Drug Dosing in Patients with Renal...

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Drug Usage in Patients with Renal Failure

Arini SetiawatiDept. Pharmacology & TherapeuticsMedical Faculty, Univ. of Indonesia

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• 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, renally excreted active/toxic metabolites

need dosage adjustment

- Clinically significant removal by hemodialysis need supplemental dose

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Renal Failure (RF) :

• Drug pharmacokinetics & pharmacodynamics frequently altered → ↑ risk of ADR

• Multiple medical problems → polypharmacy → ↑ drug interactions

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Drug absorption in RF :

• N, V, D, bowel edema drug malabsorption, worsened by NSAIDs

gastric ∀ ↑ salivary urea ammonia

ureases↑ gastric pH

↓abs. of Fe, ketoconazole, itraconazole, etc.

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Plasma protein binding in RF• Uremia

↑ FFA

• MalnutritionProteinuria

∀ ↑ 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

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Drug distribution in RF

• Edema or ascites → ↑ Vd of water-sol. drugs

• Vol. contraction → ↓ Vd of aminoglyc.Muscle wasting → ↓ Vd of digoxin

↓ ↑ plasma conc.

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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

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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

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Renal excretion in RF

Renal clearance (ClR) =

fu • GFR + active tubular secretion - active & passive tubular reabsorption

fu = fraction of unbound drug (to plasma protein)

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Drugs mainly eliminated by renal excretion • Penicillins • Ethambutol• Cephalosporins • Diuretics• Aminoglycosides • ACE inhibitors• Tetracyclines (Avoid !) • Digoxin• Sulfonamides • Atenolol• Nitrofurantoin • Disopyramide

These drugs are excreted by the kidneys in unchanged form → will accum. in RF ↓ ↑ intensity of pharmacol. effect & ↑ toxicity ↓ ↓ dosage

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Glomerular filtration in RF • only unbound drugs with MW < 60.000 are filtered by

functional nephrons

• RF → ↓ functional nephron mass → ↓ GFReg. ampicillin

aminoglycosidesdigoxin

- ampicillin : large margin of safety ↓ GFR → ↑ biliary excretion ↓ dosage only if GFR < 20 ml / min.

- aminoglycosides digoxin

↓ dosage in all degrees of RF

excreted mainly by glom. filtr.

→

low therap. ratio →

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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.

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Passive tubular reabsorption in RF

• only for nonionic lipid soluble drugs

• affected by urinary flow rate & urinary pH

• in RF : ↓ urin. flow but also ↓ tubular conc. of drugs → not affect passive tubular reabsorption

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Renal excretion of metabolites in RF

• accum. of toxic metabolites → ADReg. of meperidine → seizures

of nitrofurantoin → periph. neuropathy

of morphine → excess respir. depr.

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End-stage renal disease (ESRD)

• ESRD - glom. filtration almost none - tubular secretion of acidic drugs ↓

(competition with accum. organic acids)

→ requires dialysis

• Drugs - excreted by glomerular filtration − at least partially

dialyzable

- excreted by tubular secretion − may / may not be dialyzable

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Drug removal during Hemodialysis (HD)• Dialysate is aqueous → only water soluble drugs are

dialyzable

• Mostly by diffusion through membrane pores

• Only unbound drug is diffusible

• Diffusivity ↓ as MW ↑- MW > 1000 Daltons (very few drugs) :

negligible diffusive clearance- Small solutes : flow-dep. clearance- Larger mols. : ↓ diffusion rate

• Charged drugs are less dialyzable, because :- charged repulsion at the membrane surface- drug binding to the membrane

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Supplemental dose after HD

• Required if signif. drug removal occurs during HD

• Drugs : - MW < 500 Daltons - water soluble, uncharged - minimal protein binding - Vd < 1 l/kg

• HD clearance is clinically significant if↑ total body clearance by 30-50 %

• Suppl. dose = (desired conc. – conc. postHD) x Vd

significant removal

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• 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

aminoglycosides,24-hours CAPD removes only 25-30 % of the drug.

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Drugs requiring supplemental doses after each HD session

• Aminoglycosides • Metronidazole• Cephalosporins (most) • Flucytosine• Penicillins (most) • Ethambutol, INH• Vancomycin • Pyrazinamide• Sulfonamides, TMP • Aciclovir, Ganciclovir• Ofloxacin, ciprofloxacin • Zidovudine, Didanosine

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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

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Dosage Adjustment : DL

Loading 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

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Dosage Adjustment of DM (maint. dose)

2 methods :1. 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)

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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

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G = 1 – f (1 – GFRF / GFRN)

f = ClR / ClT

G = Giusti-Hayton correction factor

GFRF = GFR in RF

GFRN = normal GFR

ClR = renal clearance of drug

ClT = total clearance of drug

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DMF = DM

N x G DMF = DM in RF;

IF = IN x 1/G DMN = normal DM

I = dosing interval

• For small GFR in ESRD (ClCr < 10 ml/min) :use Clinulin or Cliohexol

not ClCr (some Cr – tub.secr.)

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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 µg/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)

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Pharmacodynamics in RF

Uremia :- ↑ CNS sensitivities to benzodiazepines and opiates

- ↓ pressor effects of catecholamine

- ↑ bradycardia by β-blockers

- hypokalemia → arrhythmia by digitalis

- hyperkalemia → ↑ AV block by digitalis, quinidine, procainamide, phenothiazines, TCADs

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Other Pharmacologic Problems in RF (1)

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

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2. Renal cyst infection :* Cotrimoxazole Chloramph, FQ

* Penic, Cephalosp, AG

can penetrate cyst walls →effective

poor penetration →not effective

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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

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5. Metabolic loadsAcid Aspirin, acetazolamideAlkaline Antacids, carbenicillinCreatinine Anabolic & androgenic steroidsMg Antacids, laxativesK K-penic, K-sparing diuretics, ACEINa Ampicillin, piperacillin, ticarcillinUrea Glucocorticoids, tetracyclines

(antianabolics), hyperalimentation, protein

H2O NSAIDs, carbamazepine

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Special Drugs & Circumstances (1)

1. NSAIDs – 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

* If use is necess., esp. contin. use → close monit. of ClCr & regular urinalysis

avoid use

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2. ACEI & 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.

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3. 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

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Special Drugs & Circumstances (4)4. Aminoglycosides

* Bactericidal efficacy ~ Cmax

* Toxicity ∼ Cmin

* Nephrotoxicity :

- aggrevate 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

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5. Tetracyclines↑↑ BUN in RF (due to its antianabolic effects →

worsen the renal dysf.) → do not use in RF, except doxycycline & minocycline

6. 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 !

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7. Analgesics

* acetaminophen − safe, but not always effective

* opiates − for more severe pain, but retention of active metabolites →

prolonged sedative effects

* analgesic nephropathy − avoid by using single analgesic (not mixture of > 1 analgesic, esp.

combined with caffeine or codeine)

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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, or

b) 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.

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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/kg

4. Alteration in ph’kinetics & ph’dynamics → ↑ risk of ADR

5. Multiple medication → ↑ drug interactions

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Conclusions

Drug usage in RF :1. Estimate dosage from calculation or dosing

tables

2. Avoid use if too risky and other safer drug is available

3. Refine the dosage estimation by titration of efficacy and safety in individual patient

4. Supplemental dose can be predicted from MW, water solubility, charge, protein binding, and Vd

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Note : Calculation of drug dosage in RF is based on various assumptions :• no change & no interindividual variation in drug

absorption, distribution, and metabolism• no active / toxic metabolites• drug elimination indep. of dose (linear ph’kinetics)• no change & no interindiv. variation in ph’col. response• stable renal function• ClR 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 patient’s clinical response and/or

the plasma drug concentration

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Thank You

Drug Dosing in Patients with Renal...

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