Dosing of Drugs in Renal Failure

Learning Objectives

• By the end of this topic students should be able to:
• Understand how renal failure alters every pharmacokinetic (PK) phase—absorption, distribution, metabolism, excretion (ADME)—and the clinical consequences.
• Recognise physicochemical and PK characteristics that determine how a drug is handled by the kidney (size, protein binding, polarity, active‐transport affinity).
• Accurately assess renal function (e.g. $eGFR$, $Cl_{cr}$) and convert that assessment into evidence-based dose or interval adjustments.
• Predict, prevent and monitor drug-induced renal injury (DIRI) by appreciating its biochemical, immunological, and obstructive mechanisms.

Normal Renal Function & Drug Excretion

• Primary physiological role: maintain the constancy of the “interior environment” (Milieu intérieur).
• Achieved by removing metabolic waste and regulating extracellular volume, electrolytes and pH despite variable intake or climate.
• Major excretory pathways for drugs & metabolites (ranked):
• Kidney → urine (predominant).
• Liver → bile → faeces.
• Minor: skin (sweat), lungs (expired air), breast milk, saliva.
• Three sequential renal processes for each molecule entering the nephron:
• Glomerular filtration (size‐/protein binding–dependent, passive).
• Active tubular secretion (energy-dependent carriers, e.g. organic anion transporters (OATs)).
• Passive tubular reabsorption (lipid solubility, ionisation and urinary pH govern back-diffusion).
• Any perturbation to these processes alters drug disposition.

Drug-Induced Renal Disease (DIRD)

1. Direct Biochemical (Intrinsic Toxicity)

• Acute tubular necrosis (ATN) / acute tubular injury:
• Heavy metals: mercury, gold, iron, lead; environmental exposure (e.g. vape liquids containing metals).
• Antimicrobials: aminoglycosides, cephalosporins, vancomycin, amphotericin B, acyclovir.
• Radiocontrast media (iodinated): directly toxic to proximal tubular cells → radiocontrast-induced ATN.
• Loss of concentrating/collecting-duct function; NSAID-related ischaemic injury via prostaglandin suppression.
• Cytotoxic chemotherapy: cisplatin, 5-fluorouracil, methotrexate.
• Poisons: snake venom, paraquat.

2. Indirect Biochemical (Tubular Obstruction / Crystal Nephropathy)

• Uric acid crystals: tumour lysis syndrome; precipitate in acidic distal tubule.
• Calcium deposition: vitamin D (calciferol) → hypercalcaemia → nephrocalcinosis.
• Sodium/potassium depletion: chronic diuretic or laxative abuse → secondary tubular damage.
• Anticoagulants (warfarin, heparins) → renal parenchymal haemorrhage.

3. Immunological Injury

• Drug-induced glomerulonephritis or interstitial nephritis; can progress to systemic vasculitides or lupus-like syndromes.
• Culprits: penicillins, phenytoin, hydralazine, isoniazid, rifampicin, penicillamine, probenecid, sulphonamides.
• Pathology spectrum: arteritis → glomerulitis → interstitial nephritis → full systemic lupus erythematosus (SLE).

Sites & Pathological Types of Injury

Glomerular Damage

• Large capillary surface area predisposes to immune-complex deposition → proteinuria, nephrotic syndrome.
• Classic agent: penicillamine (autoimmune complex–mediated).
• Severity gauged best by creatinine clearance (direct surrogate for $GFR$).

Tubular Damage

• Nephron must concentrate ~$180\,\text{L}$ filtrate → $1.5\,\text{L}$ urine daily; proximal tubule experiences highest toxin concentration.
• Mechanisms:
• Accumulation via active uptake: aminoglycosides, cephalosporins, salicylates.
• Heavy metals & radiocontrast injury.
• Clinical markers: glycosuria, phosphaturia, bicarbonaturia, amino-aciduria (Fanconi-like picture).
• Renal medulla concentrates drugs via counter-current system → NSAID analgesic nephropathy (ischaemia + accumulation).
• Distal nephron specific: lithium-induced nephrogenic diabetes insipidus (↓ urinary concentrating ability).

Tubular Obstruction (Crystal or Precipitate)

• Low-pH distal tubule fosters precipitation: methotrexate, sulphonamides, acyclovir.
• Tumour lysis → massive uric acid → fatal urate nephropathy.
• Other patterns:
• Vasculitis: allopurinol, isoniazid.
• Allergic interstitial nephritis: penicillins (notably), thiazides, allopurinol, phenytoin.
• Drug-induced SLE: hydralazine, procainamide, sulfasalazine.

Pharmacokinetic Changes in Renal Failure (ADME)

Absorption

• Decreased oral absorption secondary to:
• ↑ gastrin; uraemic gastric acidity shifts.
• Delayed gastric emptying (gastroparesis).
• Nausea/vomiting.
• Bowel oedema; GI hypertrophy in ESRF.

Bioavailability

• Can paradoxically rise if hepatic first-pass is reduced:
• Propranolol, cloxacillin, dihydrocodeine, zidovudine (AZT).
• Example: dihydrocodeine AUC ↑ $70\%$ in CKD.

Distribution

• Volume of distribution ($V_d$):
• ↑ with oedema/ascites → lower plasma concentrations (dilutional).
• ↓ with cachexia/dehydration → higher concentrations.
• Plasma protein binding:
• Hypoalbuminaemia + carbamylated/oxidised albumin changes affinity.
• Retained endogenous inhibitors compete (e.g. organic acids).
• Result: ↑ unbound (active) fraction; for phenytoin free fraction rises $\sim20!–!25\%$ in uraemia.

Metabolism

• Intrarenal metabolism ↓ (many CYPs, conjugation enzymes in proximal tubule).
• Hepatic metabolism variably altered (down-, up- or unchanged) via inflammatory mediators, accumulation of inhibitors, altered protein binding.

Excretion

• Loss of filtration (↓$GFR$) and secretion (↓OAT/OCT activity) → prolonged half-life ($t_{1/2}$).
• Secretory transport especially affected for NSAIDs, penicillins, methotrexate, antivirals.

Clinical Syndromes of DIRI

• Acute kidney injury (AKI): aminoglycosides, cisplatin.
• Nephrotic syndrome: penicillamine, high-dose captopril.
• Chronic kidney disease progression: chronic NSAID abuse.
• Functional (non-structural) disorders:
• Nephrogenic diabetes insipidus (lithium).
• Hypokalaemia (frusemide) or hyperkalaemia (ACEI/ARB).
• Metabolic acidosis (acetazolamide).

Fundamental PK Parameters & Relationships

• Dose → Absorption → Systemic concentration → Distribution → Effect (PK/PD link).
• Clearance ($CL$) governs maintenance dose: $Dose<em>{rate}=CL\times C</em>{ss}$.
• $CL<em>{renal}=f</em>e\times CL<em>{total}$ where $f</em>e$ = fraction excreted unchanged.
• $t<em>{1/2}=0.693\times \dfrac{V</em>d}{CL}$ — extends exponentially as $CL$ falls.

Estimating Renal Function

• Cockcroft–Gault (adults): Clcr=SCr(μmol/L)(140−Age)×Weight (kg)×K​
• $K=1.23$ (men) or $1.04$ (women).
• Provides basis for gentamicin $CL$ equivalence (i.e. CLgent≈Clcr).
• Lab-reported $eGFR$ (CKD-EPI/MDRD) standardised to $1.73\,m^2$ BSA – adjust for extremes of size.

Dosing Adjustment Strategies

• General rule-set:
• Drugs eliminated almost entirely renally → ↓ loading or maintenance dose and/or lengthen interval proportionally to $Cl<em>{cr}$. • Drugs primarily metabolised hepatically → normal dose but close monitoring (renal failure can still alter binding or metabolite clearance). • Dual elimination (renal + hepatic) → keep usual loading dose (to fill $V</em>d$) but taper maintenance or extend interval.

Aminoglycosides (Gentamicin) – Worked Example

• Gentamicin $CL\approx GFR$; target $C<em>{peak}=5!–!8\,mg\,L^{-1}$, C{trough}<1\,mg\,L^{-1}.
• If $Cl<em>{cr}$ halves, failure to adjust → accumulation → ototoxicity + further nephrotoxicity (vicious circle). • Pragmatic tactic: extend dosing interval (easier, preserves $C</em>{peak}$ for concentration-dependent killing).

ACE Inhibitors / ARBs: Renal Considerations

• Block efferent arteriolar constriction → sudden $GFR$ drop in:
• Bilateral renal artery stenosis, solitary kidney, volume depletion, heart failure on aggressive diuretics.
• High doses → hyperkalaemia, hypotension, AKI.
• Monitor $S_{Cr}$ and $K^+$ within 1 – 2 weeks of initiation or uptitration.

Clearance Patterns vs. GFR (Drug Categories)

• Drug A: mixed renal/hepatic (e.g. ciprofloxacin, rivaroxaban) — moderate adjustment.
• Drug B: purely renal (e.g. dabigatran, many β-lactams) — dose highly dependent on $GFR$.
• Drug C: hepatic (warfarin, macrolides) — limited $GFR$ impact but still evaluate protein binding, metabolite accumulation.

Potential Alterations in Distribution (Non-Renally Cleared Agents)

• Even drugs cleared hepatically may accumulate because:
• ↑ free fraction → ↑ hepatic extraction saturability.
• Fluid shifts (oedema) enlarge $V_d$ for hydrophilic agents, delaying clearance.
• Therefore review all medications in CKD for efficacy and toxicity.

Practical Dose-Adjustment Workflow

• Step 1 – Estimate kidney function (lab $eGFR$ or Cockcroft–Gault).
• Step 2 – Determine $f<em>e$ from product information. • Step 3 – Decide method: reduce dose or extend interval; maintain similar $AUC$ = efficacy.
• Example quantitative approach: $\text{New Dose}=\text{Normal Dose}\times \dfrac{\text{Patient }Cl</em>{cr}}{100\,mL\,min^{-1}}$ (simplistic linear model, refine per drug PK).
• Step 4 – Monitor: therapeutic drug monitoring (TDM) when available (aminoglycosides, vancomycin, digoxin, anticonvulsants).
• Step 5 – Assess clinical/biochemical response; iterate adjustment.

Ethical & Practical Implications

• Failure to tailor doses in CKD is a preventable cause of hospitalisation, dialysis and death—patient safety mandate.
• Economic benefit: appropriate dosing ↓ length of stay, ↓ need for RRT, ↓ litigation.
• Interprofessional collaboration: pharmacists vital for renal dose checks; laboratory timely creatinine reporting.

Key Take-Home Messages

• Always think “kidney” for any drug: How much is renally cleared? How nephrotoxic is it?
• Renal failure influences all ADME facets, not only excretion.
• Creatinine‐based equations are approximations—apply clinical judgement (cachexia, amputees, acute changes).
• When in doubt: start low, go slow, monitor often, and use TDM.

References & Further Study

• Katzung BG et al., Basic and Clinical Pharmacology (11e).
• Rang & Dale’s Pharmacology (7e).
• Video mini-series:
• https://www.youtube.com/watch?v=X2-JTuSLuvQ
• https://www.youtube.com/watch?v=P0AQ_VndPG8 (plus playlist).