Concepts and application

Question 1

Why are plasma concentrations of drugs so important in determining pharmacokinetic parameters?

Answer 1

The plasma concentrations help direct dosage and dose intervals + work out circumstances such as renal impairment, half-life and volume distribution clearance.
Interested in how much drug is at the site of action (brain, kidney, lungs etc.). Not able to measure concentrations in the tissues – the plasma concentration is a predictor of what the levels are elsewhere in the body. The concentration in the blood after a certain time predicts the levels in the body. Plasma concentration becomes the main determinant of how we work out the parameters.

Question 2

Oral bioavailability

Answer 2

the proportion of an administered dose of a drug which reaches the systemic circulation intact
bioavailability of the oral form compared with the bioavailability of the IV form. (e.g. assume IV is 100% bioavailability, oral bioavailability is a fraction of that e.g. morphine has 30% bioavailability – 3mg IV is equivalent to 10mg orally)

Question 3

Bioequivalence

Answer 3

if a drug has the same release characteristics as a comparator product (e.g. original branded tablet – ends patent and others manufacture it – these are bioequivalent if the release characteristics are within a certain range.

Question 4

If a drug has an oral bioavailability of 0.4 and the oral dose is 500mg, what is the corresponding iv dose?

Answer 4

0.4 = 40% of the oral drug has reached the circulation intact – therefore 40% = IV dose
500 x 0.4 = 200mg

Question 5

If a drug has an oral bioavailability of 0.2 and the iv dose is 30mg, what is the corresponding oral dose?

Answer 5

30 / 0.2 = 150mg

Question 6

What do you understand by the term ‘volume of distribution (Vd)’? Is it a ‘real’ volume?

Answer 6

No it is not a real volume – it is an apparent volume.
It is the volume (or space) that the drug would distribute to if it was found in the body in the same concentration as is found in the plasma after a single dose
Indicates how well the drug is distributed – does it stay in the blood stream or distribute to tissues.
Useful in loading dose

Question 7

Warfarin has a Vd of approx. 10L while digoxin has a Vd of approx. 400L, what does this tell you about their respective distribution in the body?

Answer 7

Warfarin – low Vd – tightly protein bound – stay within blood stream and not distributed to the rest of the body
Digoxin – higher Vd – readily distributed to the other tissues (out of blood stream)

Question 8

Why is renal clearance such an important consideration in the clinical use of drugs?

Answer 8

Major route of elimination of drugs – if renal clearance decrease it would take longer for drugs to be cleared and lead to accumulation and unwanted effects/toxicity.
e.g. elderly or co-morbidities – regular testing of EGFR and creatinine

Question 9

Why is creatinine the ‘marker’ that is used most often to estimate renal function?

Answer 9

Creatinine is a waste product – from the muscle of breakdown of creatinine – constant rate of production – excreted exclusively through kidneys only and not reabsorbed – if able to measure appearance of creatinine over time it will indicate renal function.

Question 10

Explain the differences between ClCr (as calculated by the Cockcroft-Gault formula) and eGFR. Are there any limitations to the use of ClCr or eGFR?

Answer 10

eGFR. Are there any limitations to the use of ClCr or eGFR?
CICr – uses age, body weight, gender and serum creat
Limits - often overestimates, extremes of weight (esp. elderly, high protein diet)
eGFR – age, gender, serum creat, ethnicity,
Limits - in less than 18, elderly, protein diet, no specific ethnicity values, extremes of weight. Normalized to a body surfaced area.

Question 11

What is half-life?

Give examples of short- and long-half-life drugs?

Answer 11

How long it takes the body to excrete 50% of the drug. Concentration decrease by half and the time interval for that to happen is constant.
Guide to frequency of dosing (dosing interval)
Short – metoprolol, morphine
Long – thyroxine, amiodarone

Question 12

Steady state

Answer 12

when the amount of drug entering bloodstream is the same as the amount of being eliminated. Steady-state is achieved after approximately 4 half-lives when repeated doses are given.
Determined by the half-life of the drug

Question 13

Loading dose

Answer 13

The initial dose is given to achieve steady-state concentration in the blood. The loading dose is to quickly attained concentration steady state – especially in drugs with long half-lives.

Question 14

Therapeutic index

Answer 14

range the drug is therapeutically effective with minimal side effects (divide minimum toxic concentration by minimum effective concentration – lower the value the more potentially toxic the drug is)

Question 15

Therapeutic window

Answer 15

the range of concentrations at which the drug is therapeutically effective with the minimum unwanted side effects

Question 16

What do you understand by the term ‘therapeutic drug monitoring’ (TDM), and give examples of drugs that are routinely monitored in this way?

Answer 16

TDM – routine measurement of plasma levels of drugs with low TI or TW, indicate where the drug sits within the TI or TW to avoid toxicity.
e.g. gentamycin, vancomycin, cyclosporine, lithium

Question 17

In terms of TDM, explain the difference in approach with the use of aminoglycosides e.g., gentamicin, and the use of anticonvulsants e.g., carbamazepine.

Answer 17

Amino – aim to have big peaks and troughs to redoes in troughs – peaks to kill bacteria, troughs to recover and avoid toxicity
Anti – maintain level – keep within therapeutic window

Question 18

what are the major routes of elimination?

Answer 18

kidney, liver, and minor routes such as sweat and lungs

Question 19

How is kidney function (i.e. clearance) is estimated?

Answer 19

eGFR

Question 20

why is creatinine used to estimate renal function?

Answer 20

It is a waste product (metabolite) produced by muscles from the breakdown of a compound called creatine and is produced at a relatively constant rate related to muscle mass
*completely filtered by the kidney and not reabsorbed by the kidney

Question 21

Drug dosing in renal impairment

Answer 21

Refer to New Zealand Formulary NZF - prescribing in renal impairment