20. Pharmacokinetics 2

Question 1

What is drug elimination?

Answer 1

Metabolic and excretory processes
Both processes closely integrated to optimise drug removal
Removes both exogenous and endogenous molecular species

Question 2

What is the role of phase I and II enzymes?

Answer 2

Metabolism drugs - increase ionic charge, enhance renal elimination
Lipophilic drugs diffuse out renal tubules back into plasma
Once metabolised drugs usually inactivated

Question 3

Which enzymes are used in phase I metabolism?

Answer 3

Cytochrome P450 enzymes (CYP450s)

Question 4

What are CYP450s?

Answer 4

Large group of isoenzymes located on external face of ER
Catalyse redox, dealkylation and hydroxylation reactions
Versatile generalists

Question 5

What happens to metabolised drugs after phase I?

Answer 5

Metabolised drugs are eliminated directly or go onto phase II

Question 6

What are pro-drugs?

Answer 6

Activated by phase I metabolism to active species

E.g. codeine to morphine

Question 7

What is phase II metabolism?

Answer 7

Carried out by hepatic enzymes - phase II enzymes (mainly cytosolic)
Still generalists but exhibit more rapid kinetics than CYP450s
Enhances renal elimination

Question 8

What do phase II enzymes do?

Answer 8

Enhance hydrophilicity by further increasing ionic charge

Catalyse sulphation, glucorinadation, glutathione conjugation, methylation and N-acetylation

Question 9

What factors affect drug metabolism?

Answer 9

Age - variable patterns in paediatric groups, reduced in elderly
Sex
General health/dietary/disease - especially hepatic, renal, CVS (HRH)
Gives decreases functional reserve

Question 10

What happens in CYP450 induction?

Answer 10

Concurrent administration of certain drugs can induce specific CYP450 isoenzymes
Induction mechanism via:
- increased transcription
- increased translation
- slower degradation
If another drug in body metabolised by induced CYP450 isoenzymes then it’s rare of elimination be increased
Plasma levels of drug will then fall

Question 11

How long does induction process occur for?

Answer 11

1-2 weeks

Question 12

Describe how carbamezepine (CBZ) work (CYP450 induction)

Answer 12

CBZ is an anti-epileptic metabolised by CYP3A4

It induces expression of CYP3A4 - lowering its own levels affecting control of epilepsy

Question 13

How does CYP450 inhibition work?

Answer 13

Concurrent administration of certain drugs can inhibit specific CYP450 isoenzymes
Inhibition mechanism is via:
- competitive or non-competitive inhibition
If another drug in body metabolised by inhibited CYP450 isoenzymes then it’s rate of elimination will be slowed down
Plasma levels of drug will then decrease

Question 14

How long does inhibition process occur for?

Answer 14

1 to a few days

Question 15

What are the routes of drug elimination?

Answer 15

Main: kidney
Minor: bile, lungs, sweat, tears, genital secretions, saliva, breast milk

Question 16

Why are the 3 processes in renal excretion?

Answer 16

Glomerular filtration
Active tubular secretion
Passive tubular reabsorption

Question 17

Where are the OAT and OCT in the kidneys?

Answer 17

In capillaries and proximal tubule

Question 18

Describe the features of proximal tubular secretion

Answer 18

Low affinity/high capacity OATs and OCTs
Competitive transport
Carry ionised molecules out
Reverse of process in small intestine
Facilitated diffusion/secondary active transport

Question 19

What are examples of OATs and OCTs in distal tubular reabsorption?

Answer 19

OATs: urate, penicillins, NSAIDs, antivirals
OCTs: morphine, histamine, chlorpromazine

Question 20

In a weak acid, what is the effect of acid urine and alkaline urine?

Answer 20

Acid grind increases absorption
Alkaline urine decreases absorption

Look at diagram

Question 21

In a weak base, what is the defect of acid urine and alkaline urine?

Answer 21

Acid urine decreases absorption
Alkaline urine increases absorption

See diagram

Question 22

What is clearance?

Answer 22

The apparent rate of elimination of a drug from he body
Total drug clearance consists of that from all routes

Total body clearance = hepatic clearance + renal clearance

Question 23

What is the formal definition of clearance?

Answer 23

The volume of plasma that is completely cleared of the drug per unit time

Question 24

What do Vd and CL provide?

Answer 24

Predicts how long drug will stay in body

Provide estimate of drug half life

Question 25

What is drug half life?

Answer 25

Amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it has when it was first measured
If CL stays sane and Vd increases, t1/2 increases
If CL increases and Vd stays same, t1/2 decreases absorption

Question 26

Why is the graph log [plasma] vs time linear?

Answer 26

Rate of metabolism or excretion is proportional to plasma concentration of drug
If there is a large functional reserve
Lots of phase I/II enzyme sites
Plenty of OAT/OCT transporters

Question 27

What happens when elimination processes become saturated?

Answer 27

When processes are saturated they become rate limited
They cannot go any faster - all enzymes or carriers are working
Referred to as saturated or zero order

Question 28

Describe drug elimination kinetics graph

Answer 28

If y axis rate of elimination
If x axis dose of drug
At low doses drug metabolism is first order, proportional to drug dose
At high doses, drug metabolism is zero order, constant and independent of drug dose

Question 29

1st order kinetics vs zero order kinetics

Answer 29

1st- predictable, therapeutic resonate from dose increases (most drugs)
Zero- therapeutic response can suddenly escalate elimination mechanisms saturate (alcohol)

Question 30

What is the clinical importance of zero order kinetics?

Answer 30

Drugs at or near therapeutic dose with saturation kinetics
More likely to result in ADRs or toxicity
Fixed rate of elimination per unit time
Relatively small doses can produce large increments in plasma [drug], lead to serious toxicity
Greater risk of drug- drug interactions due to taking up sites