Pharmacologic consideration in acute renal failure patients

Dr Shadi ZiaieBoard of Clinical PharmacyAssistant professor of SBMU 

Labbafi‐nejad Hospital

• Drug dosing in patients with AKI can be

complex as a patient's renal function is

dynamic and difficult to quantify, their volume

status also fluctuates, and drug doses need to

be frequently reassessed.

Serum Creatinine

• Delayed increase in SCr after a renal insult

• Changes in SCr may lag behind changes in GFR by several days

• SCr levels may vary with intra‐ vascular volume expansion or

depletion and with hemodynamic changes, while renal parenchymal

structure and function remain unaffected

AKI is not a steady‐state condition

Measuring glomerular function can be difficult in AKI

Hospital‐acquired acute kidney injury in the elderly. Chronopoulos, A. et al. Nat. Rev. Nephrol. 6, 141–149 (2010)

Novel biomarkers

Neutrophil Gelatinase Associated Lipocalin (NGAL)

Kidney Injury Molecule‐1 (KIM‐1)

Interleukin‐ 18 (IL‐18)

Cystatin‐ C 

liver fatty acid‐binding protein (L‐FABP)

• Useful for early diagnosis of AKI and for prognosis prediction in several 

studies.

• Not currently recommended for use in routine clinical practice.

Hospital‐acquired acute kidney injury in the elderly. Chronopoulos, A. et al. Nat. Rev. Nephrol. 6, 141–149 (2010);

• Patients with AKI exhibit altered pharmacokinetic

parameters.

• For each individual patient, drug regimens must

be adjusted to optimize pharmacodynamics and

maximize treatment efficacy.

Altered Absorption• ↓ perfusion of the gut→ GI dysmotility→ ↓ absorbtion

• Accumulation of uremic molecules cause deterioration of the

integrity of the intestinal mucosa → ↑intes nal absorption

(propranolol)

• H2‐receptor antagonists or proton pump inhibitors, which raise the

pH of the stomach and can interfere with the absorption of weak

bases that require a strongly acidic environment for absorption

(ketoconazole, itraconazole)

Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)

Altered Distribution

• Decreased urine output secondary to AKI → extravascular fluid

gains can be more marked

• Vd is an estimate of the extent to which a drug will migrate into

extravascular tissues.

• It can also increase Vd of hydrophilic antibiotics, such as

aminoglycosides, β‐lactams, and glycopeptides → subtherapeutic

plasma concentrations of these agents.

Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)

• ↓serum albumin synthesis or ↑ extracellular

shifts of serum proteins→ reduction in protein

binding

• Accumulation of certain uremic molecules that

can bind to these proteins and displace the

drug from its binding site→↑ Vd

Altered Metabolismand non‐renal clearance 

• Non‐renal clearance is the aggregate of all

drug removal pathways excluding those

related to the kidneys.

• Hepatic metabolism comprises the largest

component of non‐renal clearance.

Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)

• The metabolism of drugs that are largely

extracted by the liver, such as β‐blockers and

midazolam, is highly influenced by hepatic

blood flow→

• Hepatic blood flow↓→↓ Cl

• Metabolic enzyme activity in the liver also seems

to be decreased in patients with AKI

• Some hepatic cytochrome P450 (CYP) enzymes

are affected by AKI

• CYP3A4 activity was inversely related to plasma

blood urea nitrogen concentrations.

Altered renal Elimination

• AKI is not only associated with decreased

glomerular filtration by the kidney, but also

with impairment of tubular secretion and

reabsorption.

Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)Drug use and nephrotoxicity in the intensive care unit . Mark A. Perazella, Kidney International (2012) 81, 1172–1178

• Once formed, drug metabolites, like the parentcompound, must be cleared from the body.

• The clearance of drug metabolites is of particularimportance if the formed metabolites arepharmacologically active.

• In AKI, metabolites that are normally renally eliminatedmay be retained and accumulation is more likely to beproblematic with repeated dosing.

Pharmacodynamic

• Few studies have investigated the pharmacodynamics

of drugs in patients with renal disease.

• Clinical observations report that patients with renal

disease are more sensitive to various drugs.

• Morphine, nifedipine ,warfarin

• Transporters

Drug metabolism and 

clearance are also affected 

by transporter activity, may 

facilitate drug uptake or 

removal in various organs 

throughout the body.

Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)Drug use and nephrotoxicity in the intensive care unit . Mark A. Perazella, Kidney International (2012) 81, 1172–1178

• In addition to AKI having an effect on drugmetabolism, AKI also affects transporter function.

• The decreased activity of P‐gp and OATs in AKIwould contribute to decreased drug clearanceand may potentially result in increased drugexposure.

Drug Dosing Approaches

Loading dose 

• As the Vd of many drugs, especially hydrophilic

antibiotics, including b‐lactams, cephalosporins,

and penems, are significantly increased in the

presence of AKI, the administration of aggressive

loading doses (25–50% greater than normal) are

highly recommended.

Drug use and nephrotoxicity in the intensive care unit . Mark A. Perazella, Kidney International (2012) 81, 1172–1178Antibiotic dosing in critically ill patients with acute kidney injury. Rachel F. Eyler , Bruce A. Mueller. Nat. Rev. Nephrol. 7, 226–235 (2011)

Maintenance dose• Clinical judgment is paramount and forecasting the degree and rate of change in

kidney function and fluid volume status is fraught with uncertainty.

• Because of the

• Reduced renal drug excretion

• Preservation of nonrenal clearance for some agents such as vancomycin,

imipenem, and ceftizoxime,

• Some contribution from impaired hepatic metabolism

• Tendency to attain a positive fluid balance in the early stages of AKI

• the dosing regimen for many drugs, especially antimicrobial agents, should be

initiated at normal or near normal dosage regimens.

Drug use and nephrotoxicity in the intensive care unit . Mark A. Perazella, Kidney International (2012) 81, 1172–1178

• Concentration dependent antibiotics

• Time dependent antibiotics

Therapeutic drug monitoring• Prospective measurement of serum drug concentrations and the

subsequent use of sound PK/PD therapeutic drug monitoring

approaches should be used whenever possible, especially for

drugs with a narrow therapeutic range.

• When this is not a possibility because of the unavailability of rapid

specific analytical methods for the determination of serum drug

concentrations, the development of excessive pharmacologic effect

or toxicity may be the primary indicator of a need for dosage

adjustment.

Drug use and nephrotoxicity in the intensive care unit . Mark A. Perazella, Kidney International (2012) 81, 1172–1178

Attention to: 

Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Gary R. Matzke1, George R. Aronoff et al. Kidney International (2011) 80, 1122–1137

• AKI not only changes the renal clearance of drugs but also the nonrenal

clearance.

• Even drugs that are primarily hepatically eliminated may accumulate

during AKI.

• Periodically, monitor serum drug concentrations or pharmacodynamic

response when feasible, even for drugs that are considered to be

predominantly hepatically cleared.

• Because AKI is a dynamic process, continual monitoring of serum drug

concentration is necessary, particularly with changes in drug dose and

clinical status.

• Metabolites may accumulate with AKI.

• Be aware of potential pharmacologically active metabolite accumulation with AKI.

Also, consider dose adjustment when enough time has elapsed such that

metabolite accumulation is likely to have occurred.

• RRT affects drug removal directly, but these therapies may also have an impact on

the nonrenal clearance of drugs.

• Initiation of RRT may hasten hepatic clearance of drugs that are cleared by

CYP3A4, such as amiodarone, cyclosporine, erythromycin, midazolam, nifedipine,

quinidine, and tacrolimus.

• RRT may further modify the pharmacokinetic and dynamic changes of parent

compounds/metabolites.

• Drug dose and response should be evaluated when RRT is started and stopped.