Drug Absorption and Elimination

Question 1

What 2 factors does drug distribution depend on?

Answer 1

how lipid soluble the drug is (to pass through membranes)

how well drug binds to proteins (eg albumin)

Question 2

What is steady state and how many half-lives does this take?

Answer 2

Steady-state is where the Plasma conc of a drug is at a level which has the desired therapeutic effect and is at equilibrium with the amount of drug being eliminated

this takes 4-5 half-lives to reach

Question 3

What is definition of drug absorption?

Answer 3

passage of drug from site of administration to blood

Question 4

What is definition of drug distribution?

Answer 4

delivery of drug from blood to tissue (to exerts its effect)

Question 5

Which factors affect drug absorption?

Answer 5

blood flow

pH

non-ionised (non-polar) drugs are lipid soluble - can diffuse across CSM

ionised (polar) drugs are lipid insoluble - cannot diffuse across CSM

p-glycoprotein binding

Total surface area and contact time

Question 6

What is dissociation constant a measure of?

Answer 6

The dissociation constant of a weak acid is a measure of its tendency to lose a proton and become ionised in aqueous solution.

Question 7

What does high Ka value mean?

Answer 7

Stronger acids have higher dissociation constants, meaning that they dissociate more readily and completely than weaker acids

A high value of Ka for an acid means that it is a strong acid, and will readily dissociate into hydrogen ions and its conjugate base in solution.

Question 8

What does low Ka value mean?

Answer 8

A low value of Ka for an acid means that it is a weak acid, and will only partially dissociate into hydrogen ions and its conjugate base in solution.

Question 9

Why is important to consider the pH environment which the drug is in and how does this relate to ionisation?

Answer 9

If the pH is inappropriate, the drug cannot
become unionised (lipid soluble) and will be ineffective as the pH wil determine the amount of unionised (lipid-soluble) drug which can pass through CSM

Question 10

What effect does changing pH have on ionisation?

Answer 10

if pH is changed then ratio of U:I is changed

Question 11

what does the degree of ionisation depend on?

Answer 11

• pKa of the drug
• pH of the environment

Question 11

What is pKa of the drug?

Answer 11

The pKa of a drug is the pH value of the solution in which 50% of
the drug is dissociated, therefore half the drug is ionised (I) and
half unionised (U)

Question 12

why are most drugs absorbed via SI instead of stomach?

Answer 12

larger SA and longer transit time

Question 12

why does SL and buccal administration bypass the liver and FPE?

Answer 12

Because venous drainage from mouth and esophagus flows into SVC and not portal system

Question 13

What factors affect rate of distribution?

Answer 13

lipid permeability

plasma protein binding

blood perfusion - the amount of blood that gets to a body compartment as this will regulate how much drug can get in there

tissue perfusion

tissue binding

Question 14

What is the general order of drug distribution?

Answer 14

well perfused organs (eg kidneys, brain, liver)

less perfused organs (viscera, skin, muscle)

Question 15

What 2 factors can limit rate of distribution?

Answer 15

perfusion

permeability

Question 16

What factors affect drug distribution?

Answer 16

non-ionised drugs are lipid soluble - and can diffuse across CSM

ionised drugs are lipid insoluble - cannot diffuse across CSM

blood flow to tissue

drug lipophilicity

molecular weight of the drug

protein binding

Question 17

How do drugs obey the law of mass action?

Answer 17

Once plasma conc is greater than tissue conc, drug will move from plasma to tissue.

Question 18

when does eqm occur?

Answer 18

when plasma drug conc = tissue drug conc

Question 19

what does one-compartment model refer to?

Answer 19

drug administered IV over short time period

body is single tank where a drug is added over a period of time - drug distributes rapidly and homogenously

Question 20

what does two-compartment model refer to?

Answer 20

drug is distributed to central compartments (well-perfused organs and blood)

then more slowly to rest of body (poorly perfused tissue)

drug moves back and forth from these 2 compartments and leaves the central compartment

Question 21

Explain what a 1-compartment model plasma-conc graph would look like?

Answer 21

the drug would be rapidly distributed throughout the body

conc would decline steadily in exponential manner over entire sampling period

Question 22

Explain what a 2-compartment model plasma-conc graph would look like?

Answer 22

drug distributes to tissues in the central compartment - initially more rapid decline

then followed by a slower decline after the drug has been distributed around the body and plasma conc is lower

Question 23

what is vol of distribution (Vd) equation?

Answer 23

amount of drug in body/concentration

Question 24

what does Vd tell us?

Answer 24

small Vd = drug is not widely distributed, high plasma conc in blood

high Vd = drug is better distributed amongst tissues, low plasma conc in blood

Question 25

What does it mean if Vd > total body volume?

Answer 25

it means the drug is concentrated in the tissues, v low plasma conc in blood

Question 26

What is first-order (linear) kinetics?

Answer 26

exponential decay = first order = linear graph

rate of elimination is proportional to the drug concentration

AS DRUG CONC INCREASES IN THE BODY, THE RATE OF ELIMINATION INCREASES

elimination processes not saturated

Question 27

What is zero order (non-linear) kinetics?

Answer 27

straight line rate-conc graph as the system becomes saturated

rate of elimination remains constant despite ↑ drug conc

overall drug clearance decreases with increasing drug concentration

elimination processes are saturated

above a certain drug concentration at the absorption site, there is no further increase in the absorption rate.

Question 28

what factors affect first pass metabolism?

Answer 28

plasma protein binding

GI motility

aging: enzyme activity, hepatocytes decrease as you get older

disease: HF reduces hepatic blood flow

genetic deficiency

environmental

alcohol and drugs

Question 29

what effect does grapefruit juice have on cyp450 activity?

Answer 29

certain compounds in grapefruit juice which inhibit CYP3A4 enzymes

this leads to higher bioavailability of drug conc in plasma with high first-pass metabolism

Question 30

What effect does St Johns wort have on drug interaction?

Answer 30

herbal remedy used for anxiety, depression

induces CYP450 enzyme activity

this leads to lower bioavailability of drug conc in plasma with high first pass metabolism

Question 31

what are the 3 processes of drug excretion?

Answer 31

1. glomerular filtration
2. tubular secretion
3. tubular reabsorption

Question 32

which environments are weak acids (eg aspirin) best absorbed in?

Answer 32

acidic

best absorbed in duodenum due to high H+ concentration

Question 33

which environments are weak bases best absorbed in?

Answer 33

alkaline

eg distal ileum is more alkaline

Question 34

how does SA and contact time affect absorption?

Answer 34

↑ SA ∝ ↑ absorption

↓ SA → ↓ absorption

↓ contact time → ↓ absorption (eg diarrhoea)

↑ contact time → ↑ absorption (eg constipation)

Question 35

how does blood flow affect absorption?

Answer 35

↓ blood flow (eg shock) → ↓ absorption into bloodstream → no drug reaching system

bypass this via IV administration

Question 36

What effect does P-glcyoprotein on drug absorption?

Answer 36

when drug is bound to PBP is inactive

however, sometimes P-glycoprotein spits drug back out into GI tract for excretion

therefore ↓ absorption

Question 37

what is loading dose?

Answer 37

initial higher dose given to achieve therapeutic effect quicker

Loading doses are larger than maintenance doses and are usually administered as a single bolus, although some drugs (eg, amiodarone or digoxin) may require multiple loading doses administered over several hours to days

Question 38

what is maintenance dose