S2: clinical PK and PD

Question 1

What is bioavailability?

Answer 1

Measure of drug absorption where it can be used
Drug administered by IV bolus is said to have 100% bioavailability
Affected by:
-absorption: age, food, vomiting/malabsorption
-first pass metabolism: gut lumen, gut wall, liver

Question 2

Describe modified release preparation

Answer 2

If elimination is rapid, large fluctuations in [plasma] will be seen
Modified release preparations can help – [plasma] becomes more dependent on rate of absorption vs rate of elimination
Can help with adherence

Question 3

Outline factors which affect therapeutic agent distribution

Answer 3

Blood flow, capillary structure
Lipophilicity and hydrophilicity
Protein binding

Question 4

Explain drug-protein binding and distribution

Answer 4

Typically, only free drug will be able to afford response at target receptor site and/or be eliminated
Second drug can displace first drug from binding proteins
More free first drug to elicit a response, can potentially cause harm

Question 5

What is the equation to calculate Vd?

Answer 5

Vd = dose/[plasma drug]

Question 6

Compare a smaller and larger Vd

Answer 6

Smaller apparent Vd – suggests drug confined to plasma and ECF
Larger apparent Vd – suggests drug is distributed throughout tissues

Question 7

Describe cytochrome P450 enzymes

Answer 7

Majority of phase 1 catalysed reactions utilise the P450 system
Oxidation reactions the most important
Found abundantly in the smooth ER in hepatocytes and other tissues

Question 8

Outline important CYPs

Answer 8

CYP1A – induced by smoking 
CYP2C – many inhibitors 
CYP2D – metabolises many drugs 
CYP2E – alcohol metabolism 
CYP3A – 50% therapeutics

Question 9

Describe the importance of CYP450 enzymes in metabolism

Answer 9

Active -> inactive
Inactive -> active
Active -> active
CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase 1 metabolism eg. age, chronic alcohol, smoking

Question 10

Define drug elimination

Answer 10

Removal of drugs activity from the body metabolism and/or excretion
Fluids – primarily by the kidney, sweat, tears, breast milk
Solids – faeces, hair
Gases – volatile compounds

Question 11

Define clearance

Answer 11

Volume of blood cleared per unit time

Question 12

State the equation for half life

Answer 12

Half life = 0.693 * Vd/clearance

Question 13

Describe the clinical importance of zero order kinetics

Answer 13

Dose change can produce unpredictable change in [plasma]
Half life is not calculable
(most drugs exhibit first order kinetics at therapeutic doses)

Question 14

Describe the steady state

Answer 14

Steady state [plasma] effectively reached in 4-5 half lives
Therapeutic benefit optimal at steady state
(after termination of drug administration, 4-5 half lives for negligible drug to remain)
Infusion = elimination at steady state

Question 15

State the equation for maintenance dose

Answer 15

Maintenance dose = (CL * Css)/F * t
Cl = clearance 
Css = [plasma] we want 
t = dose interval 
F = bioavailability

Question 16

Describe loading doses

Answer 16

Rapid onset required or drug with a long half-life
Therapeutic response needed sooner rather than later
Single dose to achieve desired concentration taking into account apparent Vd

Question 17

State the equation for loading dose

Answer 17

Loading dose = Css * Vd

Question 18

Describe the importance of dosing schedules

Answer 18

Maintain a dose within the therapeutic range
To be safe
Achieve adherence
Initiating and terminating treatment – titrating up and down (increasing or decreasing dose)

Question 19

What is the therapeutic index?

Answer 19

A dose that produces toxicity in 50% of the population

AND the dose produces a clinically desired effect

Question 20

Define potency

Answer 20

A drug that causes the same affect at lower doses is more potent

Question 21

Describe phase I and phase II metabolism

Answer 21

Phase I - CYP450s
-increase ionic charge
-eliminate directly or go on to phase II
-oxidation & reduction occur during phase I metabolism
Phase II - hepatic enzymes: cytosolic
-further increase ionic charge
-enhances renal elimination
-involves conjugation reactions: sulfation & glucuronidation are the most common

Question 22

Can a partial agonist have a higher affinity for the same receptor as a full agonist?

Answer 22

YES
Partial agonists can have greater, the same or lower affinity for the same receptor as a full agonist
BUT
Partial agonists will have lower efficacy than a full agonist