Drug therapy in renal failure

Kari Laine, MD, PhDUniversity of Turku & medbase Ltd

Causes of renal failure• Kidney diseases

• Infections (glomerulonephritis); pyelonephritis seldom causes chronic renal failure

• Polycystic kidney diseases• Drug- or chemical-induced injury

• Secondary renal injury caused by a primary disease• DIABETES – type 2 diabetes a growing problem• High blood pressure and ischemic nephropathy

• Age – disease (diabetes, hypertension, ischemia)• Renal function decreases on average by 1% per year after

age 30 years

Prevalence of renal failure

• In the U.S. 35.000.000 people are estimated to suffer from chronic renal failure

• 13% of the population • Measured GFR<60 ml/min or demonstrated renal injury

• A recent meta-analysis estimated that in the Western population 23%-36% of people >64years of age has GFR<60 ml/min

Blix HS et al. Nephrol Dial Transplant 2006;21:3164-71.

• Prospective study in general hospitals• 201 patients (GFR<60 ml/min; 25% of the whole population) used an

average of 10 drugs• Approximately 40% of drugs were harmful to the kidneys or required

modification of the dose; 5% fully contraindicated• Almost all patients were co-administered a minimum of two harmful

drugs

• Typical risk drug toxicity in 62% of exposed patients• 26% of risk drug exposures caused toxicity

– Beta-lactam antibiotics, ciprofloxacin, aminoglycosides– antithrombotic agents and anticoagulants– anti-inflammatory drugs, codeine, tramadol– ACE-inhibitors/sartans, spironolactone/potassium– Allopurinol, metformin, sulphonylureas

Determination of renal function• The exact glomerular filtration rate (GFR) can

only be determined by means of radioactive markers exclusively eliminated by glomerular filtration:

• 51Cr-EDTA, 99mTc-DTPA, 125I-iothalamate• Administration: i.v.• Tracer clearance is measured from 3-5 blood samples• Determination with a gamma counter• Used also for monitoring the safety of the use of

nephrotoxic drugs

MDRD (Modification of Diet in Renal Disease)

• k uses a formula with four variables:

GFRMDRD = 186 x [serum crea]-1.154 x [age]-0.203

• For females, the coefficient is 0.742 • Accurate estimate with values less than 60 ml/min• Weakness: when GFR >60 ml/min or in critically ill

J Am Soc Nephrol 16: 459-466, 2005

MDRD accuracy

J Am Soc Nephrol 16: 459-466, 2005

Cockcroft-Gault1,23 x [140 – age (v)] x [weight (kg)]

GFRCG =

S/P-Creatinine (μmol/l)• For females, the coefficient is 0.85• In obese patients, ideal body weight must be used• Gives an accurate estimate when renal function is near

normal (GFR >60 ml/min); if value calculated with MDRD >60 ml/min, prompts for height and weight for calculating ideal body weight and determines GFR using the Cockcroft-Gault formula

Renal failure classificationDivided into four categories based on glomerular filtration rate in accordance with the guidelines of the European Medicines Agency (EMA) :

1.GFR 80-50 ml/min - mild renal failure2.GFR 50-30 ml/min - moderate renal failure3.GFR 30-10 ml/min - severe renal failure4.GFR <10 ml/min - end-stage renal failure; dialysis patient

Excretion of drugs in the nephron (1.25 million / kidney)

Glomerulus filtration- normally 125 ml/min; decreases by age- e.g. NSAIDs decrease; circulation ↓- protein binding reduces

Active transport into the tubulus- anions OAT/OATP; beta-lactams- cations OCT/OCTN; metformin- P-gp and MRP2; digoxin - Proximal tubulus

Passive reabsorption- most drugs; pH and intratubular flow rate have an influence

Active transport out of the tubulus- proximal tubulus- peptids PEPT1/2; glucose

Effects of renal injury on the pharmacokinetics of drugs

• Glomerular injury (diabetes)• Decreased glomerular filtration

• Tubular injury (drugs)• Decreased active tubular excretion

• Decreased number of nephrons– Decreased activation of vitamin D

• Active vitamin D derivatives must be used in end-stage renal failure, e.g. alfacalcidol

– Decreased clearance of insulin and glucagon

Renal clearance ↓ -significant whenever renal clearance exceeds 30% of total clearance

Relevance of metabolites• Prodrugs

– Parent drug inactive, pharmacologic effect from metabolites; e.g. codeine

• Parent drug and metabolite both active– E.g. risperidone, oxycodone

• Even glucuronide metabolites may be active– E.g. midazolam, morphine

Metabolites often accumulate in renal failure – it is important to be familiar with activity and kinetics and, if necessary, take them into account in concentration measurements!!

Extra-renal effects• Renal failure has an effect on

– Absorption of medicines• E.g. iron absorption is reduced

– Distribution of drug ingredients• Serum protein concentration and binding capacity of tissues are

reduced as a result of renal injury (albumin leaking into the urine and accumulation of uremic components)

• Total concentration is reduced but free concentration may remain unchanged or increase

– Drug metabolism and excretion into bile• Effects in phase I (2B6, 2C9, 2C19) and phase II (NAT, UGT2B7)• Hydrolysis of conjugates may occur in enterohepatic circulation;

excretion into bile may be saturated; reduced transport activity (OATP, P-gp)??

• Renal failure may affect the pharmacokinetics of a drug, even though renal clearance would not be of significant importance to total clearance:– Mechanism: uremic toxins and elevated cytokine activity,

which inhibit metabolic functions of the liver??– E.g. bupropion

• Renal clearance <1% of total clearance• Renal failure increases exposure to bupropion by 130%

The amount of the drug excreted in urine is not a fully reliable basis to determine the pharmacokinetics of the drug in

renal failure

• Response may change; e.g. beta blockers

Dialysis treatment• Dialysis treatment can be given as peritoneal

dialysis or hemodialysis• Dialysis treatment is commenced latest when

GFR falls below 10% of normal (< 10 ml/min)• Incidence figures:

– 1/3500 inhabitants in chronic dialysis treatment– Annually, 94 new treatments are commenced per

million inhabitants

Hemodialysis treatment• Intermittent, 3 times a week, 4–5 hours per session• Circulation is connected to the dialysis machine• Dialysis occurs through the thin walls of capillary walls of the

dialyser• Uremic toxins and the superfluous fluid pass through this

membrane based on their concentration and size

Peritoneal dialysis treatment• Executed via a peritoneal dialysis cannula; capillary walls of the

peritoneum serve as dialysis membranes• 2–3 litres of hyperosmolar fluid (natrium, glucose and lactate/bicarbonate

buffer) is introduced into the peritoneal cavity• The fluid “absorbs” water and uremic toxins from the system

- In CAPD (continuous ambulatory peritoneal dialysis), the patient usually makes four regular exchanges within 24 hours- In APD (automated peritoneal dialysis), the patient is hooked up to the machine every night for 4–6 fluid exchanges

Dialysis and drugs

• Both hemo- and peritoneal dialysis remove drugs• Factors affecting the removal of drugs:

– Molecular weight (e.g. vancomycin and amphotericin large – not removed)

– Plasma protein binding (if more than 90%, dialysability is often poor)

– Volume of distribution (large with e.g. tricyclics - most of the drug in tissues -> low elimination, rebound phenomenon)

– Dialysis method and equipment (i.a., dialysis membranes)– Dialysis conditions (duration, blood and dialysate flow rate)

Dialysis and drugs• Determination of dialysis clearance of a drug:

Dialysatecollection

Dialysatesolution

QB

V

A

Venous

Arterial

blood flow through the dialyzer (QB)

Dialysis and drugs

• The relative volume of the drug being removed can be calculated with the clearance achieved by dialysis

• The need of any additional dose caused by dialysis can be estimated/calculated using the elimination fraction

• Well dialysable drugs are usually administered to a dialysis patient after a dialysis session

• If the drug is removed both through dialysis and extrarenal elimination, an extra dose of the drug is usually also administered, equivalent to the volume of drug removed by dialysis

• Dialysis treatment may also alter extrarenal drug metabolism (i.a., liver metabolism) by removing uremic toxins (CYP3A4 activity ↑ 27%)

Nolin et al. J. Am. Soc. Nephrol. 2006

Renal toxicity of drugs

• Increases the risk of aggravation of already impaired renal function

• Should be avoided in patients with chronic kidney disease• Problem can often be avoided by choice of drug• Close monitoring of renal function/drug concentration

when an alternative safer option is not available• Aminoglycosides, anti-inflammatory drugs, cold, some

bisphosphonates, several immunosuppressives• Can be listed in the portal

development process– Standardised operating models for data search– Sources

• Medical literature (Pubmed)• Information published by the creator in Europe, Australia

and the United States

– Data coding using standardised methods• Mode of administration, classification, standard phrases

– Scientific assessment / inspection by a nephrologist

• Mode of administration is taken into account:– Systemic (per oral, i.v., i.m., s.c.)– Topical (dermatological, eye drops/ointments,

vagitories, local anaesthetics)

• Different recommendations for modification of the dose in different uses have been taken into account

• Any effect of the drug inducing renal injury has been assessed

classification – colour coding system

No need for modification of dose/dosage interval

The information is not available or the recommendation is estimated based on the pharmacokinetic characteristics of the substance

Modification of the dose or dosage interval is needed

Use should be avoided

For categories B and C, a detailed numerical information on the magnitude of dosage modification is provided whenever available.

A

B

C

D

Alert threshold

Distribution of classifications

References (linked to Pubmed) - approximately 5,000 references[1] Arancibia A, Drouguett MT, Fuentes G, González G, González C, Thambo S, Palombo G.

Pharmacokinetics of amoxicillin in subjects with normal and impaired renal function. Int J Clin Pharmacol Ther Toxicol 1982 Oct;20(10):447-53(PubMed Id: 7141752)

[2] Horber FF, Frey FJ, Descoeudres C, Murray AT, Reubi FC. Differential effect of impaired renal function on the kinetics of clavulanic acid and amoxicillin. Antimicrob Agents Chemother 1986 Apr;29(4):614-9(PubMed Id: 3707111)

[3] Humbert G, Spyker DA, Fillastre JP, Leroy A. Pharmacokinetics of amoxicillin: Dosage nomogram for patients with impaired renal function. Antimicrob Agents Chemother 1979 Jan;15(1):28-33(PubMed Id: 426503)

[4] Davies BE, Boon R, Horton R, Reubi FC, Descoeudres CE. Pharmacokinetics of amoxycillin and clavulanic acid in haemodialysis patients following intravenous administration of Augmentin. Br J Clin Pharmacol 1988 Oct;26(4):385-90(PubMed Id: 3190988)

[5] Lawson DH, Henderson AK, McGeachy RR. Amoxycillin: pharmacokinetic studies in normal subjects, patients with pernicious anaemia and those with renal failure. Postgrad Med J 1974 Aug;50(586):500-3(PubMed Id: 4618910)

[6] Francke EL, Appel GB, Neu HC. Kinetics of intravenous amoxicillin in patients on long-term dialysis. Clin Pharmacol Ther 1979 Jul;26(1):31-5(PubMed Id: 445959)

[7] Slaughter RL, Kohli R, Brass C. Effects of hemodialysis on the pharmacokinetics of amoxicillin/clavulanic acid combination. Ther Drug Monit 1984;6(4):424-7(PubMed Id: 6393464)

• Information on the use of more than 1,400 drugs during renal failure as well as dosage recommendations

• Includes special licence drugs• Vitamins and key micronutrients

• Search functions should always function with generic names and brand names of drugs

• Updated every 3 months

uses:• Portal use

• Doctors, dentists, pharmacists• All health care units• Drug chart reviews

• Integration to electronic patient record systems

• Doctors, dentists• Automatic decision support