Pharmacokinetics

Question 1

What is drug absorption?

Answer 1

1. The passage of a drug from its site of administration into plasma
2. Drugs must cross cell membranes

Question 2

How are drugs transported across cell membranes?

Answer 2

1. Passive diffusion
   a) Most drugs can pass through surface area of membrane via passive diffusion
   b) Concentration gradient of drug, lipid-water partition coefficient, and ionised state of drug affect rate of passive diffusion
2. Carrier-mediated transport
   a) May be active transport of passive facilitated diffusion
   b) Two main families of membrane transporters - ATP binding cassette transporters and solute carrier transporters

Question 3

What determines drug absorption?

Answer 3

1. Nature of absorbing surface
   a) Number of cell membrane layers the drug has to pass through
   b) The amount of surface area
   c) The amount of blood supply - areas with rich blood supply have better absorption rate
   d) The route of drug administration in some cases
2. Chemical structure of drug
   a) Drug must be in a form that can actually cross the lipid bilayer
   b) Lipid solubility increases rate
   c) Degree of ionisation (+ve or -ve) - ionised particles are poorly absorbed in lipids whilst unionised particles cross cell membrane easily and are absorbed in lipids
   d) pH of aqueous phase
   e) Molecular weight
   f) Dissolution rate (how well it dissolves) - can be manipulated by changing formulation
   g) Route of drug administration in some cases

Question 4

What is the hepatic first-pass effect?

Answer 4

1. The hepatic first-pass effect is not part of drug absorption
   b) It is part of drug metabolism
2. It is a variable proportion of an orally administered drug that is metabolised by the liver before entering systemic circulation and exerting an effect
3. Why can this help determine drug dose and route of administration?

Question 5

What is drug bioavailability?

Answer 5

1. Proportion of administered dose that reaches systemic circulation intact
2. Oral bioavailability depends on:
   a) Fraction of drug absorbed from GI tract (fg)
   b) Fraction of drug that escapes 1st pass metabolism (fh)
3. F = fg x fh
   a) Diagram 4

Question 6

What is drug distribution?

Answer 6

1. The process of reversible transfer of a drug between body locations
2. Many drugs exist in circulatory system bound to plasma proteins (albumin and alpha1-glycoprotein)
3. Plasma protein binding is expressed as a %
   a) Drug + protein Drug/protein complex
   b) Only “free” drugs (not bound to protein) exert pharmacological effect
4. Barriers to drug distribution:
   a) Blood-brain barrier
   b) Placenta

Question 7

What is drug metabolism?

Answer 7

1. The start of the elimination process

2. The liver modifies the lipid soluble drug into a water soluble drug that is metabolised by the kidney

Question 8

What are drug metabolism reactions?

Answer 8

1. Functionalisation reaction
   a) Involve introduction of functional group into the drug molecule via oxidation, reduction, or hydrolysis reactions
   b) These reactions produce a more water soluble drug
   c) Cytochrome P450 enzymes (CYP) are a family of enzymes that are very important in metabolising drugs via functionalisation reactions
2. Conjugation reaction
   a) Involve joining drug molecule with a endogenous polar molecule in the body
   b) The conjugated molecule is more water soluble - enhancing

Question 9

What is the interindividual variability in drug metabolism?

Answer 9

1. Genetics
2. Environmental factors - e.g. coadministration of another drug causing enzyme induction or inhibition
3. Disease states - e.g. heart failure, liver failure
4. Hormonal factors - e.g. pregnancy
5. Gut microbes

Question 10

What is drug excretion?

Answer 10

1. The irreversible loss of chemically unchanged drug from body (e.g. in urine or bile)
2. Main routes of drug excretion are:
   a) Renal
   b) Biliary
   c) Pulmonary
   d) Sweat and saliva
   e) Breast milk

Question 11

Describe the renal route of drug excretion:

Answer 11

1. Glomerular filtration
   a) Drug is transferred from blood to filtrate
   b) Only free unbound drugs and metabolites are filtered through the glomerulus - proteins and formed elements due to not get filtered through
2. Tubular reabsorption
   a) Drug is transferred from filtrate (urine) to blood
   b) Dependent on drug solubility and urinary pH
   i) If drug is free lipid soluble - drug get reabsorbed back into blood
   ii) If drug is free water soluble drug - the drug will not be able to pass through cell membrane back into blood and so will be excreted in urine
   iii) Weak acids are excreted more readily in basic urine and weak bases are excreted more readily in acidic urine - altering urinary pH can therefore increase or decrease drug excretion
3. Tubular secretion
   a) Drug is transferred from blood to filtrate (urine)
   b) Acidic and basic drugs secreted into proximal tubule by specific carrier transporters

Question 12

What is the biliary route?

Answer 12

1. Metabolites are formed when the liver metabolises drugs
2. Metabolites are transported into blood and go to kidneys to become urine or;
3. Metabolites are transported into bile to be excreted as faeces

Question 13

What is the enterohepatic cycling?

Answer 13

1. Occurs when drug is being recirculated between intestine and liver
2. Produces supply of recirculating drug and may increase bioavailability
3. Diagram 5