Introduction to Pharmacokinetics

Question 1

define pharmacokinetics

Answer 1

how drugs are processed by the body e.g. movement, absorption, distribution, excretion.

Question 2

define pharmacodynamics

Answer 2

The effect of a drug on the body

Question 3

define efficacy

Answer 3

max drug response that is achievable

Question 4

define potency

Answer 4

amount required to produce an effect

Question 5

define affinity

Answer 5

how well a drug binds to its receptor

Question 6

describe this graph

Answer 6

Graph showing how the concertation of a drug in the body from initial consumption
From start to peak shows the absorption distribution. This is the drug entering the blood plasma to go to the site of action.
From peak to end shows the metabolism and excretion of the drug - where the body tries to remove the drug form site-of-action and eventually from remove it from the body.

Question 7

explain the different parts of the graph

Answer 7

Plasma conc: conc. of the drug in the blood plasma (this is available to act at its receptor)
Effective conc.: minimum conc. of a drug required to have an effect i.e. threshold value (there is enough of the drug to force receptors into bound conformations)
Toxic conc: max conc. of drug before harmful side effects may occur
Therapeutic window/index: dosage range between effective & toxic conc. => larger index = safer drug

Question 8

what does compliance mean?

Answer 8

do people actually take the drugs (hide under tongue) checked using a drug test e.g. blood test to measure drug level.

Question 9

describe the one-compartment model

Answer 9

Modelling pharmacokinetics
- Views body as single compartment
- Once drug is administered it is equally absorbed throughout the body & concentration everywhere is uniform at all times
- The plasma concentration of a drug (Cp) is determined by the rate of drug absorption, the volume of drug distribution (Vd) and rate of drug elimination (kel).
- When the drug is administered parenterally as a bolus. ka is instantaneous and is not determined.
- log plasma conc. decreases lineally w/ time -> first order kinetic rate
- Hydrophilic drugs follow this model (can’t cross plasma membrane so stay in blood)
- Acidic, neutral and amphoteric drugs and drugs that are heavily plasma protein bound follow this model (not basic drugs)

Question 10

what is the Apparent volume of distribution (AVD)?

Answer 10

Apparent volume of distribution (AVD / Vd) = volume of fluid required to dilute absorbed dose of a drug to conc. found in plasma

Question 11

what happens if drug is heavily plasma protein bound or heavily tissue bound?

Answer 11

If Drug is heavily plasma-protein bound (AVD = 6) then it fairly follows the one compartment model (the blood is the sole compartment of the body)
If Drug is heavily tissue bound (AVD > 70) then it fairly follows the two-compartment model.

Question 12

describe the two-compartment model

Answer 12

• more suitable for the body
• extension of one-compartment model
  accommodates for unequal distribution within the body
• Lipophilic and basic drugs (tissue bound) follow this model.
• alpha phase = plasma drug conc. initially declines rapidly due to elimination from the plasma and distribution into the second compartment (which can comprise of several organs)
• beta phase = once equilibrium is reached, the plasma drug level declines more slowly due to elimination out of the body alone

Question 13

what are the 3 different routes of administration?

Answer 13

Enteral routes – oral & rectally

Parenteral routes – subcutaneous (s.c.), intra-muscular (i.m.), intra-venous (i.v.) injections

Percutaneous routes (‘by way of skin’) – inhalation, sublingual (under tongue), topical/transdermal

Question 14

what is the journey of a Drug in the body?

Answer 14

ADME
Absorption
Distribution
Metabolism
Excretion

Question 15

what is absorption dependant on?

Answer 15

Absorption – rate dependent on:
- Route of administration: enteral, parenteral & percutaneous routes
- High Blood flow at site of administration and high surface area allows for maintenance of high conc. gradient so high rate of absorption
- Dose of drug - sets up size of conc. gradient
- Active vs passive diffusion through a membrane - influenced drug solubility
hydrophilic => active transport
hydrophobic => passive diffusion

Question 16

what does distribution dependant on?

Answer 16

1. blood flow – impact on initial distribution (i.e. brain, heart & liver first as they have high blood flow; then skeletal muscle; then fat)
2. lipid solubility & diffusion barriers – drugs more able to cross barriers at brain or placenta if lipid soluble
3. tissue binding – some drugs have preference for certain tissue types
4. plasma protein binding – i.e. albumin; plasma protein prevents some of drug from moving to site of action - acts as a reservoir - equilibrium of bound to free drug dependent on affinity of bond of drug to plasma protein

Question 17

what happens during metabolism of the drug?

Answer 17

• some drugs are prodrugs - administered form is inactive until metabolised at target tissues/liver
• If a drug is ingested orally it first goes down oesophagus to the stomach and into the GIT.
• Large amounts of microbes live in GIT and they are also involved in metabolism of drugs.

Question 18

what is first pass metabolism?

Answer 18

occurs mainly in the liver, and a small amount in the kidneys skin and lungs.
Liver: Hepatic portal system (from GIT) brings the drug (via the blood) to the liver first so ingested toxic substances can be removed.
The drugs also undergo biotransformation in the liver (makes lipophilic drugs more hydrophilic)

Question 19

what are the 2 phases of biotransformation?

Answer 19

Phase I biotransformation – oxidation (compounds become more hydrophilic) by cytochrome p450 (CYP) enzymes - hydroxyl groups added

phase II biotransformation – conjugation of a charged group to compound to increase solubility (hydrophilic) i.e. sulphate group conjugated by sulfotransferases
Both phase one and two occur simultaneously
The drug then enters systemic circulation.

Question 20

what is an example of metabolism of a drug? (revisit)

Answer 20

i.e. L-DOPA (inactive) able to cross BBB whereas dopamine (active) isn’t
e.g. Diazepam => active metabolite desmethyldiazepam (oxidative demethylation by a number of CYPs)
Tamoxifen => active metabolite 4‐hydroxy‐tamoxifen (oxidation by CYP2D6 and CYP3A4) People need to be tested for their CYP2D6 status before going on tamoxifen as if they do not have the right level of the enzyme the drug will not be effective

Question 21

where is the drug excreted?

Answer 21

liver
kidney
lungs
saliva, sweat and milk
faeces

Question 22

what happens during excretion in the kidneys?

Answer 22

• Hydrophilic drugs/drug metabolites are excreted by the kidneys into urine.
• Lipophilic drug molecules are not directly excreted from the kidney. Only after they are metabolized into more hydrophilic molecules, can they be excreted through the kidneys into the urine.
• If a drug is bound to a plasma protein it can not be excreted via the kidneys

Question 23

what happens during excretion in the liver?

Answer 23

The liver secretes drugs and their metabolites into bile. The bile is eventually released into the intestinal tract. Here the drug metabolites may be converted back to the parent drug in the intestine and then reabsorbed into systemic circulation. This drug recycling process is called enterohepatic circulation. This traps the drug in the body.

Question 24

what happens if drug isnt absorbed into circulation?

Answer 24

If the drugs are not reabsorbed into systemic circulation they are excreted from the body through faeces.

Question 25

how does excretion occur in the lungs?

Answer 25

via exhalation of drug vapours

Question 26

what can saliva, urine and blood be used for?

Answer 26

urine & saliva used in addition to blood for drug analytics

Question 27

describe the fate of an orally administered drug?

Answer 27

One or more of these processes could be less efficient in a basic drug and could be a reason for failure.

Question 28

what are the pre-clinical outcomes from a pharmacokinetic study?

Answer 28

1. select compounds that have the max potential of reaching target (PK)
2. select appropriate route of administration to deliver drug
3. Work out the toxic and effective concentration
4. predict human pharmacokinetics (i.e. gender – drugs respond differently based on sex)
5. Dosage intervals
6. understand how plasma levels relate to efficacy (PK-PD) or toxicity (TK-TD) in order to select safe doses
7. decide on target frequency & duration of dosage in order to sustain drug at target for disease modification

Question 29

what are the steps in performing a PK study?

Answer 29

1. Administer dose to subject
2. collect samples (blood, urine, bile, faeces) at various timepoints
3. Analyse for drug/metabolites - use of Liquid chromatography and mass spectrometry
4. PK data analysis - to work out stuff above

Question 30

how do dose intervals affect drug concentration?

Answer 30

DOSE interval depends on plasma half-life (time taken for half of drug to be eliminated from plasma) of drug

Question 31

what 5 things need to be considered when administering a drug? (5 rights)

Answer 31

Drug administration:
right patient (-> personalised medicine)
right drug
right route of administration
right dose
right time