drug prescription in CKD 5 5 18

DRUG PRESCRIPTION IN CKD PATIENTS John Cijiang He, MD/PhD Division of Nephrology Department of Medicine Mount Sinai Scho...

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DRUG PRESCRIPTION IN CKD PATIENTS John Cijiang He, MD/PhD Division of Nephrology Department of Medicine Mount Sinai School of Medicine

Question 1 A 47 year old man with alcoholic pancreatitis develops gram negative sepsis. He is mechanically ventilated. Blood pressure is 95/60 mm Hg on a Norepinephrine infusion. He is febrile, and his heart rate is 130 per minute. Examination of the chest reveals coarse breath sounds and inspiratory crackles throughout both lungs. He has generalized anasarca. He has made 300 mL of urine over the last 24 hours. His current weight is 90 kg. His admission weight was 78 kg. The team like to start antibiotics including vancomycin and piperacillin / tazobactam. His serum Cr 2.5 mg/dl. How do we prescribe his antibiotics? What statement below is correct? A. A loading dose helps to reach higher therapeutic drug concentration than without it. B. We should use his ideal body weight to calculate the loading dose of the drug. C. If a drug has high bioavailability, the oral dosing should be similar to IV dosing. D. Renal function for drug dosing is usually estimated based on his current serum Cr levels using MDRD formulae.

Pharmacokinetics

The term pharmacokinetics (PK) refers to the processes by which a drug is handled by the body, which are grouped into the following phases known as ADME: ●Absorption (for oral drugs) ●Distribution (to different organs/body compartment) ●Metabolism (activation/inactivation by enzymes) ●Elimination (renal, hepatic)

Two-compartment model – intravenous dose • Drug is injected into the central compartment, and distributes over time to the peripheral compartment.

• Drug is eliminated by metabolism and excretion, mostly in central compartment (which includes the liver and kidneys). o Metabolism also can occur in tissues of the peripheral compartment.

Vd before and after distribution

(assuming no significant elimination)

20L

Overlapping processes of distribution and elimination Distribution – Relatively brief The drug is moving from the central compartment to equilibrate with the peripheral compartment. Elimination – Takes longer, eventually removes all of the dose The drug is being metabolized and excreted, mainly by highlyperfused organs (especially liver and kidneys)

The C vs t plot has two components • The contribution of distribution is limited to the early part of the graph.

• After distribution is complete, the slower decline in C is due solely to elimination.

• Clinically, elimination generally is the more important phase.

Distribution + Elimination

“Knee”

Determining Vd with two compartments 5 mg

We are interested in Vd after distribution is complete. Choose a region of the elimination phase when distribution is complete, well after the “knee” in the graph, and extrapolate to t=0 to obtain C0 (extrap).

Vd can be very large

Drugs with small Vd’s distribute to plasma + extracellular fluid (~10 - 15 L). Those with the largest Vd’s tend to be lipophilic and accumulate in adipose tissue.

When is the distribution phase clinically important? For some drugs that are slowly eliminated, distribution to the peripheral compartment terminates the action of the drug.

• Example: propofol is given i.v. to induce anesthesia. Its site of action is the brain (in the central compartment). Elimination is slow (t1/2 = hours to days). But the patient will regain consciousness within minutes, as the drug distributes to the peripheral compartment and concentration in brain declines.

Distribution Volume (Vd) in CKD • In renal insufficiency, the presence of edema or ascites will increase the Vd of highly protein-bound or water-soluble drugs, resulting in lower than expected plasma levels. • However, muscle loss and dehydration can decrease Vd and lead to higher than expected concentrations of these same agents.

Determining t1/2 with two compartments Same approach as with the onecompartment model, but be sure to choose time points after distribution is complete.

I chose 8 mg/L and 2 mg/L, which are separated by two multiples of 2. The corresponding times, which are separated by 2 x t1/2, are about 11 h and 18 h. So t1/2 = ~3.5 h

Administration at sites other than intravenous (one-compartment model)

• Administration at other sites necessitates the inclusion of the absorption process.

o The drug must get to the systemic circulation from the site of administration; membranes and cells must be crossed.

• Absorption is relevant to all non-intravenous routes. o Oral, intramuscular, subcutaneous, transdermal, rectal, etc.

Bioavailability (F): • How much of a dose actually reaches the systemic circulation? o If the drug is administered intravenously: All of it o Otherwise: Typically less than the full dose

• The fraction of the drug that reaches the systemic circulation is its bioavailability (F). of drug that A is the amount reaches the systemic circulation

D is the administered dose

• Bioavailability ranges from 0 to 1 o 0: None of the dose reaches the systemic circulation. o 1: All of the dose reaches the systemic circulation.

What determines oral bioavailability? Two factors: • Absorption from the gut to the portal circulation • First-pass metabolism by the liver

Absorption • Before it reaches the portal circulation, the drug must

• •

pass through the epithelial cells. Drug polarity or other physicochemical properties can impede entry into epithelial cells. Transporters in the apical membrane of epithelium can return drug to the gut. Most prominent is P-glycoprotein (aka multidrug resistance protein 1), which also is a component of the blood-brain barrier that keeps some drugs out of the CNS.

• Within the epithelial cell, the drug might be metabolized.

First-pass metabolism • Before an orally administered drug reaches the systemic circulation, the liver has an opportunity to metabolize it.

• If the liver is very efficient in metabolizing the drug, then relatively little will reach the systemic circulation. o Not necessarily a bad thing. Statins are drugs that act in the liver, while their systemic distribution is linked to adverse effects.

o For drugs that are efficiently eliminated by the liver, liver

Example: Oral bioavailability 1. 100% of the dose is taken up by intestinal epithelial cells.

2. The epithelial cells express enzymes that metabolize 20% of the drug as it passes through. The remaining 80% enters the portal circulation. 3. Next stop: the liver, which metabolizes 75% of the drug as it passes through. 20% of the dose reaches

What is the bioavailability of furosemide? A.20% B. 40% C. 60% D.80%

Bioavailability of drugs in CKD • In CKD, numerous factors, such as nausea, vomiting, diabetic gastroparesis, and intestinal edema, may decrease gastrointestinal absorption. • The use of antacids and alkalating agents such as bicarbonate and citrate increases gastric pH, thereby reducing the levels of drugs that require an acidic milieu for absorption. • Some drugs are bound by antacids and phosphate binders, which are commonly used in renal failure. • First-pass hepatic metabolism may also be diminished in uremia.

Drug infusions and repeated dosing • To maintain a therapeutic level for a drug:

o The drug is administered as a continuous i.v. infusion. o Repeated oral doses are taken.

When a drug is infused at a constant rate, C gradually approaches a steady state value (CSS).

How long does it take to reach CSS? • One half-life is required to bring C halfway from its current value to CSS.

• After 4-5 half-lives, C is considered to have essentially reached CSS. At this time, C is ~ 95% of CSS. # half-lives

% CSS

1

50

2

75

3

88

4

94

5

97

Reaching CSS faster with a loading dose To reach CSS without waiting 4-5 half-lives, a loading dose (DL) can be injected at the start of the infusion. The correct loading dose is:

DL + infusion

C was brought immediately to 1 mg/L, so elimination is proceeding according to elimination rate = C x Cl.

Infusion only DL only

The IR matches this elimination rate, so C remains constant (CSS).

Repeated oral dosing • If a second oral dose is given before the previous dose is completely eliminated, drug accumulates. • As the concentration rises, so does the rate of elimination. When the rate of elimination is high enough to remove all of the previous dose, an average CSS is achieved: CSS(av). • The time to reach CSS(av) is 4-5 x t1/2 – the same as for i.v. infusion.

Loading dose for oral administration A large first dose can serve as a loading dose (DL) to quickly achieve CSS(av): Essentially the same as the equation for infusion loading dose:

Different dosing regimens can yield the same CSS(av) with a different min-max range Using this dose, schedule, and drug formulation, C ranges outside the therapeutic range. Cmin is too low to be effective, and Cmax is so high it’s toxic.

Taking half the dose, but twice as often, yields the same CSS(av) while keeping C within the therapeutic range. Staying with the original dose and schedule, but with a slow-release formulation (same bioavailability but absorbed more slowly) also keeps C within the therapeutic

Question 3 You are prescribing for a 72-year old male with chronic glomerulonephritis. His serum creatinine has been stable at 2 mg/dl for approximately eight months. He now develops an upper respiratory illness characterized by fever, chest pain, cough, hemoptosis, and his chest x-ray shows a left lower lobe infiltrate. He was started on levofloxin The best choice of therapy for this patient would be: A. Dose him as if he had normal renal function. B. After loading dose, calculate his estimated GFR and cut his maintenance dose proportionate to his GFR decline but give at the usual dose intervals. C. Calculate his estimated GFR and increase the interval between maintenance doses depending on the percent reduction of his GFR, but no loading dose. D. Reduce his loading dose based on his GFR and then give him the usual maintenance dose at regular interval.

What would happen if clearance decreases? Assume that this drug is eliminated mainly by the kidney, and clearance suddenly is reduced by 50% due to acute kidney injury.

As C increases, so does elimination rate, until it’s high enough to remove all of the previous dose. New steady-state reached. Initially, the rate of elimination is not sufficient to remove all of the previous dose. Drug accumulates.

How to correct for decreased clearance?

Levofloxacin Crcl (ml/min)

Dose

20 – 50

500mg stat then 250mg bid*

10 – 20

500mg stat then 125mg bid*