Pharmacokinetics: Drug absorption and distribution

Question 1

What’s the difference between pharmacokinetics and pharmacodynamics?

Answer 1

Pharmacodynamics: how the drug actually works- the physiological effect on the body ex) ion transport inhibitor etc. These are specific to the drug class. Pharmacokinetics: effect that the body has on the drug - to do with the movement of drugs into/around/out of the body- these are general processes we can apply to ALL drugs

Question 2

What is Bioavailability?

Answer 2

the fraction of the administered dose that reaches the systemic circulation as intact drug - To determine the bioavailability we use the IV route to compare plasma levels before and after the drug is given.

Question 3

What does the term ‘apparent volume of distribution’ mean?

Answer 3

it is the theoretical volume of fluid a drug would occupy if the total amor of drug in the body was in solution at the same concentration as in the plasma - gives us a measure of the tendency of the drug to move out of the plasma - If the drug has a small volume of distribution - the drug stays in the plasma for the most part If the drug has a large volume of distribution - then the drug easily moves into the tissue - it is essentially mopped up by the tissue and we will not easily reach the therapeutic levels in the plasma -The larger the volume of distribution, the more likely that the drug is found in the tissues of the body

Question 4

How do we calculate Volume of distribution?

Answer 4

Vd= dose/(plasma Conc. at time 0)

Question 5

What is the fastest and most certain parenteral route of administration?

Answer 5

Intravenous injection

Question 6

Why would you choose to give an injection in a muscle vs. intradermal?

Answer 6

Muscle injections are good for larger volumes and when faster absorption is desired ie. antibiotics Intradermal injections are used for drugs that you want to absorb slowly like for allergy tests or local anesthesia

Question 7

Why would you choose a subcutaneous injection?

Answer 7

(inject below the dermis and epidermis) you use this when a slower more prolonged effect is desired i.e.) insulin or heparin

Question 8

Could a drug taken per orally or per rectally be introduced into the portal system?

Answer 8

Yes! Through the gut, the drug may enter the portal system - then into the liver where it is likely metabolised by the liver- the drug may or may not have had the opportunity to absorb into the plasma in this case

Question 9

Oral administration- weigh the pros and cons

Answer 9

Pro: common and convenient Con: faces most barriers to entry into the systematic circulation

Question 10

What factors influence drug absorption from the gut?

Answer 10

Drug structure: highly polarised compounds are poorly absorbed, weak acids and bases undergo pH partitioning, and peptides broken down by digestive enzymes Formulation: capsule/tablet must disintegrate, modified release formulations Gastric emptying can effect the rate but not quantity - food can slow down drug absorption due to delayed gastric emptying - food can cause stimulation of gastric acid secretion which effects drug absorption First- pass metabolism:

Question 11

What is ‘First-pass metabolism?’

Answer 11

aka pre systemic metabolism - drug is absorbed in the gut and flows into the portal system where it is metabolised by the liver - the broken down version of the drug is passed out of the liver- only a small proportion of the drug will actually reach the circulation example of first pass metabolism drug = insulin and penicillin are broken down by enzymes before systemic circulation This is associated mainly with drugs given orally- but can happen in many administration routes

Question 12

If a drug is known to be effected by ‘first pass metabolism’ what do we do?

Answer 12

We give the drug via a different route - if it is effected by first pass metabolism we likely cannot give orally.

Question 13

Why are drugs given sublingually and rectally beneficial?

Answer 13

They avoid first pass metabolism generally because the portal system doesn’t come down that far -

Question 14

Give an example of a drug that must be given via intravenous route?

Answer 14

Lignocaine - analgesic which is 100% bioavailable via intravenous route

Question 15

Give an example of a drug that must be given sublingually

Answer 15

glyceryl trinitrate - for angina attacks - given sublingually straight into the systemic circulation without entering the portal system - avoid first pass metabolism

Question 16

Give an example of a drug that must be given per rectum

Answer 16

Diazepam - for epilepsy - absorption is unreliable but useful in patients vomiting or postoperative- avoids intestinal enzymes and low pH

Question 17

Give an example of a drug that must be given transdermally-

Answer 17

Nicotine patches - must be a lipid soluble drug so it could pass the lipid bilayer

Question 18

How do you determine the route of administration for a drug?

Answer 18

1) physical characteristic of drug 2) speed the drug is absorbed 3) need to bypass the hepatic metabolism?

Question 19

How to calculate bioavailability

Answer 19

bioavailability (F) = (AUCoral/AUCinjected) X 100 quoted as percentage ‘AUC’ = area under curve - referring to the area under the concentration vs. time curve - this area represents the total systemic exposure the patient has to the drug - Always compare to the area under the curve of the drug when given intravenously. This is why the IV route always has “100% bioavailability”

Question 20

What is a bolus injection?

Answer 20

It is the opposite of gradual administration it is a once off high concentration injection as an intravenous infusion - used to visualise the distribution of drug and the elimination of the drug by the body

Question 21

What does the term drug distribution refer to?

Answer 21

the process by which the drug is transferred from the general circulation to the target tissue

Question 22

What is the ‘blood brain barrier’?

Answer 22

The tight regulation of substances in and out of the brain capillaries - in the brain the capillaries are different in structure - there are tight junctions between the cells and there is an extra layer of astrocytes - this structure tightly regulates the movement of substances in and out of the brain

Question 23

Hydrophobic vs. Hydrophilic drugs

Answer 23

Hydrophobic - no net charge - easily cross most membranes Hydrophilic - charged - do not easily cross membranes

Question 24

Describe the associations of drugs with plasma proteins

Answer 24

Albumin - binds to acidic and neutral drugs Alpha 1 glycoprotein - binds to basic drugs

Question 25

Why is protein association in the plasma with drugs relevant clinically?

Answer 25

Drug/protein interactions limits the amount of ‘free drug’ available. These proteins keep a ‘store’ of drugs - as a result you’ll see very little pharmacological effect while they’re bound and you’ll see very little excreted - therefore they stay in the body longer Remember only ‘free circulating’ drugs can act -

Question 26

What is the consequence of reduced plasma protein as it relates to drug distribution?

Answer 26

reduced protein like hypoalbuminaemia - reduce the amount of bound drug therefore you’ll have a much quicker response of drug with more freely circulating drug- also this will result in a quicker excretion of the drug

Question 27

What is the consequence of uraemia as it relates to drug distribution?

Answer 27

Excess urea in blood from kidney damage, affects the binding sites such that drugs are less extensively bound than in non-uraemic patients.

Question 28

What is the consequence of age as it relates to drug distribution?

Answer 28

–Lower binding capacity in the foetus and neonates- leads to more free circulating drug

Question 29

What is the consequence of ‘competitive binding’ as it relates to drug distribution?

Answer 29

Drug removed from its binding site as a result of competition with another compound e.g. warfarin vs. aspirin

Question 30

Describe the competitive binding predicament with aspiring vs. warfarin

Answer 30

Administration of a highly protein bound drug (aspirin) to a patient already receiving maintenance therapy with a drug that binds reversibly to plasma proteins (warfarin) If patient takes normal dose of aspirin at same time (normally occupies ~50% of protein binding sites), the aspirin displaces warfarin so that ~96% of the warfarin dose is protein-bound; •Thus, 0.2 mg warfarin free; thus, doubles the dose.

Question 31

What is a ‘loading dose’

Answer 31

given for drugs that has a high volume of distribution - we need to load them up before they have a therapeutic dose - This occurs when we have a large volume of distribution drug - where the drug has a tendency to move out of the plasma and is instead ‘mopped up’ by the tissue. we give them a large initial dose so that your body mops up the drug and then we still have some leftover in the plasma as a therapeutic dose

Question 32

Calculate the volume of distribution of an intravenous drug dose 30mg. When a few minutes later the drug plasma level = 0.5 micrograms/ml

Answer 32

Vd= Dose/Conc. 30,000/.5= 60,000 ml = 60L

Question 33

What does it mean when a drug has a large volume of distribution?

Answer 33

It means that the drug will be mainly located in the tissue with very little in the plasma - in this case you give a ‘loading’ dose.

Question 34

What does it mean when a drug has a small volume of distribution?

Answer 34

it means that the drug will exist mainly in the plasma with very little drug in the tissues -