Pharmacokinetics (session 7)

Question 1

What are the enteral methods of drug delivery into the internal environment of the body?

Answer 1

Oral
Sublingual
Rectal

Question 2

What are the parenteral methods of drug delivery into the internal environment of the body?

Answer 2

Intravenous
Subcutaneous
Intramuscular

Question 3

What are the methods of drug absorption on a molecular level (that we need to know about)? (3)

Answer 3

Passive diffusion
Facilitated diffusion
Secondary active transport

Question 4

Which method of drug absorption do lipophilic drugs use?

Answer 4

Passive diffusion

Question 5

True or false: Molecules (or solutes) with net ionic positive or negative charge within the GI pH range can be carried across the GI epithelia

Answer 5

TRUE

Question 6

Solute carriers (SLCs) can either be one of two types of transporters-what are these?

Answer 6

OAT=organic anion transporter

OCT=organic cation transporter

Question 7

Which two things are SLCs pharmacokinetically important for?

Answer 7

Drug absorption and elimination

Question 8

Where are SLCs highly expressed?

Answer 8

GI, hepatic and renal epithelia

Question 9

True or false: SLCs can only enable drug transport in GI by facilitated diffusion

Answer 9

FALSE - also by secondary active transport

Question 10

What do SLCs use instead of ATP in secondary active transport?

Answer 10

Transport is driven by pre-existing electrochemical gradient across GI epithelial membrane

Question 11

Give two examples of SLCs that use secondary active transport?

Answer 11

1. Fluoxetine/Prozac - antidepressant co-transported with Na+ ion
2. B-lactam antibiotics/penicillin - co-transported with H+ ion

Question 12

Name three physicochemical factors that affect drug absorption

Answer 12

GI length/SA
Drug lipophilicity/pKa
Density of SLC expression in GI

Question 13

Name three GI physiology related factors that affect drug absorption

Answer 13

Blood flow
GI motility
Food IpH (low pH destroys some drugs)

Question 14

What is ‘first pass’ metabolism?

Answer 14

Reduces availability of drug reaching systemic circulation (part of CV system that carries oxygenated blood away from heart to body and deoxygenated blood back to heart) and therefore affects therapeutic potential

Question 15

What carries out first pass metabolism? (2)

Answer 15

GI and liver

Question 16

Which two major enzyme groups are some drugs metabolised bY?

Answer 16

Cytochrome P450s - Phase I enzymes

Conjugating - Phase II enzymes

Question 17

True or false: there is much larger expression of Phase I and II enzymes in the liver than in the GI

Answer 17

TRUE

Question 18

Define bioavailability

Answer 18

Fraction of a defined dose which reaches its way into a specific body compartment

Question 19

What is the bioavailability reference for the CV system?

Answer 19

IV bolus=100%

Question 20

What does the first stage of drug distribution involve? (3)

Answer 20

1. Bulk flow - arteries to capillaries
2. Diffusion - capillaries to interstitial fluid to cell membranes to targets
3. Barriers to diffusion - interactions/local permeability/non-target binding

Question 21

True or false: if a drug is largely lipophilic, it can freely move across membrane barriers

Answer 21

TRUE

Question 22

If a drug is largely hydrophilic, its journey across membrane barriers is dependent on which factors? (3)

Answer 22

Capillary permeability
Drug pKa and local pH
Presence of OATs/OCTs

Question 23

What does a smaller Vd (apparent volume of distribution) mean?

Answer 23

Less penetration of interstitial/intracellular fluid compartment

Question 24

Where does drug metabolism largely occur?

Answer 24

In the liver via phase I and II enzymes

Question 25

What do phase I and II enzymes do?

Answer 25

Metabolise drugs - increase ionic charge and enhance renal elimination Lipophilic drugs diffuse out of renal tubules and back into plasma and once metabolised, drugs are usually inactivated

Question 26

Which enzyme carries out phase I metabolism?

Answer 26

Cytochrome P450 enzymes (CYP450s)

Question 27

What are the two options for drugs metabolised in phase I?

Answer 27

Eliminated directly or go onto phase II

Question 28

Give an example of when prodrugs activated by phase I metabolism activate to active species

Answer 28

Codeine to morphine

Question 29

What carries out phase II metabolism?

Answer 29

Hepatic enzymes

Question 30

True or false: phase I enzymes are versatile generalists

Answer 30

TRUE

Question 31

True or false: phase I and II metabolism decreases ionic charge

Answer 31

FALSE - increases ionic charge

Question 32

What are the three superfamilies of cytochrome P450 enzymes?

Answer 32

1, 2 and 3

Question 33

What is an isozyme?

Answer 33

Each of two or more enzymes with identical function but different structure

Question 34

Complete the sentence: If another drug in the body is metabolised by induced CYP450 isozyme then its rate of elimination will be ___________

Answer 34

Increased

Question 35

What is an example of CYP450 induction and how does it work?

Answer 35

Carbamazepine (CBZ) = anti-epileptic metabolised by CYP3A4 | CBZ induces CYP3A4-lowers its own levels, affecting control of epilepsy

Question 36

What is an example of CYP450 inhibition and what does it inhibit?

Answer 36

Grapefruit juice inhibits CYP3A4 | CYP3A4 metabolises Verapimil, used to treat high BP. The result of this inhibition can be reduced BP and fainting

Question 37

What is the main route of drug elimination?

Answer 37

Kidney

Question 38

What are the other routes of drug elimination?

Answer 38

``` Bile Lung Breast milk Sweat Tears Genital secretions Saliva ```

Question 39

What are the three processes of renal excretion?

Answer 39

Glomerular filtration Active tubular secretion Passive tubular reabsorption

Question 40

What is clearance?

Answer 40

Rate of elimination of a drug from the body

Question 41

For most drugs, total body clearance is approximately equal to what?

Answer 41

Hepatic clearance + renal clearance

Question 42

What are the units of clearance (CL)?

Answer 42

ml/min

Question 43

What is the real plasma volume?

Answer 43

3L

Question 44

True or false: Clearance (CL) and Vd provide an estimate of drug half-life or t1/2

Answer 44

TRUE

Question 45

Define drug half-life

Answer 45

Amount of time over which the concentration of a drug in plasma decreases to a half of its original concentration

Question 46

If CL stays the same and Vd increases, what happens to t1/2?

Answer 46

Increases

Question 47

If CL increases and Vd stays the same, what happens to t1/2?

Answer 47

Decreases

Question 48

True or false: the rate of metabolism or excretion is proportional to concentration of drug

Answer 48

TRUE

Question 49

When is the rate of metabolism or excretion proportional to concentration of drug?

Answer 49

When there are: Plenty of phase I/II enzyme sites Plenty of OAT/OCT transporters

Question 50

What happens when eliminated processes becomes saturated?

Answer 50

They become rate limited and elimination kinetics are referred to as saturated or zero order

Question 51

True or false: most drugs exhibit zero order kinetics at lower doses

Answer 51

FALSE-at higher doses