Pharm Considerations in Kidney Disease Flashcards
What is pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Elimination
ADME of a drug
What do you know about absorption if you give a drug parenterally?
All of it will enter circulation
PO drugs, on the other hand, must be absorbed in the GI tract. What are the fates once absorbed?
The drug can either be bound (by proteins) or unbound. The unbound percentage is then free to distribute
What is fe?
fraction of drug RENALLY eliminated
What is the equation for Css of a drug?
If you give an infusion, Css will be equal to Dose/Clearance
How could you estimate how long it would take a drug to reach Css?
if giving an infusion, it usually takes about 4-5 half lives (it also takes about 4-5 half lives for the drug to be eliminated)
What do you do if you want to reach steady state more quickly?
give a loading dose
A 40 year old white male with CKD stage 3b is admitted to the hospital for sepsis and is started on empiric antibiotic therapy that includes gentamicin (an aminoglycoside which has concentration-dependent activity). His serum creatinine on admission is 2.5 mg/dL (estimated GFR 31 mL/min/1.73 m2). The dose of gentamicin for normal kidney function is 1.7 mg/kg every 8 hours with a target trough concentration of
Prolong the dosing interval (see similar peaks and troughs)
What happens if you reduce the dose?
Takes longer to reach steady state and you see lower peaks (less effective) and high troughs (more side effects)
So what is the best option for someone with kidney dysfunction and taking aminoglycosides to limit AEs?
prolong the dosing interval
What would be the best change if you needed to shorten the drug therapeutic window?
lower the dose (digoxin does this)
Why would kidney disease change drug absorption?
in many of the primary diseases that cause CKD (diabetic nephropathy) you see gastroparesis (delayed gastric emptying) or uremic gastritis or the gastric pH may change
What are some common drug interactions of someone with CKD?
patients are frequently on calcium-containing phosphate binders (aka antacids) and iron supplements (flouroquinolones!!)
Case. 47-year-old type I diabetic with end-stage renal disease has severe autonomic neuropathy, including severe gastroparesis with delayed gastric emptying and almost daily episodes of nausea and vomiting. She received a living related donor kidney transplant with excellent function. Postoperative day 4 serum creatinine is 1.0 mg/dL, however, tacrolimus level is subtherapeutic, leading to an increase in the daily dosage. Over the next 3-4 weeks nausea and vomiting significantly improved and tacrolimus level is supra-therapeutic, requiring a reduction in dosage. What’s happening?
The N/V and gastropheresis likely made it so that much of the drug wasn’t being absorbed and when it subsided, levels became too high
What are some drugs that see decreases protein or tissue binding in uremic pts.?
- Phenytoin
- Diazepan
- Salicylate
- Valproic Acid
- Pentobarbital
- Warfarin
so effective dose goes up!
Describe the protein binding of phenytoin.
Phenytoin is about 90% protein bound typically. It is an acidic drug so it binds to albumin
In kidney disease albumin levels may not be decreased but you still see increased unbound phenytoin levels. Why?
Albumin is displaced from normal binding sites
What is the overall effect of this change?
The effect of this change in phenytoin’s protein binding is that the measured total concentration could be low, but still therapeutic because the ratio between the free and total concentration has increased.
Example of slide 18.
Thus, at a normal protein binding level of 90%, a total phenytoin concentration of 7 mg/L is subtherapeutic (free concentration = 0.1 x 7 mg/L = 0. 7 mg/L), but if protein binding is decreased to 85%, then a measured total concentration of 7 mg/L would be therapeutic (free concentration = 0.15 x 7 = 1.05 mg/L).
Ideally, dosing changes should be based on unbound phenytoin concentrations (free phenytoin therapeutic range = 1.0 – 2.0 mg/L) and clinical response. Why aren’t they?
Due to challenges of measuring unbound concentrations available, estimating equations to “correct” the total phenytoin concentrations are used to (e.g., Sheiner-Tozer Equation); however, it is important to emphasize these are estimates.
An ESRD patient with a seizure disorder has been taking 300 mg/day of phenytoin for the past 2 months. The measured total phenytoin concentration is 5 mg/L (therapeutic range 10-20 mg/L). Albumin =3.3 g/dL. The resident suggests increasing the dose of phenytoin to achieve the therapeutic range. What is the appropriate clinical next step?
- Increase the phenytoin dose to achieve a total concentration within the therapeutic range
- Repeat the measurement once the patient is at steady state before changing the dose
- Decrease the phenytoin dose to avoid drug accumulation
- Determine the corrected phenytoin concentration before making changes
- Measure the unbound phenytoin concentration to determine if dosing changes are warranted
Determine the corrected phenytoin concentration before making changes
Measuring the unbound phenytoin concentration to determine if dosing changes are warranted is a good idea but takes too long
Patient is definitely in Css by this point
Why wouldn’t decreasing the phenytoin dose to avoid drug accumulation be a good option?
Because it is hepatically eliminated
What is the Sheiner-Tozer equation?
Cadj= Cobs/((0.1*albumin)+0.1)
When is the Sheiner-Tozer equation valid?
in patients with creatinine clearance less than 10ml/min
Why do certain drugs, although extensively bound to plasma proteins, exhibit large CLRenal values?
Secretion is an active process.
Cellular processes (e.g., presence of active anionic and cationic transporters) exist to facilitate tubular secretion.
Drugs that are secreted may compete with other drugs that are secreted by the same transport system.
The secretion process is so avid that even drug bound to plasma protein does not protect it from being secreted (i.e., non-restrictive).
What is the cationic drug transporter in the BL of the PT?
OCT2 (creatinine)
What is the anionic drug transporter in the BL of the PT?
OAT1/2
What are some drugs that block OCT2 (competitively)?
Ethidium, Cimetidine, trimethaphan
What are some drugs that block OAT1/2 (competitively)?
probenecid
T or F. Drug renal reabsorption is a passive process
T. By diffusion and depends on the conc. gradient
Note that only unionized drugs are reabsorbed to any great extent
What things can change the reabsorption of a drug?
changing the pH (aspirin alkanizes the urine)
What is the equation for renal clearance (CLrenal) of drugs?
= (CLfiltration + CL secretion)*(1-Freabsorbed)
What is the CLratio?
=(CLrenal)/CLfiltration or
=(CLrenal)/(fupX125mL/min)
What does a
CLratio less than 1.0 mean?.
the drug is filtered and undergoes net reabsorption. This does not mean that secretion did not occur.
CLratio = 1.0, the drug is filtered and reabsorption = secretion, or f reabsorbed = 0 and CLsecretion = 0.
CLratio >1.0, the drug is said to be filtered and undergoes net secretion
What is the Cockcroft-Gault equation for estimating CrCl (ml/min)?
Crcl= (140-age)WGT/(Scr72) * 0.85 (if female)
WGT is adjusted for fatties
What is the urine collection method for estimating CrCl (ml/min)?
CrCl= UcrUvolume/(Scrtime)
Recommendations for Medication Management in CKD
Recommend that clinical laboratories should:
1) report eGFR in addition to the serum creatinine concentration in adults and specify the equation used whenever reporting eGFR
2) take GFR into account when drug dosing.
3) Where precision is required for dosing (due to narrow therapeutic or toxic range) and/or estimates may be unreliable (e.g., due to low muscle mass), recommend methods based upon cystatin C or direct measurement of GFR.
What are some times when using a eGFR report would be inappropriate?
- AKI
- dialysis
What must you do to a eGFR?
multiply by BSA/1.73m^2 to account for body weight
What do you always have to look for when assessing eGFR?
creatinine (it needs to be stable for the eGFR to be a good estimate)
Estimating GFR
Can use CG, CG-IBW (ideal body weight), CG-ABW (adjusted body weight)
or computer will give
CKD-EPI and then you can adjust by multiplying by BSA/1.73
estimated and computed will not be that different if not very obese
T or F. The CKD-EPI does not account for BSA
T. So a fat man and a skinny man will have the same CKD-EPI (but you can adjust by multiplying by BSA/1.73) but CG will be much higher in a fat man so you should adjust to the CG-ABW for drug-dosing
What estimations of GFR should you use for drug dosing?
CG-ABW and CKD-EPI (BSA)
What is CKD-EPI used for?
staging kidney disease. you want to use the CKD-EPI (BSA) for drug dosing
Which Crcl estimation would use in a 85 yo female with Cr of 0.7 near ideal BW?
CG will then to underestimate and CKD-EPI will over-estimate so do a 24-urine CrCl estimate
What are some other situations where measuring CrCl in urine may be the most appropriate route?
-extremes of age (children, elderly)
-extremes of body size
-severe malnutrition
abnormal muscle mass (amputation, paralysis)
-pregnancy
or AKI or before giving highly toxic drugs
Step-wise approach for drug regiment in patients with CKD. Steps 1-3
- Identify if Selected Drug is Eliminated by the kidney
(Use resources to assess PK parameters: e.g., fe) - Assess Kidney Function
(Estimate GFR or measure GFR if more accurate assessment is warranted) - Is the Patient Requiring any “High‐Risk” Drugs?
(Drugs with a narrow TI or high potential for toxicity)
Step-wise approach for drug regiment in patients with CKD. Steps 4-7
- If yes and/or if the estimating equations are unrealiable in the patient, consider measuring GFR to best assess kidney function.
- Determine the dosing regimen based on recommendations by the manufacturer and/or PK studies in CKD dosing.
- Monitor the patient for ADRs and drug interactions and perform TDM when appropriate.
- Regularly review medications and reassess drug dosing regimen as kidney function changes.
