Introduction to Pharmacokinetics

Question 1

What is quality use of medicines?

Answer 1

Selecting management options wisely
Choosing suitable medicines if a medicine is considered necessary
Using medicines safely and effectively

Question 2

What is pharmacokinetics and pharmacodynamics?

Answer 2

Pharmacokinetics = what the body does to the drug

Pharmacodynamics = what the drug does to the body

Question 3

What are the pharmacokinetic considerations?

Answer 3

Remember ADME

Absorption
Distribution
Metabolism
Excretion

Question 4

Why focus on blood concentrations?

Answer 4

Easiest to measure

Difficult to measure concentration at effect site (invasive), pharmacological effect, and outcome

Question 5

How and where does oral absorption take place?

Answer 5

Drugs can be absorbed by passive diffusion or active transpoort across the mucosa
Site of oral absorption varies:
Intestine = large surface area, rich bloody supply, pH 6.5 - 7
Stomach = smaller surface area, coated in thick mucus, highly acidic

NOTE: pKa and pH don’t necessarily predict absorption

Question 6

What is gastric emptying and what does it do?

Answer 6

Movement of material from the stomach into the intestine
Determines time to reach intestine
Influences onset and rate of absorption
Influenced by otehr drugs and food
Importance and influence depend on dissolution-rate and permeability-rate

Question 7

What is metoclopramide and propantheline and what are they used for?

Answer 7

Used to increase or delay gastric emptying when combined with drugs

Metclopramide = increase
Propantheline = delays by slowing GI transit

Question 8

What impact on GI transit time do polar drugs have?

Answer 8

Polar drugs are absorbed slowly due to poor intestinal permeability - GI transit may remove them from the site of absorption

They are active transporters and are transit dependent

Question 9

What is an acid labile drug?

Answer 9

A drug that is easily destroyed in an acidic environment

Slow gastric emptying will lead to prolonged exposure to acid and drug degradation

Question 10

What are barriers to systemic absorption?

Answer 10

Degradation in the lumen
Metabolisation by CYP3A4 in enterocytes
Exportation by P-glycoprotein
Metabolisation in portal blood
Metabolisation of excretion in the liver

Question 11

What are two causes of low bioavailability?

Answer 11

Poor intestinal permeability

Extensive first pass hepatic elimination

Question 12

What factors affect the rate and extent of drug absorption from the GI tract?

Answer 12

Formulation of drug characteristics such as tablet dissoltion / disintegration, influence of excipients, and stability of drug GI lumen

Pharmacokinetic characteristics of drug such as first pass effect (metabolism by bacteria, gut wall, liver etc)

Patient characteristics such as GI transit time and influence of disease

Presence of substances in GI tract such as food or drugs (co-administration slows down absorption)

Question 13

What are the different routes of elimination?

Answer 13

Metabolic biotransformation in liver, intestine, kindeys, or lungs
Renal elimination
Biliary excretion
Exhalation
Other routes eg lactation

Question 14

What is metabolic biotransformation?

Answer 14

Biotransformation can be oxidationn, reduction, or conjugation
Enzymatic chemical conversaion or conjugation that makes a metabolite more soluble
Generally detoxification but may be activation

Question 15

What are the ofur common reactions involved in drug metabolism?

Answer 15

Oxidation
Reduction
Hydrolysis
Conjugation

Question 16

What is clearance (CL) and what is its significance?

Answer 16

Measure of efficiency of drug elimination from the body used to estimate the maintenance dose rate

Calculated from volume of blood cleared of a drug per unit of time (Volume / Time eg L/h)

MOST IMPORTANT clinical pharmacokinetic parameter because it determines the average concentration achieved if a drug is administered at regular intervals

Question 17

How is clearance calculated?

Answer 17

After a single dose: CL = F x Dose / AUC

During steady-state dosing: CL = F x Dose rate / Css
(Css = concentration at steady-rate when input rate = output rate)

Clearance is additive so if the drug has more than one route of elimination the total clearance is the sum of each individual clearance
(CL = CL renal + CL metab + CL bile etc)

Question 18

What are the three processes involved in renal elimination?

Answer 18

Filtration (glomerulus) = all unbound drug in plasma is filtered

Secretion (proximal tubule) = Carrier mediated, drugs may interact for the same carrier

Passive reabsorption (distal tubule) = relatively insoluble and uncharged drugs undergo passive reabsorption

Therefore, renal clearance = total of all types of clearance methods

Question 19

How are the characteristics of active secretion in the renal excretion process?

Answer 19

Transporter for anions (-ve) and cations (+ve) ions
May be saturated at higher doses
Competitive drug interactions

Question 20

What are the characteristics of reabsorption in the renal excretion process?

Answer 20

Generally a passive reabsorption in proximal tubule
Lipophilic molecules tend to be reabsorbed
Polar molecules do not tend to be reabsorbed

Question 21

What is variability in drug response?

Answer 21

The product of pharcokinetics and pharmacodynamics

Old age can impact varaibility as it changes clearance factors, changes pharmacokinetics

Question 22

What is the clinical significance of drug interactions?

Answer 22

Patient characteristics
Mechanism interaction
Nature of pharmacodynamic response
Safety margin of the interacting herb and drug
Dose and duration of therapy
Time course of drug interaction
Order and timing of administration

Question 23

What are the 4 basic pharmacokinetic parameters and what do they affect?

Answer 23

1. Clearance (CL) = volume / time
   The efficiency of drug elimination which then determines the dose rate
2. Volume of Distribution (V) = volume
   Th extent of distribution which then determines the loading dose
3. Bioavailability (F)
   A fraction representing the dose absorbed after an oral administration which then determines the dose adjustment between routes of administration
4. Half life = Time (t 1/2)
   A description of how long a drug / metabolite stays in the body (interplay of V and CL) which the determines the frequency of dosing