Topic 3 - Pharmkokinetics General Principles

Question 1

What is pharmacokinetics?

Answer 1

The way drugs are processed in the body.

Question 2

Pharmacokinetic factors

Answer 2

• Absorption
• Distribution
• Metabolism
• Excretion
  These determine concentration and time constant of drug distribution hence determines optimal dose and dosing regimen

Question 3

Drug absorption

Answer 3

To circulate to tissues via the plasma: 6 categories of routes of administration.

Question 4

Oral route

Answer 4

• Most common route
• In GI tract drug = exposed to a highly acidic and enzymatic environment.
  This leads to dehydration of drug.

Question 5

Sublingual route

Answer 5

• Simpler + faster route
• Absorption from oral cavity
• Glycerol trinitrate taken by patients suffering from angina ( alert pain prior to heart attack)
• Glyc.tri = induces phase 2 dilation

Question 6

Rectal route

Answer 6

Rapid + alternative route used when patient suffers from nausea/ vomitting

Question 7

Epithelial surface route

Answer 7

Skin, cornea and nasal mucosa
Nasal mucosa receives very extensive blood supply

Question 8

Inhalation route

Answer 8

Gaseous anaesthetics + several bronchodilators used (for asthma treatments).

Question 9

Injection

Answer 9

• Fastest + most direct route
• Intravenous ( hence fast), subcutaneous ( under the skin), intramuscular ( in the muscle) and intrathecal ( lumbar puncture)
  Lumbar puncture = getting drug directly into cerebral spine fluid.

Question 10

Factors affecting absorption

Answer 10

1. Site/ method of administration
2. Molecular weight
3. Lipid solubility
4. pH and ionization
5. Carrier mediated transport- active or facilitated

Question 11

Site/ method of administration

Answer 11

• Affects the speed of absorption.

Question 12

Molecular weight

Answer 12

• Main determinant of rate of diffusion
  -diffusion coefficient is the key component of the Fick’s laws.

Question 13

Fick’s law of diffusion

Answer 13

Rate of diffusion is directly proportional to 1/ square root of the molecular weight.
- hence the higher the molecular weight the lower the rate of diffusion

Question 14

Lipid solubility

Answer 14

The ability to cross lipid membrane by diffusion.
- It is a major factor determining how rapidly and to which extent drugs are absorbed.

Question 15

pH and ionisation - the effect

Answer 15

Drugs in ionised form don’t easily cross a plasma membrane / lipid bilayer of cells forming and epithelial surface.

Question 16

pH and ionisation- the explanation

Answer 16

• Many drugs are weak acids or bases.
• At low pH weak acids will be un ionised, only uncharged species can cross lipid bilayer.
• use Henderson’s equation

Question 17

Carrier mediated transport- active or facilitated

Answer 17

• Route used for absorption from the gut to the blood.
• For polar molecules ( e.g. amino acids and metal ions) used by drugs similar to natural substances.

Question 18

Drug distribution

Answer 18

Distribution of a drug is based on permeability and lipid solubility.
Split into major body compartments:
- Extracellular fluids
- Intracelluar fluids
- transcellular fluids
- Fat

Question 19

Extracellular fluids

Answer 19

• Plasma 4.5% b.w.
• Interstitial fluid 16%
• Lymph 1-2%
  Usually pretty accessible

Question 20

Intracellular fluids

Answer 20

• 30-40%
• largest distribution

Question 21

Transcellular fluids

Answer 21

• 2.5% e.g. CSF ( cerebrospinal fluid), intraocular fluid
• Not readily accessible

Question 22

Fat

Answer 22

20% distribution

Question 23

Blood brain barrier + CSF

Answer 23

Barrier between the brain and the rest of the body.
Endothelial cells of blood vessels supplying the brain form tight junctions.
- Drugs can’t pass between cells so must cross the membrane.
- only drugs smaller than 500 daltons / lipophilic drugs can pass between cells

Question 24

Paul Ehrlich

Answer 24

• First to describe the barrier separation brain + CSF
• Stained brain and organs with trypan blue dye. Result = dye injected in brain stays in brain and dye injected in rest of body doesn’t stain the brain.
• Hence there is a barrier

Question 25

IMP consideration for drugs to work on the brain/ CSF…

Answer 25

…tight junctions may become leaky due to inflammation.