Topic 3 - Pharmkokinetics General Principles Flashcards
What is pharmacokinetics?
The way drugs are processed in the body.
Pharmacokinetic factors
- Absorption
- Distribution
- Metabolism
- Excretion
These determine concentration and time constant of drug distribution hence determines optimal dose and dosing regimen
Drug absorption
To circulate to tissues via the plasma: 6 categories of routes of administration.
Oral route
- Most common route
- In GI tract drug = exposed to a highly acidic and enzymatic environment.
This leads to dehydration of drug.
Sublingual route
- 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
Rectal route
Rapid + alternative route used when patient suffers from nausea/ vomitting
Epithelial surface route
Skin, cornea and nasal mucosa
Nasal mucosa receives very extensive blood supply
Inhalation route
Gaseous anaesthetics + several bronchodilators used (for asthma treatments).
Injection
- 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.
Factors affecting absorption
- Site/ method of administration
- Molecular weight
- Lipid solubility
- pH and ionization
- Carrier mediated transport- active or facilitated
Site/ method of administration
- Affects the speed of absorption.
Molecular weight
- Main determinant of rate of diffusion
-diffusion coefficient is the key component of the Fick’s laws.
Fick’s law of diffusion
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
Lipid solubility
The ability to cross lipid membrane by diffusion.
- It is a major factor determining how rapidly and to which extent drugs are absorbed.
pH and ionisation - the effect
Drugs in ionised form don’t easily cross a plasma membrane / lipid bilayer of cells forming and epithelial surface.
pH and ionisation- the explanation
- 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
Carrier mediated transport- active or facilitated
- 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.
Drug distribution
Distribution of a drug is based on permeability and lipid solubility.
Split into major body compartments:
- Extracellular fluids
- Intracelluar fluids
- transcellular fluids
- Fat
Extracellular fluids
- Plasma 4.5% b.w.
- Interstitial fluid 16%
- Lymph 1-2%
Usually pretty accessible
Intracellular fluids
- 30-40%
- largest distribution
Transcellular fluids
- 2.5% e.g. CSF ( cerebrospinal fluid), intraocular fluid
- Not readily accessible
Fat
20% distribution
Blood brain barrier + CSF
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
Paul Ehrlich
- 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
