Professional Documents
Culture Documents
Pharmacology - Section 02 - Pharmacokinetics
Pharmacology - Section 02 - Pharmacokinetics
Pharmacokinetics
Pharmacokinetic principles
The dose-concentration part of the interaction between a drug and a patient (i.e. what the body does to the drug)
Drug pharmacokinetics determine how rapidly and for how long the drug will appear at the target organ
Incorporates 3 main events:
o Absorption → Distribution → Elimination
Prodrug: Inactive precursor with greater lipid-solubility than active metabolite (the drug); facilitates distribution prior to
conversion to drug
Permeation
A. Aqueous diffusion – A passive process driven by concentration gradient (and Fick’s law), where molecules cross
from the vascular space to the interstitial fluid between the endothelial cells (e.g. through gap junctions and aqueous
pores)
B. Lipid diffusion – The most “important” process, requiring the molecule to be permeable to the phospholipid bilayer
of the cells between body compartments, resulting in trans-cellular diffusion. For a weak acids and bases, rate of lipid
diffusion can be altered by changing the body pH, and therefore the proportion of unionised, less polar substance (see
below).
C. Carrier-mediated diffusion – Diffusion that takes place when special carrier proteins facilitate the passage or a
molecule across the cell membrane, usually for large and otherwise impermeant molecules.
D. Endocytosis and exocytosis – Invagination of the cell membrane to create a membrane bound intracellular vesicle
containing the molecule. This first requires the molecule to bind to a surface receptor, triggering endocytosis.
(Example: Vitamin B12)
Fick’s Law: The magnitude of the diffusing tendency is proportional to both the concentration gradient and cross sectional
area across which diffusion takes place and is inversely proportional to the thickness of the membrane.
( )
Weak acids and weak bases occur in a neutral and an ionised form; the ionised form is more polar, more water-soluble, less
lipid-soluble → Ionisation of molecules may markedly reduce their ability to permeate membranes
o Weak acid: Neutral molecule that can reversibly dissociate into an anion (negatively charged molecule) and a
proton
Example: Aspirin: Neutral Aspirin (C8H7O2COOH) ↔ Aspirin anion (C8H7O2COO-) + Proton (H+)
o Weak base: Neutral molecule that can form a cation (positively charged molecule) by combining with a proton
Example: Pyrimethamine (an antimalarial): Pyrimethamine cation (C12H11CIN3NH3+) ↔ Neutral
Pyrimethamine (C12H11CIN3NH2) + Proton (H+)
o Note that the protonated form of a weak acid is the neutral, more lipid-soluble form, whereas the unprotonated form
of a weak base is the neutral form
o These reactions move to the left in an acid environment (low pH, excess protons available)
o The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid/base to the
molecule’s pKa and the pH of the medium:
[ ]
[ ]
This equation applies to both acidic and basic drugs. The lower the pH, relative to the pKa, the greater will be
the fraction of the drug in the protonated form
At a lower pH: More of a weak acid will be in the neutral form → More lipid-soluble!
At a higher pH: More of a weak base will be in the neutral form → More lipid-soluble!
o Manipulation of drug excretion in the kidney (e.g. in overdose).
Almost all drugs are filtered at the glomerulus → If a drug is lipid-soluble, a significant fraction of it will be
reabsorbed by passive diffusion. A way to accelerate excretion of the drug is to prevent this reabsorption.
This can often be accomplished by adjusting the urine pH, so that most of the drug is in the ionized (and less
lipid-soluble) state.
Weakly acidic drugs are usually excreted faster in alkaline urine (more of the drug in lipid-insoluble ionic
form)
Weakly basic drugs are usually excreted faster in acidic urine (more of the drug in lipid-insoluble ionic
form).
This is called drug trapping or pH-partitioning, and can occur in many body fluid compartments with a pH
that differs from those nearby (Example: Bupivocaine local anaesthetic injections)
Volume of distribution
You need to know examples
The apparent space in the body available to contain a drug
The two major sites of elimination are the kidneys and the liver:
o Kidney → Clearance of unchanged drug in the urine
o Liver → Biotransformation of the drug to one or more metabolites, and/or excretion of unchanged drug into bile
Elimination can either be first-order elimination, capacity-limited elimination or flow-limited elimination
o First-order elimination: Clearance is constant over the concentration range encountered in clinical settings.
Elimination is not saturable.
Uses first-order kinetics, and the area under the curve (of a time-concentration profile) can be used to
measure clearance
Rate of elimination = CL x C
o Capacity-limited elimination: Clearance will vary depending on the concentration of drug that is achieved. Most
drug elimination pathways will become saturated if the dose is high enough. Also described as saturable, dose- or
concentration-dependent, nonlinear, or Michaelis-Menten elimination
Uses zero-order kinetics
Examples: Phenytoin, ethanol, aspirin
Vmax = maximum elimination capacity
Km = the drug concentration at which the elimination rate is 50% of Vmax
CL has no real meaning in capacity-limited elimination and the area under the curve cannot be used to
describe the elimination
o Flow-limited elimination
Some drugs are cleared very readily by the organ of elimination → At any realistic concentration of the drug,
most is cleared in the first pass of the drug through it
Elimination will vary primarily on the rate of drug delivery to the organ of elimination
Examples: Morphine, amitriptyline
An alternative way of viewing elimination is in terms of the kinetic order: First-order, zero-order, or mixed-order
o First-order kinetics: The rate of elimination is constant,
regardless of the concentration. Elimination is not saturable, and rate
of elimination is directly proportional to concentration.
Equivalent to the concept of first-order elimination
o Zero-order kinetics: A constant amount of drug is metabolised per
unit time. The rate of reaction is independent of concentration
o Mixed-order kinetics: Usually describes a situation where
metabolism is initially first-order, but becomes zero-order at
higher concentrations. This is a real-world pattern of elimination seen
in vivo for many drugs, where metabolism slows as enzymes are
saturated.
Example: Phenytoin - kinetics change to zero-order
within the therapeutic dose range → After a certain
point, a small increase in dose can lead to profound toxicity (popular viva subject)
Half-life
Half-life (t½): The time required to change the amount of drug in the body by one-half during elimination (or a constant
infusion)
( )
Absorption
Absorption: The process of entering the body.
For every route of administration, the mechanism of absorption is different.
Incomplete absorption:
o Drug factors:
Too hydrophilic (Example: Atenolol)
Ideal pKa is gut pH (7-8)
Too lipophilic (Example: Acyclovir)
Sometimes: reverse transporter associated with P-glycoprotein
Large size (MW > 1000)
Metabolism by gut flora (Example: Digoxin)
o Gut factors:
Fast transit time (Example: Diarrhoeal illness)
Reduced gut surface area (Examples: Coeliac disease, resection)
Poor gut circulation
Co-ingested substances (Example: Food will reduce penicillin absorption)
Dosing regimens
Rational dosing regimens are based on a target
concentration (TC) that will produce the therapeutic effect.
The TC can be different for different desired effects
(Example: Digoxin - 2ng/mL for AF, 1ng/mL for CCF)
Maintenance dose: A repeated dose that will maintain a
steady state of drug in the body. A dose that is just enough to
replace the drug eliminated since the last dose.
SS = steady-state
TC = target concentration
CL = clearance
o For a drug with bioavailability < 100%: Infusion vs 8-hourly, vs 24-hourly dosing