Pharmacokinetics and Drug Metabolism

Question 1

State the five stages of the journey of a drug through the body.

Answer 1

Administration 
Absorption 
Distribution 
Metabolism 
Excretion 
(Voiding)

Question 2

What is the difference between enteral and parenteral administration?

Answer 2

Enteral – using the GI tract
Parenteral – everything except the GI tract
enteral is easier, paraentral generally requires more skill

Question 3

What are the advantages/disadvantages of intravenous administration?

Answer 3

It gives rapid systemic exposure and a high bioavailability, but is invasive and requires training

Question 4

State the two ways in which drug molecules move around the body.

Answer 4

Bulk Flow Transfer – in the bloodstream it will move in bulk to the tissues
Diffusion Transfer – molecule by molecule over short distances

Question 5

State four methods by which drugs can cross barriers. And define barriers and compartments

Answer 5

• barriers are lipid (eg cell membrane) and compartments are aqueous
• Diffusion through the lipid membrane (if appropriately lipophilic)
  Diffusion through aqueous pores
  Carrier molecules
  Pinocytosis

Question 6

Finish the sentence: most drugs are either …… or ……

Answer 6

Weak acids or weak bases

Question 7

Drugs exist in an equilibrium between ionized and non-ionized forms. Which factors affect the ratio of ionized (polar) to non-ionized (non-polar) drug?

Answer 7

pKa of the drug

pH of the environment

Question 8

Describe and explain the difference in absorption of aspirin in the stomach and the small intestine. and liver

Answer 8

Aspirin has a pKa of 3.4
The stomach has a pH of around 1 so when the aspirin enters the stomach, as the pH of the stomach is lower than the pKa of aspirin, the equilibrium of the aspirin is shifted towards the unionized state
So in the stomach, aspirin mainly exists in the unionized state and is rapidly absorbed
Eventually, the aspirin will reach the small intestines which has a muchmore basic pH (which is greater than the pKa of aspirin)
This means that aspirin in the small intestine is mainly ionized and hence absorption is SLOWER in the small intestine.
Once aspirin gets to liver and gets into hepatic portal circulation and systemic circulation it is in an aqueous fair;y basic enviroment. So is effectively trapped in its ionized form and ion trapped bc cant leave circulation as easily.

Question 9

What is ion trapping?

Answer 9

Some ionized aspirin will enter the systemic circulation, which is an aqueous environment
As it is ionized it will not be able to move into the tissues and hence is ‘trapped

Question 10

State four factors affecting drug distribution.

Answer 10

Regional blood flow (more perfused - exposed to more of the drug, some tissues increase perfusion in activities such as exercise. Highly metabolically active tissues tend to have greater perfusion)
Extracellular binding (plasma-protein binding, 50-80% of drugs are plasma protien bound)
Capillary permeability
Localisation in tissue

Question 11

In which state can albumin bind to drugs? Ionized or non-ionized?

Answer 11

Both ionised and unionised

Question 12

State three types of capillary architecture. And their affect on drug distribution

Answer 12

Continuous (found in normal vessels, has water filled gap junctions)
Fenestrated (more permeable to drugs)
Discontinuous (large gaps)

Question 13

Give a broad example of localization of a drug in tissue.

Answer 13

Lipophilic drugs tend to localise in fatty tissues e.g. brain and testes

Question 14

What are the two main routes of drug excretion? and details

Answer 14

Kidneys (mainly) - body often converts drugs to water soluble substances you then wee out
Liver - drugs conc into bile which is then released into the intestines

Question 15

What types of molecule tend to get excreted via the biliary route? and which by kidneys?

Answer 15

LIVER: Large molecule weight molecules
The liver allows concentration of large molecular weight molecules that are very lipophilic

KIDNEYS: excrete most xenobiotics

Question 16

Via what form of molecular movement do most drugs tend to getexcreted into urine? & why

Answer 16

Active secretion, because can’t use ultrafiltration for large, protien bound drug complexes

Question 17

What happens to drug-protein complexes at the glomerulus?

Answer 17

They are not filtered into the filtrate

Question 18

Where does active secretion of acids and bases occur in the nephron?

Answer 18

Proximal convoluted tubule

Question 19

What can happen to lipid soluble drugs in the proximal and distal convoluted tubules?

Answer 19

They could be reabsorbed, if have something that is a lipid that was secreted into the urine from the glomerular filtration, or something that has become more lipid by becoming unionized bc of urine pH (if its pKa is larger than urine pH) it has the ability to be reabsorbed

Question 20

Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?

Answer 20

IV sodium bicarbonate will increase the pH of the blood
This will increase the amount of aspirin that is ionised
Becoming ionised will mean that the aspirin is more water-soluble and less lipid-soluble so the kidneys can more easily excrete it and less aspirin is reabsorbed in the proximal and distal tubules
This increases the rate of aspirin excretion

Question 21

What is the main purpose of the active transport systems that secrete drugs into bile?

Answer 21

They are meant to be for the active transport of glucuronides and bileacids into the bile but drugs can hitch a ride on this mechanism

Question 22

What is a potential problem with biliary excretion of xenobiotics?

Answer 22

Enterohepatic cycling – it can become reabsorbed and return to the liver via the enterohepatic circulation
This leads to drug persistence

Question 23

Define bioavailability.

Answer 23

The proportion of the administered drug that is available within thebody to exert its pharmacological effect

Question 24

Define apparent volume of distribution.

Answer 24

The volume in which a drug appears to be distributed – an indicator of pattern of distribution

Question 25

Define biological half-life.

Answer 25

The time taken for the concentration of a drug (in blood/plasma) to fall to half its original value

Question 26

Define clearance.

Answer 26

The volume of plasma cleared of a drug per unit time

Question 27

Define First-Order kinetics.

Answer 27

When the rate of drug excretion is proportional to the concentration of drug remaining within the body
Log of drug concentration is proportional to time

Question 28

State the equation for half-life in first-order kinetics reactions.

Answer 28

T1/2 = Vd x log(2)/Cl 
Vd = volume of distribution  
Cl = clearance

Question 29

Define Zero-Order kinetics. And examples

Answer 29

A constant amount of drug is removed from the body per unit time (ethanol, salicylates, phenytoin)

Question 30

What does zero-order kinetics suggest about the enzymes involved?

Answer 30

It suggests that the enzymes are saturated
Once the enzymes are saturated, the rate of removal of a drug peaks and remains constant
NOTE: most drugs follow first-order kinetics

Question 31

explain absorbtion

Answer 31

• drug goes to the liver and absorbed into the blood stream
• travels in hepatic portal circulation into the systemic circulation
• inhalation is also a good route as lungs are well perfused
• there is a risk with inhalation though if inhaling something like a powder

Question 32

effect of plasma protiens on absorbtion

Answer 32

if p.protein is bound to a drug cant be absorbed

Question 33

how can ionised aspirin travel

Answer 33

can travel through aqueous enviroment in gaps between endo cells

Question 34

what would first order and zero order kinetics graphs look like and how would you work out inital conc of drug in plasam

Answer 34

1st ORDER:
x axis: t1/2
y axis: log plasma concentration
straight line graph, extropolate back to y axis to work out inital dose

ZERO ORDER:
x axis: time
y: drug concentration
straight line for zero order drugs, extrapolate to y to get inital conc
- if plotting a 1st order on this graph start high and curve down lower steeply

Question 35

are most drugs first order or zero order kinetics?

Answer 35

first

Question 36

what would you treat a patient with to increase aspirin excretion?

Answer 36

I.V sodium bicarbonate