Alfred consortium pharmacology

Question 1

What are the cellular transporter proteins and their functions?

Answer 1

1. ATP-binding cassette
   
   1. Efflux (stops drugs from getting in)
2. Solute-linked carrier
   
   1. Influx

Found in the proximal tubule, BBB, intestinal lumen

Question 2

What are substrates of P-gp?

Answer 2

Dabigatran

Digoxin

Verapamil

Amiodarone

Atorvastatin

Question 3

What are potent inhibitors of P-gp?

Answer 3

Quinidine

Verapamil

Azole

Question 4

Interaction between probenecid and penicillin

Answer 4

Probenecid is an inibitor of OAT1 so will increase penicillin levels

Question 5

What is the unit for clearance?

Answer 5

volume/time

(L/hour)

can also be calculated with:

CL = blood flow (volume/time) x extraction ratio (no unit)

Question 6

What is the unit for dosing rate (DR)

Answer 6

DR = maintainence dose/dosing interval

mg/hour

Question 7

Is clearance only the active drug or both active and inactive?

Answer 7

Clearance is only the active drug - so includes metabolic conversion but does not include renal removal of inactive metabolite

Question 8

How to calculate the elimination rate?

Answer 8

Clearance of drug (by organ/body) x plasma drug concentration (mg/hour)

(elimination rate is dependent on the plasma drug concentration where as volume distribution is independent of that)

Question 9

How to calculate the steady state?

Answer 9

when the maintainence dose rate is the same as the elimination rate

dose rate (at steady state) = clearance x Css (divided by bioavailability if not given IV)

Question 10

With a constant dose/interval, how long does it take for the Css to be reached?

Answer 10

4-5 half lives

Question 11

How to calculate clearance using steady state?

Answer 11

Use constant IV infusion until steady stae and formula Cl = DR / Css OR CL = dose / AUC (mg x hour/L)

Question 12

How to calculate renal clearance?

Answer 12

drug filtered + drug secreted - drug reabsorption

Question 13

Which phase of metabolism is CYP proteins involved in?

Answer 13

Phase I of 1st pass metabolism in the liver

Question 14

paracetamol metabolism

Answer 14

Normally undergoes phase II metabolism (95% of the total excreted metabolites) to produce a nontoxic metabolite (glucoronide)

The phase I metabolism pathway (CYP) is only 5% and it can produce a nucleophilic cell macromolecules pathway

In paracetamol toxicity, the normal pathways become saturdated and the toxic metabolite is produced

Question 15

How does lipid solubility affect volume of distribution?

Answer 15

Lipid soluble drugs will disperse more into the tissues and have a large volume of distribution

If a drug is tightly bound to proteins and not tissues, the volume of distribution is very close to blood volume

Question 16

What happens when you increase the dose of a drug that has a saturable binding protein

Answer 16

The unbound concentration initially increases linearly with the dose

Less proportionate increase in total concentration

Fraction unbound increases

Question 17

What is an example of a drug that has saturable binding protein?

Answer 17

Aspirin

Question 18

How to calculte half life?

Answer 18

0.693 x Vd / CL

Question 19

How much increase to the duration of action does doubling the dose affect?

Answer 19

Increase of 1 half life (not doubling time of action)

Question 20

How to calculate oral bioavailability?

Answer 20

fraction absorbed x (1-hepatic extraction ratio)

OR AUC(oral)/AUC(IV)

Question 21

What is Emax?

Answer 21

maximal effect at high concentrations (When receptors are saturated)

Question 22

What is the therapeutic index

Answer 22

TD50/ED50

dose to reach 50% toxic effect / dose to reach 50% therapeutic effect

the bigger the better

this is different from the therapeutic window - the affectable dose window without unacceptable adverse effects

Question 23

What is the difference in pharmacodynamics for competitive inhibitors and non competitive inhibitors

Answer 23

Competitive inhibition reduces potency

Noncompetitive inhibition reduces efficacy

Question 24

How often to dose a drug?

Answer 24

T1/2 = 8-24hr: dosing = half life

T1/2 <8hr = slow release or if short half life with large therapeutic index can give wider dosing

T1/2 >24hr = daily dosing

Question 25

What does it mean for a drug to be Cmax:MIC concentration dependent?

And what is an example of that?

Answer 25

That the peak concentration to MIC is the most important factor

e.g. aminoglycosides

Question 26

What drugs are time>MIC dependent?

Answer 26

beta-lactams

Question 27

What are examples of drugs which are AUC:MIC concentration dependent?

Answer 27

Vancomycin, fluoroquinolones, macroides, ketolides

Question 28

Do inducing/inhibiting the liver metabolism enzymes affect drugs that have a high hepatic extraction ratio more or low hepatic extraction ratio?

Question 29

What direction is the hysteresis graph in

1) delayed distribution?
2) acute tolerance?

Answer 29

1) anticlockwise
2) clockwise (essentially tachyphylaxis is the only cause of clockwise hysteresis curve)