Pharmacokinetics 2: Drug Elimination

Question 1

What is drug elimination?

Answer 1

irreversible loss of drug from the body

Question 2

What are the two ways drugs are eliminated?

Answer 2

1) metabolism - lipid soluble chemicals are converted to water soluble species
- phase 1 = oxidation, reduction, hydrolysis of drug
- phase 2= conjugation - add on functional groups to make more water soluble
2) excretion - in the form of urine, bile, sweat, tears, breast milk, hair, faces etc.

Question 3

What are the three processes accounting for renal excretion?

Answer 3

1) glomerular filtration - free drug enters the filtrate
2) active tubular secretion -
3) passive reabsorption - some of the drug is reabsorbed

Question 4

What are the circumstances that allow a drug to be filtered by glomerular filtration?

Answer 4

To go through glomerular filtration, the drug must be free from proteins and less than 20kDa in size for it to enter filtrate

Question 5

What is tubular secretion of drugs mediated by ?

Answer 5

Tubular secretion is mediated by active carriers - they allow for secretion of drugs that are protein bound or larger in size

Question 6

What is the relevance of a lipid soluble drug as it relates to drug elimination in the nephron?

Answer 6

Lipid soluble drugs have a high tubular permeability - so they are excreted slowly do to their affinity for reabsorption back into circulation

Question 7

what molecules cannot passively diffuse across a membrane?

Answer 7

large polar molecules and charged molecules (aka.large water soluble molecules)

Question 8

most drugs are either weak acids or weak bases … what does that mean?

Answer 8

It means they can be ionised or de-ionised dependent on the conditions (uncharged or charged)

Question 9

What determines a drugs ionisation state?

Answer 9

The Ka of the drug = the acid ionisation constant - the Ka is intrinsic to the drug itself -

So the extent of ionisation depends on the

1) pKa of the molecule
2) pH of the environment

Question 10

In a high pH solution, is a weak acid more likely to be ionised or non-ionised?

Answer 10

in a high pH condition (more alkaline conditions) the acid will be ionised (it will lack a hydrogen)

Question 11

In a low pH solution is a weak base more likely to ionised or non-ionised?

Answer 11

in a low pH solution (acidic environment) the base is more likely to be ionised (acquires a proton)

Question 12

What are the implications of environment mediated ionisation of drugs as it relates to drug elimination?

What is ‘ion trapping?’

Answer 12

Because a weak acid or base can be charged or uncharged based on environmental pH - we can trap drugs in one compartment based on the pH and their ionisation (remember that charged molecules cannot passively diffuse across a membrane - therefore you trap the drug by charging it)
This is known as ‘ion trapping’

Question 13

When is biliary excretion effective? Under what circumstances is biliary excretion NOT effective?

Answer 13

the hepatocytes uptake of lipid soluble drugs metabolises and excretes these lipid drugs into bile - where (if they’re small) they will be reabsorbed with water in the small intestine - So small lipid soluble drugs are not excreted effectively in the biliary system

The biliary system works effectively if it is a HIGH molecular weight drug -

Question 14

What is the potential effect on drug excretion by the bacteria in the lower intestine?

Answer 14

The bacteria can deconjugate the drugs that have been conjugated by the liver- therefore making them ‘free to circulate’ again - this prolongs the drug action in the body - the body therefore retains the drug much longer - and it enters this cycle of liver conjugation- bacterial deconjugation - reabsorption in the small intestine- over and over again

Question 15

What molecules are commonly excreted through pulmonary excretion?

Answer 15

Very volatile molecules including ethanol and anaesthetics (which is why we test for alcohol in a breath test)

Question 16

How are drugs secreted into the sweat?

Answer 16

Via passive diffusion

Question 17

how are drugs secreted into the mammary?

Answer 17

Via passive diffusion - * the concentration in milk reflects the free concentration in blood * not including ion trapping

Question 18

What is an example of a drug that is excreted in the mammary and is particularly harmful to breast fed babies?

Answer 18

chloramphenicol =antibiotic - for its bone marrow toxicity and tendency to cause ‘grey baby’ syndrome - infant’s body cannot metabolise the drug effectively due to lack of liver enzymes

Question 19

What are the downsides to using saliva for drug monitoring?

Answer 19

It can only be used to detect short term drug use - not historical use. Also, salivary pH is variable so ionised drugs are a problem - there is a variable degree of ion trapping.

Question 20

What are the two parts to the definition of ‘first order elimination’?

Answer 20

1) the amount of drug eliminated is directly proportional to the serum drug concentration
2) the fraction of the drug eliminated is constant (note: not the amount of drug eliminated)
ex) the drug plasma conc. goes from 80 to 40 to 20 to 10, but it’s constantly decreasing by 50% get it?

Question 21

Define the ‘Zero order kinetics rate of reaction’

Answer 21

in zero order kinetics, elimination occurs at a fixed maximum rate independent of drug concentration most drugs are first order kinetics

Question 22

What is plasma half life?

Answer 22

time for plasma concentration to fall by 50%

Question 23

What is plasma half life determined by?

Answer 23

by the activity of metabolising enzymes or excretion mechanisms
It is also determined by the distribution of dug between the blood and tissues (High Vd (mainly in tissue) results in prolonged half life)

Question 24

What is ‘clearance?’

Answer 24

It is the volume of blood that is cleared of drug with time (volume/time)
ex) if hepatic blood flow = 800 ml/min and 10% of the drug is metabolised with each pass through the liver, then 80ml/min of blood cleared of the drug.

Clearance is essentially the efficiency of the elimination process

Question 25

What is the ‘steady state?’

Answer 25

Steady state is when the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted - our aim is normally to maintain a steady state concentration of drug within the therapeutic range.

Question 26

At steady state, x=y

Answer 26

infusion rate = elimination rate

Question 27

how can we take a ‘shortcut’ to achieve the steady state of a drug?

Answer 27

We can give a ‘loading dose’ and then switch to a maintenance dose -

Question 28

How do we calculate the loading dose?

Answer 28

Loading dose = Vd x desired plasma concentration

Question 29

What is the therapeutic window?

Answer 29

It is the useful range of concentration over which a drug is therapeutically beneficial - may vary from patient to patient

Drugs with small therapeutic windows require smaller and more frequent doses, need to consider method of administration

Question 30

What is the concern when giving a loading dose of a drug that has a slow elimination rate?

Answer 30

You could potentially accumulate to toxic levels - very dangerous.

Question 31

Why do we use therapeutic drug monitoring?

Answer 31

Because the therapeutic window of drugs may vary from patient to patient, we should monitor drugs with a small therapeutic window in intervals to make sure we maintain a steady state. This way we can maximise the therapeutic use of the drug and minimise the toxic side effects

Question 32

In general, which drugs should be under therapeutic drug monitoring?

Answer 32

Antibiotics like Aminoglycosides and vancomycin

Anticonvulsants like phenytoin and phenobarbital

cardiac drugs like digoxin and quinidine

bronchodilators like caffeine and theophylline

anti-rejection/immunosuppressants like cyclosporine.

Question 33

What is the most important route for drug elimination?

Answer 33

renal and decal excretion

Question 34

What rate order to most drugs follow?

Answer 34

Most drugs are eliminated via the first order process