Drug Metabolism + Pharmacokinetics

Question 1

What is a prodrug metabolised into?

Answer 1

More active form

Question 2

What are some elimination routes?

Answer 2

Liver
Kidney
Skin
Lungs

Question 3

What is Cmax?

Answer 3

Highest plasma con

Question 4

What is Tmax?

Answer 4

Time at which it takes to reach Cmax

Question 5

What is AUC?

Answer 5

Total systemic exposure to drug

Question 6

What is vol of distribution?

Answer 6

Apparent vol in which drug is dissolved in

Question 7

What is t1/2?

Answer 7

Time taken for plasma conc to fall by 50%

Question 8

What is clearance?

Answer 8

The rate of drug elimination

Question 9

When does a drug reach steady state?

Answer 9

In about 4-5 half-lives

Question 10

What happens when it is an infusion?

Answer 10

Continuous increase until infusion stopped then decreases

Question 11

What happens when you have increased clearance?

Answer 11

Increased dose needed

Question 12

How do you calculate dosing rate?

Answer 12

(Target plasma con X clearance)/ Fraction absorbed

Question 13

What is the loading dose?

Answer 13

Drug administered followed by maintenance dose

Question 14

How do you calculate loading dose?

Answer 14

(Vol of distribution X desired steady state plasma conc)/ F

Question 15

Describe brief route of oral drug metabolism

Answer 15

Gut —> Liver —> Site of action OR kidney

Question 16

What are the drug metabolising enzymes found in liver?

Answer 16

Cytochrome 540s
Alcohol dehydrogenase
Esterases

Question 17

What is 1st pass effect?

Answer 17

Drugs extracted so efficiently by liver only small amount reaches systemic system

Question 18

What are some examples of drugs that undergo substantial 1st pass?

Answer 18

Aspirin
Levodopa
Propranolol

Question 19

What are the 2 processes of metabolism?

Answer 19

Phase I
Phase II

Question 20

What happens in Phase I?

Answer 20

Made into more polar
OXIDATION

Question 21

What happens in Phase II?

Answer 21

Conjugation

Question 22

What is an outcome of Phase I?
1

Answer 22

More pharmacologically active after metabolism
eg. Enalaprilat poorly absorbed so rely on metabolism to convert

Question 23

What is an outcome of Phase I?
2

Answer 23

Alter pharmacological action of drug
eg. aspirin inhibits platelet function + NSAID
BUT hydrolysed to salicylic acid = NSAID

Question 24

What is an outcome of Phase I?
3

Answer 24

Metabolites have similar actions to parent compound
eg. benzodiazepines form active metabolites that cause sedation

Question 25

What is an outcome of Phase I? 4

Answer 25

Metabolites responsible for toxicity

Question 26

What is the 1 of the most important cytochrome P450s in metabolism?

Answer 26

CYP34A

Question 27

What can CYP450 genetic variability cause?

Answer 27

Gain of function effect OR Loss of function effect

Question 28

What can some drugs do to CYP450s?

Answer 28

Induce them = increase biotransformation of drugs = decreases plasma conc

Question 29

What are examples of drugs that are CYP inducers?

Answer 29

Phenobarbital Rifampin

Question 30

What can inhibition of CYP lead to?

Answer 30

Significant increase in plasma drug conc + potential drug toxicity

Question 31

What is an example of CYP inhibitor?

Answer 31

Omeprazole = CYP2C19 Involved in clopidogrel metabolism When taken with omeprazole, clopidogrel (inactive) plasma conc increases = decreases anti-platelet effect

Question 32

What happens in Phase II?

Answer 32

X

Question 33

What is the most common Phase II?

Answer 33

Catalysis by UDP (UGT)

Question 34

What are UGTs?

Answer 34

Superfamily of enzymes that catalyse conjugation f glucuronic acid to facilitate systemic elimination

Question 35

What happens with elderly?

Answer 35

Changes in all PK areas = metabolism + excretion decrease = 1st-pass decreases = hepatic metabolism by CYP450s decrease

Question 36

Why can toxicity in elderly patients develop slowly?

Answer 36

Concs of chronically used drugs increase to 5-6 half-lives

Question 37

What does research show about age?

Answer 37

Does NOT affect clearance of drugs that are metabolised by conjugation (Phase II)

Question 38

What does inflammatory disease of liver effect?

Answer 38

Function of hepatocytes + blood flow = reduce drug extraction = increased systemic availability

Question 39

What is the effect of pregnancy on metabolism?

Answer 39

Hormone levels raised = regulate expression of metabolising enzymes

Question 40

What is BBB?

Answer 40

Selectively permeable membrane = between blood stream + extracellular space of brain

Question 41

What is function of BBB?

Answer 41

Regulate passage of molecules

Question 42

What does the BBB contain?

Answer 42

Endothelial cells lining capillaries Tight junctions that lack intra-cellular pores Glial tissues cover capillaries

Question 43

What does BBB allow?

Answer 43

High lipophilic drugs to diffuse passively

Question 44

How does moderately lipid soluble of partially ionised molecules penetrate BBB?

Answer 44

At slow rate

Question 45

How does glucose cross BBB?

Answer 45

Glucose transporter 1 (GLUT1)

Question 46

What is Parkinson disease (PD)?

Answer 46

Degeneration of dopaminergic neurons

Question 47

Can dopamine cross BBB?

Answer 47

NO

Question 48

What is used to treat PD BUT what is problem?

Answer 48

Levodopa BUT extensively decarboxylated to dopamine in peripheral tissues

Question 49

So how is levodopa given?

Answer 49

Given in combination with DOPA decarboxylase inhibitor that does NOT cross BBB

Question 50

What are the approaches to cross BBB?

Answer 50

Enhance lipid solubility Use of transporters/carriers Inhibition of efflux transporters Prodrug bioconversion