Pharmacokinetics

Question 1

what determines the loading dose

what determines the maintenance dose

what determines the dosing interval?

Answer 1

loading dose is Vd (distribution)

maintenance is the clearance

half life is the dose interval

Question 2

what does the symbol F mean, and how does it relate to blood levels?

Answer 2

this is bioavailability

you could also call that oral availability

F is the fraction that reaches the systemic circulation, e.g. F = 0.7 means 70% makes the systemic circ

Question 3

what is the formula for F (oral availability)?

Answer 3

f= oral AUC / IV AUC

Question 4

what is the role of p-glycoprotein in the gut?

Answer 4

this is an EFFLUX pump that pushes drugs back into the lumen

inhibition of this p-gp will lead to increased bioavailability

this happens with verapamil –> inc digoxin bioavail

Question 5

what is the time to reach steady state?

Answer 5

five half-lives

Question 6

how long does it take to eliminate a drug that is at steady state?

Answer 6

five half lives takes it down to 6.25%

this is what we accept as the “eliminated”

Question 7

what is the formula for drug half life?

Answer 7

the drug half life is directly proportional to the volume of distribution and inversely proportional clearance

the official formula is 0.693 * Vd / Cl

probably could make the ratio 0.7 * Vd/Cl

Question 8

when should we measure the steady state concentration of digoxin?

Answer 8

the half life is about 24 - 30 hours,

therefore we should check it around 1 week

Question 9

if you have a graph showing you plasma concentrations following doses, how do you determine the half life?

Answer 9

it’s just the time it takes to reduce to half the max concentration

be careful not to mis-interpret, and read it as the time to complete clearance

Question 10

describe the definition of volume of distribution please

Answer 10

the total volume of plasma that you would have to have in order to replicate the current plasma concentration

(Example: If the blood conc. is 10 mg/L when there is 1000 mg in the body, Vd = 100 L (ie dissolving 1000 mg in 100L would give a conc. of 10 mg/L))

Question 11

what is the major determinant of volume of distribution?

Answer 11

the relative avidity of a drug for the tissue compared to plasma

we would expect lipophilic drugs to have a high Vd

Question 12

how do we determine the loading dose for a drug?

Answer 12

this is the volume of distribution X desired plasma concentration

Question 13

During a phase 1 clinical trial, a new drug, neobantrine, radio-labelled with tritium, was administered orally to volunteer subjects.

Recovery of radioactivity over the next 48 hours was as follows:
faeces 4%, all as neobantrine glucuronide

urine 80%, as neobantrine glucuronide

12%, as unchanged neobantrine.

An earlier study had examined plasma concentrations of unchanged neobantrine after intravenous administration, compared to oral administration.

The analysis of the concentration versus time for oral and IV administration, which was expressed as area under the curve (AUC) was as follows:

AUC oral/AUC IV = 0.2

The best description of the metabolic pathways of neobantrine, based on this study is:

A. good gut absorption, extensive first pass effect, clearance primarily by hepatic conjugation.

B. good gut absorption, little first pass effect, clearance primarily by hepatic conjugation.

C. good absorption from the gut, little first pass effect, clearance primarily by renal excretion.

D. poor gut absorption, extensive first pass effect, clearance primarily by hepatic conjugation.

E. poor absorption from the gut, little first pass effect, clearance primarily by renal excretion.

Answer 13

so, very little is excreted unchanged (12%)

this means that there is pretty good absorption

there is high first pass metabolism, as seen by the poor oral bioavailability.

with regards to what how it is excreted, Clearance is the IRREVERSIBLE elimination step. You can see that the drug is changed from neobantrine to neobantrine glucuronide, which is HEPATIC

so the answer is actually A

Question 14

what is the clearance of gentamicin?

Answer 14

this is 60% of the creatinine clearance

Question 15

The product information for a new anticonvulsant states that in normal individuals it has a volume of distribution of around 2L/kg, hepatic clearance of 5L/hour, a renal clearance of 8L/hour, respiratory clearance of 2L/hour and has 98% protein binding.

The usual half-life is stated to be six hours. The usual dose is 100 mg four times a day.
When considering efficacy, safety and
compliance, what is the best dosing regime to try in someone with end stage renal disease on haemodialysis?

Answer 15

so, the half life is proportional to Vd / clearance

this means, that with impaired renal function, we have a clearance which has halved

therefore, the half life has doubled

what about dialysis? well, this drug is highly protein bound, and therefore, the dialysis will have very little impact on levels

so, the trick would be to continue at 100mg BD

Question 16

what are important factors in determining a drug’s response to haemodialysis?

Answer 16

volume of distribution is important. if it is highly bound to the tissues, then it will be unable to be dialysed. this is what happens in TCAs

highly protein bound is important

molecular size is also important, with larger molecules more difficult

Question 17

what is the significance of Km?

Answer 17

For drugs with “first order” (linear) kinetics the rate of elimination is proportional to the plasma conc (below the Km).

Above the Km, the rate of elimination becomes independent of conc - “zero-order” elimination.

Question 18

what is the meaning of EC50?

what is the meaning of efficacy? (Emax)

Answer 18

this is the concentration at which 50% effect occurs and is an index of potency

however, this definition of potency is laboratory - do not confuse it with the meaning in English usage

highest potency is the fastest to reach half max effect

Efficacy, by contrast, is about maximum effect. So this is actually closer to our common sense understanding of potency. This is about the drug EFFECT at maximum

Question 19

how do we determine the Therapeutic Index (TI) for a drug?

Answer 19

this is the TD50/ ED50

that is, it is the maximum drug concentration by 50% of the population divided by the minimum effective conc for 50%

Note: this is bigger number/ smaller number. should always be >1

Question 20

what is the reason for an anti clockwise hysteresis loop?

Answer 20

Anti-clockwise hysteresis loop

Digoxin has an anti-clockwise hysteresis loop as it has to distribute to its site of action

Response for a given (high) plasma concentration is initially low, but increases as the drug is distributed out of the plasma to the site of action

Question 21

what is the reason for a clockwise hysteresis loop?

Answer 21

Occurs when rapid tolerance (tachyphylaxis) develops,

eg with GTN, cocaine, pseudoephedrine

The response for a given plasma concentration is initially high, but decreases as tolerance rapidly develops

Question 22

how does albumin (and renal failure) impact phenytoin binding?

what about therapeutic drug monitoring?

Answer 22

phenytoin binds less easily in setting of acidosis (renal failure) and is also dependent on albumin levels

in these situations the UNBOUND concentration remains the same (provided the clearance is the same).

when we monitor someone’s drug level, we are only able to measure TOTAL concentration. If we measured the unbound concentration, it would be much safer for therapeutic monitoring. However, we can’t.

In low albumin states, we are aiming for the same unbound level, but the total level will be lower, and so, we might aim for a level of 5-10, instead of 10- 20 (as seen in normal patients)