F9. Intro to pharmacokinetics

Question 1

drug delivery challenge?

Answer 1

Supply active drug to cellular targets at an effective
dose, with minimal side effects

Question 2

how can a drug reach target site?

Answer 2

direct to site:
-Relatively easy for skin, eye, gut, lung
-Much more difficult for other sites, but can be done
Indirect:
* Via systemic circulation (i.e. blood)
* Introduces problems of loss or dilution of dose

Question 3

How can drugs be removed from the body?

Answer 3

Metabolism and/or Excretion

Question 4

Inhalation medicines?

Answer 4

Gases
Volatiles

Question 5

oral medicines?

Answer 5

Tablets
Capsules
Solutions
Buccal

Question 6

Injection medicines?

Answer 6

Intravenous (i. v.)
Intramuscular (i. m.)
Subcutaneous (s. c.)
Intrathecal

Question 7

transdermal medicines?

Answer 7

Patch
Cream

Question 8

where does absorption of drug into bloodstream happen in oral medicines?

Answer 8

Somewhere along the gastrointestinal tract

Question 9

where does absorption of drug into bloodstream happen in transdermal medicines?

Answer 9

Across the skin

Question 10

where does absorption of drug into bloodstream happen in hypodermic injection medicines?

Answer 10

From injection site (muscle, adipose tissue)

Question 11

where does absorption of drug into bloodstream happen in lung medicines?

Answer 11

Alveolar surface

Question 12

Describe passive diffusion of drugs across lipid bilayer

Answer 12

Passive diffusion across lipid bilayer down concentration gradient, determined
by lipophilicity of drug

Question 13

Describe active transport of drugs across lipid bilayer

Answer 13

Active transport can carry some drugs with low lipid solubility into the cell, regardless of gradient. This depends from charge (depends on pH) and size.

Question 14

what is a closed system?

Answer 14

Blood makes continuous,
multiple passes around the
vascular system

Question 15

what determines drug distribution?

Answer 15

-binding to plasma proteins
-structure of vascular endothelium
-accumulation in tissue depots

Question 16

Describe how binding of plasma proteins affects drug distribution?

Answer 16

• Reversible binding can ferry drug around the circulatory system
• Very high affinity binding can limit escape from plasma

Question 17

Describe how the structure of the vascular endothelium affects drug distribution

Answer 17

• Pores between endothelial cells in most vessel beds
• Some special cases: blood brain barrier, placenta

Question 18

How does accumulation in tissue depots affect drug distribution?

Answer 18

• Protein binding sites (including target!)
• Adipose tissue

Question 19

accumulation of drugs depends on?

Answer 19

blood flow

Question 20

highly- perfused lean tissue groups?

Answer 20

blood cells, heart, lung, liver, kidney, glands, brain

Question 21

poorly-perfused lean tissue groups?

Answer 21

muscle, skin

Question 22

Fat group tissues?

Answer 22

adipose tissue, bone marrow

Question 23

Negligible perfusion tissue groups?

Answer 23

teeth, hair, bone, tendon, cartilage

Question 24

Describe how the liver is involved in metabolism

Answer 24

-The liver is packed full of broad-spectrum metabolic enzymes
-Evolved to protect against environmental toxicants

Question 25

Two phases of metabolism?

Answer 25

1. Redox reactions to add charge and/or reactive centres
2. Conjugation reactions to add bulky groups
   ONE NOTE

Question 26

how does metabolism affect drugs?

Answer 26

increases:
-hydrophilicity
-reactivity
-size

Question 27

how are drugs usually excreted from the body?

Answer 27

Mainly in the urine via the kidney
* Some large drugs excreted in bile

Question 28

what are the three key stages of excretion in the kidneys?

Answer 28

-Passive filtration
-Active secretion
-Reabsorption
ONE NOTE

Question 29

Describe passive filtration in glomerulus stage of excretion in kidneys

Answer 29

Plasma is forced from blood into Bowman’s capsule of the tubule. Any drug in free solution will be passively carried over into the filtrate.

Question 30

Describe active secretion in proximal tubule stage of excretion in kidneys

Answer 30

Transporter proteins extract drug from blood and
drive into filtrate (using counter-ion transport and
ATP hydrolysis). Drug can be concentrated.

Question 31

Describe reabsorption in distal tubule stage of excretion in kidneys

Answer 31

Lipid soluble drugs can diffuse back out of the filtrate and into the blood

Question 32

Describe how the concentration of drug changes in the plasma

Answer 32

Concentration in plasma rises during absorption phase, peaks, then declines due to elimination
ONE NOTE

Question 33

Why do we measure drug plasma concentration?

Answer 33

• We cannot realistically measure drug concentration at target site
• Plasma concentration is more accessible
• Assume a direct correlation between plasma concentration,
  concentration at the target, and drug effect

Question 34

Quantification of processes?

Answer 34

ONE NOTE

Question 35

what is the therapeutic window?

Answer 35

Plasma concentration range
spanning minimum required
for therapeutic effect, and
onset of side effects
ONE NOTE

Question 36

Challenges with systemic delivery?

Answer 36

Drugs with a narrow therapeutic range:
-Difficult to use
-Patient may need frequent therapeutic drug monitoring:
-therapeutic effect, side effect, or blood level
Relationship to plasma concentration may not hold if:
-Effect is mediated through a metabolite
-Effect is irreversible
-Kinetics in the target compartment is different from that in blood