Pharmacokinetics

Question 1

What are the 4 elements encompassed in pharmacokinetics?

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

What is a concentration-time profile?

Where are the ADME processes most predominant on the concentration-time profile?

Answer 2

A measure of the concentration of a drug in the body over time

Question 3

True or false, Absorption and metabolism/excretion cannot occur at the same time

Answer 3

False. As soon as a drug enters the body metabolism and excretion can begin

Question 4

What drug qualities influence the movement of a drug?

Answer 4

Water/Fat solubility
- Absorption, distribution & excretion
- Especially important to movement across membranes

Chemical structure
- Susceptibility to destruction by metabolism

Question 5

What is passive diffusion?

What drug properties will make drugs favour transcellular diffusion over paracellular diffusion?

Answer 5

Passive diffusion is the non-mediated, electrochemical gradient-driven movement of a substance through a membrane

Transcellular diffusion is favoured by small, lipid-soluble and non-ionised molecules

Paracellular diffusion is favoured by highly water-soluble molecules

Question 6

What is facilitated diffusion?

What is an example of facilitated diffusion?

Answer 6

Facilitated diffusion is the carrier-mediated, electrochemical gradient-driven movement of a substance through a membrane

An example of this is organic anion transporters which are found in the kidneys, transporting organic anions into the proximal tubule

Question 7

What is active transport?

Answer 7

Active transport is the channel-mediated, ATP-driven movement of substances against their electrochemical gradient

Question 8

What is pinocytosis/endocytosis?

Answer 8

The envelopment of extracellular fluid (pinocytosis) or drug bound to cell surface receptor (endocytosis), forming a vesicle to transport inside the cell

Question 9

What is absorption?

What does the rate of absorption determine?

What does the extent of absorption determine?

Answer 9

Absorption of a drug is the phase in which it’s moving from the site of administration to systemic circulation

The rate of absorption determines the speed of onset
- How rapidly the drug gets from the administration site to systemic circulation

The extent of absorption determines the duration of drug action
- How much administered drug enters general circulation (% bioavailability)

Question 10

What is bioavailability dependent on?

Answer 10

First pass metabolism

Accumulation into local fat stores

Degradation by enzymes or pH

Question 11

What factors influence oral absorption?

Answer 11

Interactions with food
e.g. tetracycline can form ionic complexes with calcium, impairing transport across membranes

Stomach emptying rate
- A faster rate speeds up absorption rate (Hunger, mild exercise)
- A slower rate slows down absorption rate (Hot meals, vigorous exercise, pain)

Intestinal motility
- Increased motility decreases time for absorption (e.g. diarrhoea)
- Decreased motility increases time for absorption (e.g. opioids, antidepressants)

Question 12

What is bioequivalence?

Answer 12

Two drug formulations having similar rates and extents of absorption (80-125%)

Question 13

What is distribution?

What affects the extent of distribution?

Answer 13

Distribution is the transport of a drug through systemic circulation and how well it moves into peripheral tissue

Distribution factors
- Lipid solubility
- pH/ionisation of the drug
- Protein binding

Question 14

How does pH/drug ionisation affect distribution?

Answer 14

Ionised drugs can’t pass through membranes as easily, altering passive diffusion (ion trapping)

Question 15

How does protein binding affect distribution?

Answer 15

Plasma proteins can bind to some drugs, trapping the drug in plasma (e.g. penicillins bind to albumin)

Question 16

How is distribution measured?

Answer 16

The volume of distribution (Vd). It is an intrinsic property of the drug which is difficult to change without altering the drug itself

Question 17

What are the two mechanisms of elimination?

Answer 17

Metabolism/biotransformation and Excretion

Question 18

What sorts of drugs does metabolism usually affect?

Where do the byproducts of metabolism end up?

Answer 18

Metabolism typically acts on lipid-soluble drugs to make them more water-soluble

Metabolism byproducts usually end up back in the bloodstream

Question 19

What sorts of drugs does excretion usually affect?

What happens to them during excretion?

Answer 19

Excretion typically acts on water-soluble drugs

No conversion happens to these drugs, they just get removed from the body

Question 20

What are the ways drugs can be excreted?

Answer 20

Bile
Urine
Sweat
Breast milk
Exhaled air

Question 21

Where does metabolism primarily occur?

Answer 21

The liver

Question 22

What are the two main reactions in metabolism?

Answer 22

Functionalisation - Exposing a reactive group on a drug

Conjugation - attaching something to a drug

Question 23

What is first-pass metabolism?

Answer 23

The first time a drug encounters the liver through the hepatic portal vein after oral administration

Question 24

What can metabolism do to drug activity?

Answer 24

Terminate drug activity

Promote activity (Prodrugs)
- Codeine –> Morphine
- ACE inhibitors

No change
- Diazepam –> Nordiazepam

Produce toxic metabolites
- Paracetamol

Question 25

What enzyme family typically performs functionalisation reactions?

Answer 25

Cytochrome P450 (CYP450)

Question 26

What is the purpose of conjugation reactions?

Answer 26

To make a small, lipid-soluble molecule into a larger, water-soluble molecule

Question 27

How is paracetamol turned into a toxic metabolite?

What breaks down this toxic metabolite?

What happens in a paracetamol overdose?

Answer 27

Paracetamol –> NAPQI (Toxic metabolite) by CYP2E1 enzyme (functionalisation reaction)

NAPQI –> Mercapturic Acid (safe metabolite) by GSH

In an overdose, NAPQI acts as a free radical and damages liver cells

Question 28

What can affect metabolism?

Answer 28

Age - Lower metabolism when very young and getting older

Disease - e.g. hepatitis

Other drugs

Diet - e.g. grapefruit juice

Genetics - e.g. CYP2D6 enzyme deficiency

Question 29

What are the two different classes of factors affecting metabolism?

Answer 29

Inducers (increase enzyme production and metabolism)
- Diet (e.g. BBQ meat, cruciferous vegetables)
- Environmental factors (e.g. pesticides, cigarette smoke)
- Other drugs (e.g. phenytoin, carbamazepine)

Inhibitors (decrease metabolism)
- Blocks enzymes from metabolising drugs
- Reversible inhibitors (Cimetidine, ketoconazole, grapefruit juice)
- Heavy metals (lead, mercury)

Question 30

What is renal excretion determined by?

What are they?

Answer 30

Renal excretion = Filtration + Secretion - Reabsorption

Filtration = Drugs filtered in through glomerulus

Secretion = Drugs entering the proximal tubule from the bloodstream

Reabsorption = Drugs re-entering the bloodstream from the loop of henle

Question 31

What factors can influence renal excretion?

Answer 31

Sex - Females have 80-90% renal function compared to males

Age - Decreases with age

Pregnancy - Increase in renal function

Disease - Renal disease, heart failure

Question 32

What is an adverse drug reaction?

What are the types of drug reactions?

Answer 32

An adverse drug reaction is an unwanted or harmful reaction suspected to be related to the administration of a drug/drugs under normal conditions of use

Type A (1) - Predictable based on pharmacology e.g. bleeding with anticoagulants

Type B (2) - Unpredictable e.g. anaphylaxis

Question 33

What are drug interactions?

Answer 33

When the effect of one drug is influenced by the co-administration of another drug/compound