Section 2 Pharmacology

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.

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 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

o Examples: Frusemide has a small Vd (7.7 L/70kg)

 Other examples (<50L/70kg): Aspirin, phenytoin, lithium, warfarin, valproate, heparin, antibiotics
(gentamicin, amoxicillin, cephalexin)
o Examples: Fluoxetine and chloroquine have a large Vd (2500 and 13,000 L/70kg)
 Other examples (>70L/70kg): Morphine, digoxin, diazepam, TCAs, propranolol
 Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular
compartment (i.e. they are not homogenously distributed)
 Drugs that are completely retained within the vascular compartment have a minimum possible Vd equal to the blood
component in which they are distributed (= 0.04 L/kg body weight)
o Homogenous distribution in the total body water leads to a Vd of 0.6L/kg (~42L)
 Vd is altered by patient factors:
o Gender
o Age
o Body fat/composition
o Disease states (Examples: CCF, hypoalbuminaemia)

Clearance and elimination

 Clearance predicts the rate of elimination in relation to the drug concentration (or the ability of the body to eliminate a drug)
 Clearance (CL) of a drug: The volume of plasma from which the drug is completely removed per unit time. The amount
eliminated is proportional to the concentration of the drug in the blood.

o Total body clearance is the sum of individual organ clearances:

Other sites = Lungs, blood, muscle (depending on the 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)

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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)

Bioavailability and 1st-pass elimination Route

IV
Bioavailability
100%
Characteristics
Most rapid onset
 Bioavailability (F): The fraction of unchanged drug IM 75 to ≤ 100% Large volumes often feasible; may be painful
reaching the systemic circulation following administration SC 75 to ≤ 100% Smaller volumes than IM; may be painful
by any route PO 5 to < 100% Most convenient; first-pass effect may be
significant
 AUC (area under the curve) of a blood concentration-time PR 30 to < 100% Less first-pass effect than oral
curve is a common measure of bioavailability INH 5 to < 100% Often very rapid onset
 When bioavailability is <100%, it can be due to incomplete TOP 80 to ≤ 100% Usually very slow absorption; used for lack of
first-pass effect; prolonged duration of action
absorption or first-pass elimination
 o ( )
Q = hepatic blood flow = 90L/h (in 70kg person)
o ( ) ( )
f = extent of absorption (f = 1 = all of drug is absorbed)
o First-pass elimination:
 Absorption of drug across gut wall → Enters portal circulation → Delivered to liver → Metabolised by
liver and/or excreted in bile
 Never reaches systemic circulation
 First-pass elimination: Oral > Rectal > Transdermal, SL > IM, SC > IV
 Example: Morphine is almost completely absorbed (f=1) but the ER = 0.67
 Therefore, ( )
 Rate of absorption, while not affecting bioavailability, can Blood concentration-
influence the clinical effectiveness of a drug. In figure 3.4, time curves, illustrating
drug forms A and C have the same bioavailability, but remain how changes in the rate
of absorption and extent
above the TC for different lengths of time. of bioavailability can
o For a sleep-inducing hypnotic, you want to rapidly influence both the
duration of action and
achieve TC, but do not need to remain there for long - the effectiveness of the
you want a fast rate of absorption. same total dose of a
o For an analgesic to be used in chronic pain, a long drug administered in
three different
duration of action is more important, and a slow rate formulations. The
of absorption can be beneficial. dashed line indicates the
target concentration
 Examples: Morphine has a low oral bioavailability, diazepam (TC) of the drug in the
has a high oral bioavailability blood.

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

o Assuming intermittent dosing:

o Note that the dosing rate affects the maximum and minimum concentrations of the drug, but not the average steady-
state concentration
 Loading dose: A dose that promptly raises the concentration of drug in plasma to the target concentration. This is useful
when the drug has a long t½ and time to steady-state is appreciable. In general:
o
 This formula will only give you the average steady-state concentration, not the peak concentration (which
may mean the drug does not reach the therapeutic range)
o Often, for rapid IV bolus dosing (when the absorption phase is rapid relative to the distribution phase) there is a
transient plasma concentration that is considerably higher than TC → Risk of toxic adverse effects.
 This can be overcome by slow IV administration of the loading dose (Example: Theophylline IV should be
given over 20 minutes).