L22 Dosing in Kidney Disease & Nephrotoxic Drugs Flashcards
Effect of Renal Impairment on Drug Usage
Change in drug distribution (Decrease in Bound, Increased Free)
Accumulation of drugs “normally” excreted
Accumulation of “active” metabolites
Decrease in renal and hepatic drug metabolism
Pharmacodynamic effects (“sensitivity” to some drugs)
GFR: Measurement vs Estimation?
Measuring: 24-hour urine collection for Creatinine and Urea
– GFR = Ccr in normal individuals and patients with mild CKD
– GFR = (Ccr + Curea)/2 in more advanced CKD
Formulas for estimating GFR
Cockroft-Gault (estimated Creatinine CL in ml/min):
MDRD (estimated GFR)
Prescribing for a Patient with Renal Dysfunction?
Ascertain level of renal function (estimated GFR/CCr)
Establish integrity of liver metabolism
Establish loading dose (if indicated)
Maintenance dose - dose reduction vs. interval extension
Check for drug interactions
Avoid nephrotoxins
Decide whether blood level monitoring is indicated
Prescribing Aminoglycacides in Renal Impairment?
Excretion of aminoglycosides is principally via the kidney & accumulation occurs in renal impairment
The interval between doses must be increased; if renal impairment is severe, the dose should be reduced as well.
Serum concentrations must be monitored closely
Risk of Aminoglycoside Nephrotoxicity: (Esp. Gentamicin)
- AKI secondary to Acute Tubular Necrosis
- Freely filtered at the glomerulus
- 5-10% of dose taken up by proximal tubule
Assume GFR _______ if oliguria/AKI present
Assume GFR <10ml/min if oliguria/AKI present
Classifications of Causes of Acute Kidney Injury?
Drugs Causing Prerenal AKI?
Pre-Renal AKI: Haemodynamically-mediated AKI caused by reduced glomerular blood flow
Common drug causes:
ACE-inhibitors/Angiotensin-2 Receptor Blockers
NSAIDs
Diuretics
Calcineurin Inhibitors (transplant immunosuppression)
When to Exercise Caution with ACE-Is/ARBs?
ACEi/ARBs Vasodilate EFFERENT > AFFERENT arteriole=>LOWER INTRAGLOMERULAR PRESSURE (ANGII Constricts Effent more than Efferent Typically)
In certain settings, renal function depends on sustained efferent arteriole vasoconstriction by Ang II, necessitating caution w/ ACEi/ARB use.
Exercise Caution with:
- Unwell patient (“Sick Days”) – hypotension, dehydration, sepsis
- During aggressive diuresis
- Use of another medication that alters afferent or
efferent arteriolar tone e.g. NSAIDs, tacrolimus,
cyclosporine, iodinated radiocontrast - Bilateral renal artery stenosis
- Advanced CKD
NSAID-Associated Nephrotoxicity
Inhibit renal vasodilatory prostaglandins: PGE2 & PGI2 => Result in drop in GFR
Chronic: Analgesic Nephropathy:
- Daily long-term use of 2 or more analgesic agents, usually with codeine or caffeine
- Papillary necrosis & chronic tubulo-interstitial
nephritis
Causes of Acute Tubular Necrosis?
1. SHOCK/ISCHAEMIA: Any process associated with prerenal AKI can cause ATN
2. NEPHROTOXINS:
A. Endogenous (hemolysis, rhabdomyolysis, myeloma proteins, tumor lysis, sepsiscytokines)
B. Exogenous (drugs, poisons)
Drugs that can Cause Acute Tubular Necrosis?
Aminoglycosides (e.g. GENTAMICIN)
Vancomycin
Amphotericin B
Cisplatin
Iodinated radiocontrast
Tenofovir
Cidofovir
Foscarnet
Amphotericin Nephrotoxicity Manifestations/Prevention?
Manifestations
- High Incidence: reduction in renal function in ~80% when cumulative dose >2g
- Causes AKI secondary to Acute Tubular Necrosis & renal vasoconstriction
- Also causes K+ & Mg2+ wasting
Preventing Amphotericin Nephrotoxicity
- Use alternative antifungal agents?
- Avoid concomitant nephrotoxins
- Use lower doses
- Saline loading
- Use lipid formulations of amphotericin
- Ambisome, Abelcet
- Reduce the incidence & severity of AKI
Risk factors for Contrast-Induced Nephropathy?
How to prevent?
AKI occurring within 48 hours of iodinated radiographic contrast administration (& not attributable to other causes)
Most important risk factors:
- Age>75 years
- Pre-existing renal impairment
- Diabetes mellitus
Strategies to Prevent Contrast-Induced Nephropathy
- Avoid radiocontrast if possible, use lowest dose possible & avoid repeated doses
- Use low-osmolality non-ionic agents (e.g. Iohexol)
- Stop all nephrotoxins, hold ACE-i/ARB
- Volume expansion (Give Fluids w/ Dye)
- Pre- & post-contrast
- 0.9% NaCl (or isotonic bicarbonate) IV solution
Drugs that can Cause Rhabdomyolysis?
STATINS: Hold statin while on clarithromycin/erythromycin or itraconazole therapy
Fibrates
Colchicine
Anaesthetic & paralytic agents (Neuroleptic Malignant Syndrome)
Misuse
- Ethanol
- Cocaine
- LSD
- Ecstasy
- Amphetamines
- Ketamine
Drug-induced Rhabdomyolysis => AKI
- Cause?
- Pathogenesis?
- Diagnosis?
- Management?
Causes: trauma, extreme exertion, cocaine, statins, alcoholism, snake bites, severe hypophosphatemia, severe hypokalemia, and viral infection
Pathogenesis:
Muscle Necrosis
◦ Release of CPK (↑↑↑)
◦ Release of myoglobin
Leads to….
◦ Renal tubular obstruction
◦ Direct tubular injury
◦ Renal vasoconstriction
Diagnosis
- Pigmented granular casts
- Reddish urine in supernatant
- Elevated CK (Creatine Kinase = Muscle damage)
Management:
- Early aggressive volume expansion is key.
- Alkalinization to urine pH > 6.5 and mannitol diuresis may be helpful but not proven
- Do not treat hypocalcemia unless symptomatic; avoid recovery hypercalcemia from sequestered calcium stores
