ICL 1.1: Renal Pharmacology II

Question 1

which drugs are cleared primarily by the kidney and should be given with caution in renal failure?

Answer 1

1. some antibiotics: penicillins, cephalosporins, aminoglycosides, tetracycline
2. some beta blockers: atenolol, nadolol, sotalol
3. most diuretics
4. lithium
5. digoxin
6. procainamide
7. cimetidine, ranitidine

Question 2

where in the body do you measure drug concentrations?

Answer 2

drug concentrations are nearly always measured in blood, as it’s easy to measure

there is generally a proportional relationship between concentrations in blood and other organs after distribution equilibrium is achieved

Question 3

what is the impact on the blood concentration-time profile after giving an IV bolus dose vs. non-IV bolus dose of a drug?

Answer 3

after an IV bolus dose, all drug is present in blood immediately

after a non-IV bolus dose, blood concentrations rise as the drug is absorbed from administration site into blood

in both cases, distribution into other tissues and clearance from the body cause blood concentrations to decline

Question 4

what is the impact on the blood concentration-time profile after giving a continuous infusion of a drug?

Answer 4

blood concentrations rise until they reach a steady-state level then plateau

if a drug is administered on a regular schedule, and frequently enough so that each dose is given before the previous one is entirely cleared from the body, concentrations will also rise to a steady-state = maintenance dosing

Question 5

which pharmacokinetic factors can change the shape of the concentration-time profile in blood of a drug?

Answer 5

1. drug formulation
2. food effects
3. transports
4. blood flow to tissues
5. metabolism
6. excretion

Question 6

what is the definition of the drug clearance process?

Answer 6

clearance processes refer to all of the physiological processes which convert a drug into an inactive form (metabolism by enzymes) or physically remove drug from the body (excretion)

very minor routes of clearance include removal of drug via breath, sweat, etc.

major routes of clearance are via liver and kidney

Question 7

what is the equation for total clearance of a drug from the body?

Answer 7

Total clearance of drug from the body (CL) is the sum of all clearance processes that contribute for a given drug:

CL = CL renal + CL hepatic + CL other

CL is expressed as the volume of blood completely cleared of drug per unit time (units of volume / time)

many drugs are cleared by both kidney and liver; when a single organ is responsible for clearance, dose adjustments are more likely to be necessary with changes in organ function

hepatic clearance processes: phase I and II metabolism, biliary excretion

renal clearance processes: glomerular filtration, tubular secretion, reabsorption

Question 8

what are the 4 key parameters in dose regimen design?

Answer 8

1. volume of distribution
2. clearance
3. therapeutic window
4. half life

Question 9

what is the volume of distribution of a drug?

Answer 9

Vd is a proportionality constant relating the amount of drug in the body at any point in time to the blood concentration of the drug at that point in time

the larger a drug’s Vd, the more drug needed to produce a given initial blood concentration after an IV bolus dose

Question 10

what is the equation for volume of distribution of a drug?

Answer 10

𝑉𝑑=𝑋𝑡/𝐶𝑡

Xt = mass of drug in body at a given time

Ct = concentration of drug in blood at that same point in time

this parameter is used for calculating bolus loading doses (IV route only)

Question 11

what is clearance of a drug?

Answer 11

a measure of the efficiency of irreversible removal of a drug from the body by all eliminating organs, in terms of volume of plasma completely cleared of drug, per unit time

during maintenance dosing of a drug, average steady-state concentration (Css, avg) is a function of CL (rate out) and the dose rate (rate in)

CL (rate out) cannot usually be changed, so to adjust the average concentration, we adjust the dose rate (rate in)

Question 12

what is the therapeutic window of a drug?

Answer 12

the range of concentrations high enough to produce the desired therapeutic effect, and low enough to avoid toxicity

maintenance dose regimens are designed to achieve a target Css, avg and to ensure that peak (Cmax) and trough (Cmin) concentrations stay in the therapeutic window at steady-state

the degree of fluctuation between peak (Cmax) and trough (Cmin) concentrations is determined by the dosage interval (the time between doses) and the drug’s half-life (t½)

Question 13

what is the half life of a drug?

Answer 13

the time it takes for drug concentrations to fall by half after input of drug has stopped

for most drugs, elimination from the body occurs as a first-order process (rate of drug loss is proportional to plasma concentration, C, when concentrations are at or below the therapeutic range

at steady-state, the rate of input (dose rate) = rate of output (CL x average Css). Only continuous administration (infusions, or maintenance dosing) results in drug concentrations reaching steady-state

time to reach steady-state (as well as time for a dose to be eliminated) is always 5 half lives. Half life is specific for each drug (e.g., procainamide = 3 hr; phenobarbital = 98 hr); population-average values are commonly reported

C = C0*eˆ(-kt)

C0 = initial concentration
k = elimination rate constant
t = time

Question 14

how do you calculate the infusion rate for a continuous infusion?

Answer 14

continuous infusions are given to maintain a constant drug concentration within the therapeutic range

Step 1: select a target steady-state concentration (Css; often the midpoint of the therapeutic range)

Step 2: obtain an estimate of CL for the drug to be infused (usually a literature estimate; occasionally patient-specific)

Step 3: calculate the infusion rate (k0)

k0 = Css * CL

Question 15

how do you calculate the IV loading dose?

Answer 15

IV loading dose is given when there is a need to immediately produce the desired steady-state concentration; can be used with either infusion or maintenance dosing

Step 1: select a target steady-state concentration (often the midpoint of the therapeutic range)

Step 2: obtain an estimate of Vd for the drug to be infused (usually a literature estimate; occasionally patient-specific)

Step 3: calculate the loading dose (XLD)

XLD = Css*Vd

Question 16

how do you calculate the maintenance dose regimen?

Answer 16

maintenance dosing is repeated doses on a fixed schedule, to maintain drug concentrations within the therapeutic range –> the dose rate and clearance rate determine where you are within the therapeutic window

step 1: select a target average steady-state concentration, Css often the midpoint of the therapeutic range

Step 2: obtain an estimate of CL for the drug (usually a literature estimate; occasionally patient-specific)

Step 3: calculate the dose rate; mass of drug (X) per time (dose interval, τ)

X(PO)F/τ = CssCL

Css is an average concentration, with peaks and troughs that must be maintained within the therapeutic window (the range of doses high enough to produce therapeutic effects, and low enough to avoid toxicity)

dose interval (τ; time between doses) and t½ determine the peak-to-trough ratio; drugs with shorter t½ must be dosed more frequently to stay in the therapeutic range

the amount of drug (X) per dosage interval determines average CSS, but does not impact peak-to-trough ratio

Question 17

what is therapeutic drug monitoring?

Answer 17

regular measurement of plasma drug concentrations to individualize dosage regimens to stay within a target range.

monitoring is most common for drugs with a narrow therapeutic index and major toxic effects, or wide inter-patient variability in concentration produced by a given dose

usually, total (protein-bound and unbound) concentrations are measured; only unbound drug can interact with target receptors to produce effects

Question 18

when do dose regimens need to be adjusted?

Answer 18

1. when a standard dose (based on average parameters) does not produce the intended concentrations
2. when an individual patient’s parameters change over time, for example, due to disease, drug interactions or patient-specific factors

Question 19

how do you adjust dosage regimens?

Answer 19

the required changes in dose rate are usually inversely proportional to the concentration change or error

for example, to correct a concentration 2x too high, the dose rate should be reduced by half

an exception to this proportional relationship is when a drug displays nonlinear behavior, e.g., due to saturation of metabolizing enzymes or transport processes

average Css is altered by changing the dose rate (amount or interval) proportionally

a substantial increase in CL may change t½ sufficiently to necessitate closer spacing of doses (shortened dose interval) to remain in therapeutic range

with decreased CL, the dose interval will not need to be changed

Question 20

what is an example when you dose straight into your target organ?

Answer 20

1. eye drops for glaucoma
2. inhalers for COPD or asthma

this rarely happens though because when you take stuff PO it has to get to the blood and then it’ll go to all the other parts of the body including the target and non-target organs

the drug concentration at the target site is what drives the pharmacologic effect of the drug but we don’t always measure the concentration at the target site because it’s often invasive so we usually sample from blood

Question 21

what affects the maximum concentration of a drug?

Answer 21

1. how fast it gets absorbed

concentrations stops increasing when absorption is finished and from that point on you start all the clearance process – metabolism and excretion pull out the drug in equal proportions even though the exact concentration in all the different parts of the body isn’t the same

2. how fast it gets cleared

Question 22

what issues might you need to consider carefully when prescribing a narrow therapeutic window drug?

Answer 22

1. the risk associated with toxic/subtherapeutic levels

if you have an untreated serious medical condition like cardiac abnormalities it would be a problem if the dose was subtherapeutic

2. how frequently you need to dose

Question 23

Procainamide (Procanbid® & others) is a Class IA antiarrhythmic used to treat recurrent ventricular fibrillation, ventricular tachycardia, and other cardiac conditions. It is available in injection solution form (and in Canada as capsules and tablets). The therapeutic window of procainamide is considered to range from 4-8 mg/L. Serious and potentially lethal cardiac side effects occur when plasma concentrations are above the therapeutic range. Clearance of procainamide is roughly 50% renal and 50% hepatic (active metabolite). Systemic clearance of procainamide is ~24 L/hr, and the volume of distribution of this drug is reported as ~140 L (assuming 70 kg person). Procainamide half-life is 4 hours.

Vd = 140 L

therapeutic window = 4-8 mg/L

target = 6mg/L

CL = 24 L/hr

t½ = 4 hr

a 35-year-old male patient is in the emergency room, experiencing acute preexcited atrial fibrillation. Design an intravenous continuous infusion rate to produce a steady-state plasma procainamide concentration (Css) of 6 mg/L.

Answer 23

144 mg/hr

k0 = Css * CL
k0 = (6mg/L)*(24L/hr)
k0 = 144 mg/hr

k0 = continuous IV infusion rate

Question 24

Procainamide (Procanbid® & others) is a Class IA antiarrhythmic used to treat recurrent ventricular fibrillation, ventricular tachycardia, and other cardiac conditions. It is available in injection solution form (and in Canada as capsules and tablets). The therapeutic window of procainamide is considered to range from 4-8 mg/L. Serious and potentially lethal cardiac side effects occur when plasma concentrations are above the therapeutic range. Clearance of procainamide is roughly 50% renal and 50% hepatic (active metabolite). Systemic clearance of procainamide is ~24 L/hr, and the volume of distribution of this drug is reported as ~140 L (assuming 70 kg person). Procainamide half-life is 4 hours.

Vd = 140 L

therapeutic window = 4-8 mg/L

target = 6mg/L

CL = 24 L/hr

t½ = 4 hr

a 35-year-old male patient is in the emergency room, experiencing acute preexcited atrial fibrillation. How long will it take to reach steady state concentration if the IV infusion rate is 144 mg/hr?

Answer 24

time to steady state = t1/2 * 5 = 4 hrs * 5 = 20 hrs

for anything to get to steady state it takes 5 half lives!

Question 25

Vd = 140 L

therapeutic window = 4-8 mg/L

target = 6mg/L

CL = 24 L/hr

t½ = 4 hr

a 35-year-old male patient is in the emergency room, experiencing acute preexcited atrial fibrillation. design an IV bolus loading dose to immediately produce a plasma procainamide concentration of 6 mg/L

Answer 25

840 mg

XLD = Css*Vd
XLD = 6 mg/L * 140 L
XLD = 840 mG

Question 26

Vd = 140 L

therapeutic window = 4-8 mg/L

target = 6mg/L

CL = 24 L/hr

t½ = 4 hr

AUC PO = 20.9 mg/Lhr

AUC IV = 19.3 mg/Lhr

X IV = 750 mg

X PO = 1000 mg

a 35-year-old male patient is in the emergency room, experiencing acute preexcited atrial fibrillation. what is the absolute oral bioavailability of procainamide?

Answer 26

0.8 oral bioavailability

F = (AUCpo/AUCiv)*(Xiv/Xpo) where X is dose or mass administered and AUC is the literal area under the concentration-time curve

F = (20.9 mg/Lhr/19.3 mg/Lhr)(7501000mg)

F = 1.08 * 0.74 = 0.8 oral bioavailability

Question 27

what are the two major factors that contribute to an orally-administered drug’s low bioavailability?

Answer 27

1. incomplete absorption
   ex. pill doesn’t degrade all the way, doesn’t cross membranes easily
2. first-pass loss in the liver

Question 28

Your patient is to be discharged from the hospital and will transition from this IV dose regimen to oral procainamide administration (let’s assume you’re practicing in Canada).

therapeutic window = 4-8 mg/L

Vd = 140 L

CL = 24 L/hr

k0 = 144 mg/hr

XLD = 840 mg

F(PO) = 0.8

X(PO) = 4320 mg/day

What daily oral dose will be required to maintain an average Css of 6 mg/L? will the oral dose need to be higher or lower than the IV dose?

Answer 28

180 mg/hr; you’ll have to give a higher dose than the IV dose

for a drug where F(PO) = 0.5 that means that 50% of the oral dose administered reaches the systemic circulation so therefore to achieve a level of exposure similar to an IV dose, the oral dose would need to be doubled –> since this drug has a bioavailability of 0.8, then:

X(PO) = I(IV)/F(PO)
X(PO) = 144 mg/hr / 0.8
X(PO) = 180 mg/hr
X(PO) = 4320 mg/day orally

Question 29

A. If oral absorption of procainamide is very rapid (assume it behaves like an IV bolus dose), what is the maximum dosing interval that you could use to keep concentrations within the therapeutic window?

B. how long will it take for concentrations to fall from the maximum peak allowable to the minimum allowable? aka from 8 to 4 mg/L?

C. what is the maximum dose interval you can use?

therapeutic window = 4-8 mg/L

Vd = 140 L

CL = 24 L/hr

k0 = 144 mg/hr

XLD = 840 mg

F(PO) = 0.8

X(PO) = 4320 mg/day

Answer 29

A. the therapeutic window is a 2 fold difference since it’s from 4-8 mg/L

B. one 1/2 life! which is 4 hours

C. one 1/2 life = 4 hours which means you need 6 doses a day to keep your patient in the therapeutic window

Question 30

Your patient is experiencing good rate control with the oral procainamide regimen. However, he begins taking OTC cimetidine every day for heartburn. Cimetidine competes with procainamide for active tubular secretion in kidney, reducing the clearance of procainamide from 24 to 17 L/hr

for a drug with first-order elimination kinetics the half life can be calculated as t1/2 = 0.693/k where k is the slope of the terminal elimination phase and 0.693 is the natural log of 2 –> in this case k can also be calculated as k = CL/Vd

using these relationships can you calculate the new half life of procainamide? how will the half-life of procainamide change – will it get longer or shorter?

therapeutic window = 4-8 mg/L

Vd = 140 L

CL = 24 L/hr

Answer 30

the half life is going to increase since you’re not clearing it out of the body as well!

1. concentrations increase which could bump you out of the therapeutic range
2. concentrations fall more slowly so you may need to reduce dose to remain in therapeutic range
3. doses may need to be reduced and can be given less frequently for convenience

k = CL/Vd = (17 L/1hr)(1/140 L) = 1/0.121 hr

t1/2 = 0.693/k = 0.693/0.121 hrs = 5.7 hrs

so the half life went from 4 to almost 6 hours when taking this other drug

Question 31

1. what impact would cimetidine have on procainamide average Css; will it increase or disease?
2. what procainamide Css will now be produced with the original daily dose rate of 4320 mg/day?

Answer 31

1. Css will increase since there is a decrease in clearance the steady state concentration will be higher!
2. X(PO)F/τ = CssCL

CL = 17 L/hr = 408 L/day

Css = (F*XPO/τ)/CL
Css = (0.8*4320)/408
Css = 8.5 mg/L

Question 32

presume that your patient intends to continue taking cimetidine every day. what daily oral procainamide dose rate is now needed to maintain an average plasma Css of 6 mg/L?

Answer 32

the required changes in dose rate are usually inversely proportional to the concentration change or error; so to correct a concentration that’s 2x too high the dose rate should be reduced by 1/2

new dose rate = original dose rate * (target Css/current Css)

= 4320 mg/day (6/8.5 mg/L)

= 4320 mg/day * 0.7

new dose rate = 3024 mg/day

Question 33

what are the 5 main equations for dosing you need to memorize?

Answer 33

1. t1/2 = 0.693/k

k = CL/Vd

2. IV infusion rate: k0 = Css*CL
3. maintenance dose: FXPO/τ = CssCL
4. IV loading dose: XLD = Css*Vd