in RFDigoxin : maint. dose in RF monitor plasma conc.-blockers : dose of -bl mainly elim. by kidney

Diuretics * Loop diuretics : required to avoid volume overload* Extensive prot. binding not much glom. filtr. must be secreted by organic anion pump in basolateral membr. of renal tubule* Azotemia : organic acids compete for the active transp. dosage : double doses every 30-60 min. until ceiling dose is reached or diuresis occurs if ineffective + thiazide if still ineffective contin. iv inf. of loop diur.* Thiazides : generally not effective if ClCr < 25 ml/min.* Ototoxicity : mostly ethacrynic ac., but also furosemide & bumetanide

4. Antimicrobial Agents (AMs)Except AG and vancomycin, most AMs have a wide therapeutic index little or no dosage adjustiment is normally made until the GFR < 20 ml/min.Drugs that are removed by dialysis adm. after dialysis or a supplemental dose should be given after dialysis

Aminoglycosides * Bactericidal efficacy ~ Cmax* Toxicity Cmin* Nephrotoxicity :- aggravate pre-existing renal dysfunction- cause de novo ARF- usually reversible* Ototoxicity :- irreversible vestibular damage- concom. use of loop diuretics, esp. ethacrynic acid risk of ototoxicity dosage adjustm. : esp. interval approach

Vancomycin * nephrotoxic & ototoxic plasma conc. should be monitored * not dialysed after a single iv infusion, therap. conc. can be maintained for 5 days in pts with end-stage RF on dialysis

Tetracyclines BUN in RF (due to its antianabolic effects worsen the renal dysf.) do not use in RF, except doxycycline & minocycline

Antituberculosis drugs INH, rifampicin, pyrazinamide normal daily doses may be given in renal impairment; with INH, + pyridoxine to prevent periph. neuropathy Streptomycin and ethambutol avoided where possible Streptomycin : major toxicity is vestibular if required : dose 2-3 x/week for first 2 mos, monitor plasma conc. Ethambutol : cause optic neuritis if excessive dosages are used or renal function is impaired dose, give intermittently; any visual changes discont. immediately & seek medical advice

Amphotericin - nephrotoxic use in renal failure only if there is no alternative plasma conc. & renal function : monitor closely prot. binding to lipoproteins in RF low plasma concs interprete accordingly

Antiviral drugs aciclovir & ganciclovir are elim. by kidney dose in RF; accum. lead to CNS toxicity & unconsciousness

5.Antianxiety drugs, Hypnotics and Antipsychotics Adv. RF : particularly sensitive to CNS depressant effect of these drugs start T/ with a smaller than normal dose

6.Li and Antidepressants Li avoid if possible or dose with careful monitoring of plasma conc. TCADs & newer ADs prescribed in normal dosages

7.Insulin renal function insulin requirements, bec. elim. by kidney RF dosage is required Uremia : - insulin resistance due to a post-R/ defect,corrected by dialysis - response to hypoglycemia also impaired8.OADs chlopropamide t1/2 avoid ! glibenclamide prolonged hypoglycemia due to accumulation of an active metabolite wh. bind tightly to pancreatic -cells metformin : C.I. in RF bec. risk of lactic acidosis glipizide : OAD of choice in RF because of: - short duration of action - eliminated by hepatic metab. to inactive metabolites

9.GI drugsAntiulcers- ranitidine : eliminated by liver & kidney dose in severe RF- omeprazole : no dosage adjustmentAntacids- Mg trisilicate mixtures have high Na content- Al-cont.comp. ( AL(OH)3 or sucralfate) risk of Al toxicity in severe RF or dialysis pts avoid !10.Antigout drugs Allopurinol : metab. to oxypurinol, accum. in RF causes rashes (if severe potentially fatal toxic epidermolysis), bone narrow depression and GI upset daily dose to 100 mg in RF Colchicine : in excessive doses diarrhea, GI hemorhage, rashes and renal impairm. in RF

11.Nephrotic syndromeAlbumin is lost in urine bound drug is also lost- refractory to diuretic therapy- clofibrate can provoke severe muscle necrosis, all fibrates used with caution !

Summary (1)1. In general : Dosage adjustment in RF is not required, when :a) renal elimination of the drug < 33 %, and the metabolites are not active, orb) GFR still > 50 ml/min. For most antibiotics : when GFR still > 20 ml/min.2. For drugs - with narrow margin of safety &- main elimination by renal excretion (eg. aminoglycosides, vancomycin, digoxin)dosage adjustment is required in all degrees of RF.

Summary (2)3. Supplemental dose postHD :- HD clearance at least 30 % of total body clearance- Drugs with MW < 500 D, water soluble, uncharged, minimal protein binding, Vd < 1 l/kg4. Alteration in phkinetics & phdynamics risk of ADR5. Multiple medication drug interactions

Conclusions Drug usage in RF :Estimate dosage from calculation or dosing tablesAvoid use if too risky and other safer drug is availableRefine the dosage estimation by titration of efficacy and safety in individual patientSupplemental dose can be predicted from MW, water solubility, charge, protein binding, and Vd

Note : Calculation of drug dosage in RF is based on various assumptions :no change & no interindividual variation in drug absorption, distribution, and metabolismno active / toxic metabolitesdrug elimination indep. of dose (linear phkinetics)no change & no interindiv. variation in phcol. responsestable renal functionClR of drug ~ ClCr (for drugs filtered by glomerulus or secreted by renal tubule) dosage adjustment based on the above calculations -- only for initial estimation, should be followed by further adjustments based on patients clinical response and/or the plasma drug concentration

Thank You

****************************************************