Drug absorption

Question 1

Pharmacokinetics (PK)

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

How do drugs move around the body?

Answer 2

1. Bulk flow (bloodstream, lymphatics, cerebrospinal fluid)

2. Diffusion across barriers (gastrointestinal mucosa, blood-brain barrier, etc)

Question 3

Diffusion through lipid

Answer 3

Unionised lipid-soluble drugs can diffuse readily through layers
Drugs that are poorly lipid-soluble have a small volume of distribution.

Question 4

Diffusion through the aqueous channel

Answer 4

Water-soluble small molecular drugs may transfer through water channels.

Question 5

Diffusion through a carrier protein

Answer 5

1. Solute carrier transporters - passive movement down electrochemical gradients
2. ATP-binding cassettes - use active pumps (ATP)

Question 6

Quickest to slowest routes of administration

Answer 6

Intravenous
Oral - rapid absorption
Oral - slower absorption
Dermal - very slow absorption

Question 7

Routes of administration - Injections

Answer 7

The drug is poorly absorbed
The drug is unstable or metabolised in the GI tract
High dose control is required
The rate of infusion depends on diffusion through tissue or removal by local blood flow

Question 8

Routes of administration - Oral administration (enteral/GI)

Answer 8

The stomach and Small intestine are the sites of most orally administered exogenous compounds.
Enterocyte enzymes and transporters (Uptake - pumps drugs into cell. Efflux - pumps drugs out of cells) = limit absorption and prevent toxicity
FIRST PASS METABOLISM
Drug transport / bioavailabilty is affected by:
Drug formulation
Drug pKa
pH of gastric fluid
GI motility

Question 9

Routes of administration - Oral administration - Stomach

Answer 9

Low pH (acidic, unionised)

Question 10

Routes of administration - Oral administration - Small intestine

Answer 10

Large, highly permeable surface area
Excellent blood supply (vascularised)
pH from 6 to 7.4
Enterocytes of epithelium contain metabolic enzymes and transporters.

Question 11

Routes of administration - Enterohepatic recirculation (EHR)

Answer 11

Moves through gut
Absorption into blood
Enters hepatic portal vein
Transferred to liver and gall bladder in bile
Secreted into the small intestine
SUBSTANTIAL FIRST-PASS METABOLISM

Question 12

Routes of administration - Sublingual

Answer 12

Films and sprays
Taste important
Excellent network of capillaries under the tongue - drug delivered directly to bloodstream.
BYPASSES FIRST PASS METABOLISM = RAPID ACTION

Question 13

Routes of administration - Rectal

Answer 13

Suppositories and enemas
Useful for local effects
Middle and inferior rectal veins (systemic circulation)
Absorption unreliable but useful if vomiting or no IV access
EG managing opioid withdrawal, motion sickness

Question 14

Routes of administration - Parenteral (besides enteric)

Answer 14

Inhalation
Powders, gases, suspension
Excellent network of capillaries 
BYPASSES FIRST-PASS METABOLISM
Local lung effects achieved (Bronchodilators)

Question 15

Routes of administration - Parenteral (Cornea)

Answer 15

Local eye effects achieved without systemic effects.

EG Dorzolamide to lower ocular pressure

Question 16

Routes of administration - Parenteral (Nasal Mucosa)

Answer 16

Nasal Spray

EG Gonadotrophin releasing hormone to stimulate ovulation

Question 17

Routes of administration - Parenteral (Vaginal)

Answer 17

Gels, pessaries, and rings
AVOIDS THE FIRST-PASS METABOLISM
Useful for local drug effects with reduced systemic side effects.

Question 18

Routes of administration - Parenteral (pH variance)

Answer 18

May affect absorption
Normal premenopausal pH 3.5-4.5
May be elevated during menstruation, after menopause, after intercourse, with the use of hygiene products.

Question 19

Routes of administration - Parenteral (Transdermal)

Answer 19

Stick on patches
A steady rate of drug delivery
BYPASSES THE FIRST-PASS METABOLISM
Even highly lipid-soluble drugs slow to enter the bloodstream through the skin

Question 20

Factors affecting absorption via the skin.

Answer 20

1. Size of drug molecule
2. Membrane permeability of drug delivery system
3. Skin hydration
4. pKa of the drug
5. Drug metabolism by skin flora
6. Lipid solubility
7. Stratum corneum reservoir of drug

Question 21

Factors affecting absorption

Answer 21

Solubility and permeability (Oral)

Biopharmaceutics classification system

Question 22

Biopharmaceutics classification system

Answer 22

Predict in vivo performance of a drug.
I - Highly soluble and permeable (EG Propranolol)
II - Low solubility and high permeability (EG Naproxen)
III - Highly soluble and low permeability (EG Kanitidine)
IV - Low solubility and permeability (EG Pacitaxel)

Question 23

Cmax =

Answer 23

The maximum concentration of compound after dosing

Question 24

Tmax =

Answer 24

Time take to reach maximum drug concentration

Question 25

AUC =

Answer 25

The area under the concentration-time curve
Measurement of total systemic exposure
AUC of trapezoid = average cp x time interval

Question 26

Bioavailability (f)

Answer 26

The fraction of the drug administered that is absorbed and available to have an effect on the body
IV is 100% into the bloodstream (systemic system) and so avoids the first-pass metabolism
After intravenous administration the major factor determining the initial plasma concentration of the drug is bioavailability

Question 27

Bioavailability (f) equation

Answer 27

F = (AUC oral / AUC iv) x (Dose iv / Dose oral)

Question 28

IV administration

Answer 28

Whole dose straight into the bloodstream

Question 29

Oral administration

Answer 29

Some drug lost to the first-pass metabolism, lower overall exposure (observed as a lower AUC)