Drugs and the Kidneys Flashcards
To estimate a patient’s renal function based on a simple lab test
creatinine clearance or estimated creatinine clearance
Explain the ways that the kidney can “handle” the excretion of drug and/or metabolite
via diffusion or through transport proteins. Should assume that any drug will affect all parts of the nephron (though of course, some are more affected than others based on the drug
Predict the effect of kidney dysfunction on drug handling
ADME
Describe the major mechanisms and patterns by which drugs can adversely affect the kidney (cause nephrotoxicity)
ADME
- important to understand all of the medications a pt is on
Explain the significance of appropriate dosing in patients with kidney dysfunction/ requiring dial
Look up the product insert
Need to dose adjust in Chronic Kidney Disease == Important for drugs that have narrow therapeutic index
(1) Loading Dose = Vd x Cp
== unchanged in most drugs (exception: digoxin)
Vd –liters/kg. CP – desired plasma concentration
(2) Maintenance dose (strategies: reduce dose and/or expand dosing interval)
- - (a) reduced dose = [calc. creatinine clearance / nml creatinine clearance] * nml dose
- - (b) expanded dosing interval = [nml creatinine clearance / calc. creatinine clearance] * nml dosing interval
what pts are at risk for iatrogenic AKI?
25% due to meds
usually older, with lower baseline CrCl
Pre-existing cardio-vascular disease, on multiple medications, infectious diseases, neoplasms and respiratory disease
what Factors determining drug PK which -> PD
ADME:
- Absorption == passively or through protein uptake from intestinal lumen –> portal circulation
- Distribution /protein binding
- Metabolism
- Excretion -renal clearance
what Factors determining drug PK which -> PD
ADME:
- Absorption == passively or through protein uptake from intestinal lumen –> portal circulation
- Distribution /protein binding
- Metabolism
- Excretion -renal clearance
A 68-y.o. Caucasian male with PMHx of HTN and OA is admitted for redness of Rt. LE
Baseline Cr of 1.2mg/dL and weighs 72kg. His home medications include hydrochlorothiazide, metoprolol, and acetaminophen as needed for pain.
You are the intern on the ward - see that he has significant cellulitis for the foot - and order cephalexin for this condition.
0200, RN call you that the patient is having an exacerbation of his arthritic pain and you order scheduled ibuprofen as the patient is opiate naive
Within 36hrs his creatinine has increased from baseline of 1.2mg/dL to 2.4mg/dL
- what was the problem (ADME)?
- pathophysiology?
PROBLEM WITH ABSORPTION
- Ibuprofen inhibits COX - nonseclectively
- Inhibition of renal prostaglandins production with resulting altered renal vascular tone -> reduced renal blood flow
- Altered Na+ and H20 reabsorption -> renal insufficiency
==> retention == worsening kidney fx
A 40 yo male with nephrotic syndrome is admitted anuric and in acute on chronic renal failure ( K-6.0, Cr 2.5). 15lbs weight gain in 3 days. You decide to A. Give furosemide 40mg PO B.Give hydrochlorthiazide 25mg PO C. Give furosemide 40mg IV D. Give amiloride 10mg PO E. Give spironolactone 25mg PO F. Acetazolomide 375mg IV
C. Give furosemide 40mg IV
==> get rid of the water.
Bioavailability of lasix increased with renal dysfunction
48 year old male with PMHx of seizures, ESRD on HD, CAD, hypertension and hyperlipidemia is admitted for confusion and lethargy.
The day before presentation patient was found to be drowsy, not eating or drinking, had slurred speech, frequent falls and complaining of dizziness. He had been vomiting, with no abdominal pain or diarrhea, and no fever or chills
Medications: Lisinopril 40 mg, Metoprolol 50 mg BID, Atorvastatin 20 mg , NTG SL prn, Quetiapine 100 mg BID, Sertraline 50 mg, ASA 81 mg and phenytoin 200 mg BID.
P/E: T 36.9C, HR 98/min, RR 18/min, BP 124/72 mm hg. Drowsy, bil. nystagmus with lateral gaze, pupils reacting to light. Moving all four extremities, tone increased, DTR 3+/4, bil. plantars are down going. Patient could not stand up to assess gait. Rest of the PE is normal.
Labs: WBC 3, 200, Hb 12.8 gm/dl, Plt 186K. Na 134 mmol/l, K 4.6 mmol/l, CO2 26 mmol/l, BUN 68 mg/dl, Cr 4.8 mg/dl, phenytoin 15 mg/l, albumin 2.0mg/dl, LFT’s wnl. ECG: NSR, no new changes. CT of Head-No acute intracranial process.
What is the diagnosis?
What investigations need to be considered
How do you treat the patient?
Dx = phenytoin toxicity – even though that value is WNL
- phenytoin bound to albumin –> low albumin –> increased free phenytoin
- Serum total phenytoin (PHT) concentrations > 15 mg/L or free PHT concentrations > 5 mg/L are associated with toxicity; as serum conc. >20 mg/L, initial cerebellar symptoms (nystagmus, ataxia, and drowsiness) occur and are followed by basal ganglia signs (movement disorders).
- Competition of accumulated endogenous substances with drug binding sites on proteins Factoid: albumin for acidic drugs and α1 acid glycoprotein for basic drugs
Tests =
Tx =
what happens to each of the factors ADME in renal injury?
- absorption
1) reduced quantitative & qualitative proteins involved in transportation and metabolism ==> leading to some bioavailability increased (dihydrocodeine, propanolol, sildenafil, HIV protease inhibitors), some decreased (pindolol), some unchanged (fluoroquinolones)
2) increased gastric pH == reduced bioavailability (furosemide); increased drug interactions (GI binders for K/phosphate, PPI); N&V from severe renal injury
what happens to each of the factors ADME in renal injury?
- Distribution /protein binding
- Distribution /protein binding
1) Alterations in protein and tissue binding (esp for drugs that are highly protein bound) ==> Diminished protein binding (functional & quantitative)→ increased free drug conc. (phenytoin, valproate Na and warfarin)
2) Alterations in body weight and composition == ↑ TBW can have effects on distribution of hydrophilic drugs such as MTX, pravastatin, fluvastatin, morphine and codeine
3) Alterations in drug solubility
48 year old male with PMHx of seizures, ESRD on HD, CAD, hypertension and hyperlipidemia is admitted for confusion and lethargy.
The day before presentation patient was found to be drowsy, not eating or drinking, had slurred speech, frequent falls and complaining of dizziness. He had been vomiting, with no abdominal pain or diarrhea, and no fever or chills
Medications: Lisinopril 40 mg, Metoprolol 50 mg BID, Atorvastatin 20 mg , NTG SL prn, Quetiapine 100 mg BID, Sertraline 50 mg, ASA 81 mg and phenytoin 200 mg BID.
P/E: T 36.9C, HR 98/min, RR 18/min, BP 124/72 mm hg. Drowsy, bil. nystagmus with lateral gaze, pupils reacting to light. Moving all four extremities, tone increased, DTR 3+/4, bil. plantars are down going. Patient could not stand up to assess gait. Rest of the PE is normal.
Labs: WBC 3, 200, Hb 12.8 gm/dl, Plt 186K. Na 134 mmol/l, K 4.6 mmol/l, CO2 26 mmol/l, BUN 68 mg/dl, Cr 4.8 mg/dl, phenytoin 15 mg/l, albumin 2.0mg/dl, LFT’s wnl. ECG: NSR, no new changes. CT of Head-No acute intracranial process.
what was the problem (ADME)?
What is the diagnosis?
What investigations need to be considered
How do you treat the patient?
PROBLEM WITH DISTRIBUTION (binding to protein)
Dx = phenytoin toxicity – even though that value is WNL
- phenytoin bound to albumin –> low albumin –> increased free phenytoin
- Serum total phenytoin (PHT) concentrations > 15 mg/L or free PHT concentrations > 5 mg/L are associated with toxicity; as serum conc. >20 mg/L, initial cerebellar symptoms (nystagmus, ataxia, and drowsiness) occur and are followed by basal ganglia signs (movement disorders).
- Competition of accumulated endogenous substances with drug binding sites on proteins Factoid: albumin for acidic drugs and α1 acid glycoprotein for basic drugs
Tests = free phenytoin levels
Tx =
76 year old male with PMHx of chronic back pain & hypertension was brought to ED post fall with a left inter- trochantric fracture. He takes ASA 325 mg, atenolol 25 mg, Hctz 25 mg, morphine ER 20 mg BID and morphine IR 5mg q 6hrs prn for breakthrough pain .
Vital signs and examination unremarkable except for flexed and externally rotated left hip.
Labs: Normal blood counts, liver enzymes and chemistry (including renal function)
Fracture is successfully repaired and post-op morphine pump changed to home opiate regimen.( Regular morphine ER 15 mg BID and morphine IR 5mg q 6 hrs) RN worried about respiratory depression & you order ketorolac 60 mg IV every 12 hrs. POD #3 patient was discharged to SNF for rehab.
2 days later patient was sent to the ED from SNF as patient was found to be unresponsive and not breathing. En route to hospital patient was intubated.
What was the problem (ADME)?
what happened?
PROBLEM WITH EXCRETION
Opioid overdose ==> d/t renal insufficiency from NSAID use –> causing increased conc. of morphine
3-glucuronide (50%), 6-glucuronide (5% to 15%), and 3,6-glucuronide and other minor metabolites. Morphine 3-glucuronide has a low affinity for opioid receptors, has no analgesic activity, and may cause hyperalgesia (hyperesthesia), myoclonus, and allodynia
what happens to each of the factors ADME in renal injury?
- metabolism
-Metabolism
reduced drug metabolism: reduced Cyp3A activity in pts with ESRD ==> causing accumulation of active drug metabolites
- allopurinol, diazepam, glyburide, hydromorphone, meperidine, procainamide
what happens to each of the factors ADME in renal injury?
- excretion
-Excretion -decreased GFR ==> decreased renal clearance = increased exposure to drugs & their metabolites (esp in getting rid of drug metabolites –> builds up - ex. morphine, procainamide)
Saturation of tubular secretion process contributes to reduced renal clearance
Competition between drugs for secretion (e.g penicillin and probenecid, lithium and NSAID’s)
GFR vs CrCl in the everyday clinical evaluation of renal dysfunction
what happens to each of the factors ADME in renal injury?
- excretion
Kidneys are a major route of drug elimination
Either as parent drug, active or inactive metabolite
-Excretion -decreased GFR ==> decreased renal clearance = increased exposure to drugs & their metabolites (esp in getting rid of drug metabolites –> builds up - ex. morphine, procainamide)
Saturation of tubular secretion process contributes to reduced renal clearance
Competition between drugs for secretion (e.g penicillin and probenecid, lithium and NSAID’s)
GFR vs CrCl in the everyday clinical evaluation of renal dysfunction
A 43 year old man with IDDM and hypertension, has end stage renal disease, but is not on dialysis. He is seen at a local hospital ED because of persistent headache and nasal discharge, and is started on sulphamethoxazole/trimethoprim (Bactrim DS) 1 tab. bid for sinusitis. Because of persistent sinus pain he starts to take an OTC oral decongestant called Clearnase (ibuprofen, caffeine and diphenhydramine).
Three days later he collapsed while shopping and was brought to DHMC ED and noted to be bradycardic with HR 35/min, and EKG - peaked, long T waves, long QRS intervals
What is the problem here ?
What further management would you implement?
Hyperkalemia == d/t drugs (iatrogenic), foods, juices, worsening kidney dysfunction (leading to increased K+)
–> Therapy depends on how high the K+ is and the clinical state of the patient
IV calcium gluconate or chloride AND/OR Oral sodium polystyrene sulfonate (Kayexelate)
Glucose - insulin [esp. b/c DM]
NaHCO3
Hemodialysis
Albuterol-nebulized
Chronic therapy == kayexelate; patiromer
Why are the kidneys so vulnerable to drug induced damage?
25-30% cardiac output
High oxygen consumption/ATP production/utilization
High tubular concentration of drug/metabolite (b/c so involved in excretion)
how to establish cause & effect relationship in drug-induced kidney injury
- Temporal relationship between drug and disease
- Previous description of association
- Resolution with withdrawal of drug
- Re-introduction associated with recurrence
- Alternative diagnosis more plausible
Describe patterns of acute kidney injury
pre-renal failure (60-70%)
intrinsic (25-40%) = acute tubular injury; tubulointerstitial nephritis, thrombotic microangiopathy, glomerulonephropathy
post-renal (5-10%)
Describe patterns of chronic kidney injury
- tubulointerstitial nephritis
- glomerulopathy
What can cause pre renal failure
what pattern would you see in the labs?
how would you treat?
1) Medications that impair glomerular hemofiltration
- Salt (Na+/K+/Mg 2+) and water depletion e.g. diuretics
- NSAIDs
- Diuretics
- ACE inhibitors
- AT-II blockers (ARBs)
- Cyclosporine/tacrolimus etc.
2) Reduced LVEF (indirect)
- Beta-blockers, calcium channel blockers
- Cytotoxic; doxorubicin, high dose cyclophosphamide
- EGFR targeted Mab; trastuzumab
- EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib)
- Multi-targeted TKIs (sorafenib, pazopanib, etc)
==> UNa decreased, urinary sediment clear
Tx= increase fluids, can clear out these drugs Complication = renal necrosis
