Lecture 53 – Drug absorption, distribution and elimination

Question 1

bioavailability

Answer 1

the quantity of drug reaching the systemic circulation/quantity of drug administered

Question 2

issues with bioavailability

Answer 2

o failure to be absorbed
 destruction within the GIT
 stomach acid, enzymes
 enzymes in the intestinal wall
 insolubility
 destructions before reaching systemic circulation
 hepatic first-pass elimination

Question 3

bioavailability 10%?

Answer 3

Just multiple dose by 10, the necessary dose increases as bioavailability decreases

Question 4

Volume of distribution, Vd

Answer 4

The volume which would have to hold the amount of drug in the body for it to be at a concentration equal to the plasma drug concentration

Question 5

Vd is influenced by

Answer 5

o Protein binding
o Access to body compartments
o Lipid solubility

Question 6

clearance

Answer 6

o = metabolism + excretion/ [drug] plasma
o Imagine a drug that is 100% cleared in a single pass through the kidney. Its clearance will be equal to the renal blood flow rate.

Question 7

Clearance is mostly influenced by

Answer 7

o Most of the drug clearance happens from the blood
o Liver function
o Renal function

Question 8

Half-life t1/2

Answer 8

o The time taken for C plasma to fall by half

Question 9

Half-life is affected by

Answer 9

o Clearance
o Volume of distribution
o T ½ = 0.693 x Vd / clearance

Question 10

Principles of pharmacokinetics

Answer 10

o ADME
o Absorption, distribution, metabolism, excretion

Question 11

absorption

Answer 11

o All routes of drug delivery require absorption across barriers, except injection into the blood

Question 12

Methods of drug administration

Answer 12

o Intravenous = fastest, always 100% bioavailability
o Intramuscular = Faster than oral, usually 100% bioavailability
o Oral = slowest, subject to elimination on the way thus possible low bioavailability

Question 13

Absorption and Fick’s law

Answer 13

o Absorption usually follows Fick’s law
o Thus for rapid absorption:
 Large SA
 Increase C1 = larger dose
 Decrease C2 = high blood flow
 Thin barrier
 Lipid-solubility, small size

Question 14

Absorption after oral administration

Answer 14

• Absorption after oral administration

Question 15

villi

Answer 15

o Are capillarioricious
o Solutes are washed away as they are absorbed: C1-C2 maximised so absorption rate is maximised
o Villi on villi = huge SA for absorption

Question 16

Mechanisms of absorption from the gut

Answer 16

o Lipid diffusion = passive
o Aqueous diffusion = through aqueous pores
o Carrier transport = facilitated diffusion/active transport

Question 17

distribution

Answer 17

o Blood goes to most tissues
o Again related to Fick’s law of diffusion

Question 18

The basics of distribution (mostly happens at capillaries)

Answer 18

o Higher free concentration in than out = drug diffuses out
o Higher free concentration out than in = drug diffuses in
o Also there are specific transporters for some drugs

Question 19

Barriers to permeation: cell membranes

Answer 19

Membrane area&raquo_space; area of pores: lipid soluble drugs permeate much more rapidly than water-soluble drugs

Question 20

Brain capillaries are ‘tight’

Answer 20

Tight junction between brain capillary endothelial cells prevents pericellular passage

Question 21

Blood-brain barrier

Answer 21

o Capillaries in the brain are ‘tight’ and have active export transport systems
o To get from the blood to the brain, a drug has to cross the endothelium transcellularly
 Active transport/lipid diffusion

Question 22

Capillary structure and drug distribution

Answer 22

o Organs with fenestrated capillaries (kidneys, intestines, liver) are readily accessible to all drugs
o Organs with diffusionally-tight capillaries (brain, testes) are accessible mainly to lipid-soluble drugs
o Other organs have intermediate accessibility

Question 23

Drugs binding to proteins (basics)

Answer 23

o Equilibrium process
o Albumin is a general binding protein, but specific proteins exist for several hormones (e.g. thyroxin binding globulin)

Question 24

Thyroxine (T4)

Answer 24

o 99.96% protein bound in the plasma (mostly to thyroxine binding globulin)
o Volume is distribution about 10L
o Half-life about 7 days

Question 25

Binding of protein to drugs

Answer 25

o Effect of the binding depends on affinity and amount of protein relative to drug
o If the protein is in the blood, then
 Volume of distribution is decreased
 Renal filtration is decreased
o If the protein is outside the blood
 Volume of distribution is increased
o Half-life is typically increased (either way)

Question 26

Metabolism

Answer 26

Many cells can metabolise some drugs, but the vast majority of drug metabolism is in the liver

Question 27

First-pass metabolism

Answer 27

Hepatic first-pass metabolism = venous drainage of the GIT goes to the liver

Question 28

Hepatic metabolism of drugs

Answer 28

o Inactivates drugs
o Activates drugs (prodrugs)
o Makes drugs more easily excreted by the kidneys
o 2 main phases

Question 29

Hepatic metabolism of drugs: phase I

Answer 29

o Modification of functional groups
o Mostly by cytochrome P450 enzymes (CYP)

Question 30

Hepatic metabolism of drugs: Phase II

Answer 30

o Attachment of a sugar derivative (conjugation)
o Enhances water solubility

Question 31

Enzymatic reactions are saturable

Answer 31

V = reaction velocity = Vmax x [substrate]/Km + [substrate]

Question 32

Excretion

Answer 32

o The kidneys are specialised organs of excretion
o They convert red liquid (blood) into yellow liquid (urine) of variable intensity

Question 33

The nephron/renal mechanisms

Answer 33

Filtration, secretion, reabsorption

Question 34

Filtration

Answer 34

o About 180L per day
o Physical separation on the basis of size and charge
o Driven by blood pressure
o Non-saturable
o Small solutes only, proteins excluded

Question 35

secretion

Answer 35

o Active pumping of solutes into the filtrate
o Competition between substrates can occur
o Specific classes of molecules
o Saturable

Question 36

reabsorption

Answer 36

o Active processes/pumping (as for secretion)
o Passive diffusion (lipid soluble molecules, non-saturable)

Question 37

Forced alkaline diuresis in aspirin overdose

Answer 37

o Maximises filtration
o Prevents reabsorption of aspirin by pH trapping the aspirin in the urine

Question 38

Renal mechanisms

Answer 38

filtration