Principles of pharmacokinetics/
pharmacodynamics 1:
January 18, 2021
Dylan Burger, PhD
dburger@uottawa.ca
RGN2513
Outline
• Pharmacokinetics- basic principles
• Drug absorption
•
•
•
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Movement of drug across membranes
Drug ionization
Routes of absorption
Bioavailability
• Distribution
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Compartments and drug sequestration
Volume of distribution
Blood brain barrier
Placental drug transfer and teratogenicity
Protein binding
Format
• Pre-recorded lectures
• Teams Q&A session
• Review of sample problems
• Additional “Practice Problems”
• Key terms crossword
• Self-assessment quiz
• Released closer to the exam. This will mostly consist of the problems
reviewed in the tutorials +/- a handful of additional problems.
A few notes
1. There will be math!
• On the exam only basic math skills will be assumed (i.e. 500/10=50;
200-100=100 etc…).
2. Where possible I prefer to test applied knowledge.
3. I was born in the 80s…sorry
FACTORS INFLUENCING DRUG RESPONSES
Administered dose of drug
Pharmacokinetics
Concentration of drug at site
of action, duration of effect
Pharmacodynamics
Drug Response
Pharmacology
Pharmacokinetics vs. Pharmacodynamics
Pharmacokinetics
Pharmacodynamics
 Study of the factors
determining the amount of
drug at the receptor site
• Study of the mechanisms by
which drugs produce their
biological effects
 What the body does to the drug
• What the drug does to the
body
 absorption, distribution,
metabolism and excretion
(ADME)
 Dose – Concentration
• Drug receptor interactions
• Dose – Response relationship
relationship
(January 21)
PHARMACOKINETICS
Pharmakon (greek for drug/poison) + kinesis (motion)- a drugs movement
throughout the body. Determines ability of drug to act and duration of action
Knowledge of pharmacokinetics helps choose most effective route, dosage &
schedule and permits prediction of changes in concentration of a drug with
time.
PHARMACOKINETICS- Absorption
Absorption – Movement of drug from site of administration into blood
- Generally this involves crossing a biological membrane
- CRITICAL determinant of how rapidly effects of a drug will be
seen
o Dependent upon
o Chemical and physical (i.e. size) properties of the drug
o Larger drugs [i.e. tissue plasminogen activators, Alteplase]
have difficulty crossing membranes
o Surface area for penetration
o Greater surface area means a greater chance for
absorption
o Route of Administration
o pH at site of absorption
Movement across cell membranes
• Membranes function as a barrier to the free movement of drug into
(and out of) the bloodstream
• Ability to cross membrane determines where and how long a drug
will be present in the body
Membrane Structure
Passage of Drugs Across Membranes
3 ways to
cross a
membrane
• Channels and pores
• Transport Systems
• Penetration of the
membrane
Passage of Drugs Across MembranesChannels and Pores
• Typically used to facilitate ion flow (i.e. potassium and sodium)
• May be exploited for absorption of certain drugs (i.e. lithium)
• Rare mechanism of drug absorption
• Only very small compounds (molecular weight below 200 Da)
can pass through channels/pores
13
Passage of Drugs Across MembranesTransport Systems
• Large protein-mediated movement of drugs across a membrane.
• Structure-specific/selective
Most drugs absorbed via transport share similarity with endogenous
compounds (i.e. vitamins)
• In some cases no expenditure of energy is necessary and a drug moves
with a concentration gradient (passive transport)
• In other cases direct expenditure of energy is needed to move a drug
against a concentration gradient (active transport)
• ATP-dependent- primary active transport
• Coupled transport down a concentration gradient is used to fuel
movement- secondary active transport
Passage of Drugs Across MembranesPenetration of the Membrane
• Most common mechanism of absorption
• Most drugs are too large for channels and lack transport systems
• Cell membranes are primarily lipids.
• “Like dissolves like”. Thus to directly penetrate membranes, a drug must be
lipid soluble (lipophilic).
• Many drugs are weak acids/bases
• They exist as both ionized and unionized (charged/uncharged) forms in
a ratio that varies according the pH of the surrounding environment
• Uncharged (unionized) is sufficiently soluble in membrane lipids to
cross cell membranes
• Ionized form is incapable of crossing membranes.
How to cross a membranes
Movement Across Membranes
Unionized form, capable of crossing membranes
HowDrug
to cross
a membranes
Ionization
The Henderson Hasselbach Equation can be used to assess
a drug’s ionization state
HA+H2O⇋ H++A−
pH = pKa + log ( [A-] / [HA] )
Ionized form
(does not cross)
Unionized form
(crosses membrane)
Note if pH= pKa then A- = HA
50% of drug will be ionized
Variation in pH in digestive system
• The pH at the site of
absorption can vary
greatly in the intestine.
• Major impact on
orally administered
drugs
Do NOT
Memorize
Me!
Cook et al. (2012) J Contr Rel
morphine pKa 8
aspirin pKa 3.5
HA
H+ + A-
BH+
H+ + B
pH
3
7
10
if pHenv < pKa, then relatively more HA or BH+
[i.e. stomach, pH =1], then aspirin (A) would be absorbed more readily
but base (morphine) would be absorbed less
if pHenv > pKa, then relatively more A- or B
[i.e. intestine, pH=7], then morphine (B) is absorbed more readily but
acid (aspirin) would be absorbed less
pH and Absorption- Clinical Considerations
• The high acidity of the stomach can lead to inactivation of many drugs.
• Conversely many drugs can be particularly damaging to stomach
lining.
• Enteric coating- a polymer barrier applied to oral drugs to prevent
exposure in the stomach.
• Surface is stable at low pH but breaks down in more neutral/alkaline
environments (i.e. small intestine)
Routes of absorption
3 Classes
of
Absorption
21
• Topical
• Enteral
• Parenteral
Via GI tract
Avoids digestive system
Routes of absorption- Topical (local effect)
• Drug administered externally directly at site of action
Examples:
ear/eye drops, antibiotic creams (polysporin),
sunscreens
Barriers to absorption
Advantages
• No barriers, drug immediately
reaches site of action
• Easiest route of administration
• Drug administered=drug at site of
action.
Absorption pattern
N/A
Disadvantages
• Irritation can occur at site of
action.
• Limited applicability, site of action
must be external.
Routes of absorption- Topical (systemic effect)
•
Drug administered externally, is absorbed through skin and enters
bloodstream through dermal vessels.
Examples:
Nicotine, nitroglycerine, estrogen patches
Barriers to absorption
Advantages
• Skin and adventitia around dermal
blood vessels
• Convenience, sustained release
reduces need for repeated dosing
Absorption pattern
Disadvantages
• Generally slow and incomplete
• Best with low dose, low MW, lipid
soluble drugs
• Limited uses (few drugs will cross
the skin at sufficient
concentrations)
Routes of absorption- Oral (PO)
• Drug is swallowed and absorbed through the digestive
system
Examples: Acetominophen, ACE inhibitors, Statins
Barriers to absorption
- Epithelial lining of GI tract
- Capillary wall of blood vessels in
GI system
Absorption pattern
- Slow and variable
Advantages
• Painless
• Easy
• Economical
• Can be done at home
• Potential reversibility
Disadvantages
• Requires conscious and
cooperative patient
• Potential for inactivation in
stomach
• Variability in absorption (first-pass
effect)
Routes of absorption- Sublingual (SL)
• Drug is placed beneath the tongue
Examples:
Buprenorphine (suboxone), nitroglycerin,
nifedipine
Barriers to absorption
• Dermal layer in the tongue (highly
vascularized)
Absorption pattern
• Rapid entry to bloodstream
Advantages
• Rapid absorption
• Reversible (spit out drug)
• First pass effect avoided (largely)
• May be used in unconscious
patients.
Disadvantages
• Drug may have unpleasant taste
• Irritation of mucous membrane
can occur
• Drug may inadvertently be
swallowed (altered PK)
• Note sublingual may be considered either enteral (since it involves the mouth) or parenteral (since
it avoids the first-pass effect).
Routes of absorption- Intravenous (IV)
• Drug administered by injection directly to vein
Examples: morphine, anesthetics
Barriers to absorption- None
Absorption pattern- N/A
Advantages
• Immediate action
• No first pass effect takes place.
• Preferred in emergency situations
• Compatible with unconscious
patient
• Real-time titration of dose is
possible.
• Large volume of drug might be
injected by this route
• Diluted irritant might be injected
• Blood plasma or fluids might be
injected in conjunction with drug.
Disadvantages
• Irreversible, greater risk associated
with dosing calculations
• Potential for infection
• Phlebitis(Inflammation of the
blood vessel) might occur
• Infiltration of surrounding tissues
might result.
• Highly lipid soluble drugs not
compatible
Routes of absorption- Rectal (PR)
• Drug administered rectally
•
•
Solid form- suppository
Liquid or gas - enema
Examples: indomethacin (anti-inflammatory)
Barriers to absorption
Advantages
• Drug is absorbed through rectal
lining and enters enteric
circulation
• Compatible with unconscious
patients
• Avoids nausea and vomiting
• Cannot be destroyed by stomach
enzymes
Absorption pattern
• Slow, although more rapid than
oral.
• Partial “first pass effect”
Disadvantages
• Its rectal
• Partial first pass effect
Routes of absorption- Subcutaneous (SC)
• Drug is administered under the skin
Examples: Insulin
Barriers to absorption
Advantages
• Capillary wall of dermal vessels
• Absorption is slow and constant
• Compatible with highly lipid
soluble drugs
Absorption pattern
• Generally slow
Disadvantages
• Limited volume may be injected
• Potential for local inflammation/
abscess formation
• Absorption dependent upon
blood flow to the region
Routes of absorption- Intramuscular (IM)
• Drug injected directly into muscle
Examples:
Barriers to absorption
Advantages
• Capillary wall of muscle vessels
• Absorption is slow and constant
• Compatible with highly lipid
soluble drugs
Absorption pattern
• Generally slow
Disadvantages
• Limited volume may be injected
• Potential for local inflammation/
abscess formation
• Absorption dependent upon
blood flow to the region
Routes of absorption- Inhalation
• Drug is taken in during breathing through lung
Examples: inhaled corticosteroids, nitrous oxide
Barriers to absorption
Advantages
• Alveolar lining, lung capillary wall
• Rapid onset of action
• Certain drugs can be targeted to
lung with lower systemic levels
(bronchodilators)
Absorption pattern
Disadvantages
• Better for gaseous drugs than
solids
• Technique can impact degree of
drug delivery/absorption
• Rapid
Routes of absorption- Time to action
Route of Drug Administration
Delay time for Action (rough
approximation)
Intravenous
30-60 seconds
Inhalation
2-3 minutes
Sublingual
3-5 minutes
Intramuscular /Subcutaneous
10-20 minutes
Rectal
5-30 minutes
Ingestion
30-90 minutes
Absorption- First Pass Effect
(Pre-systemic metabolism)
- A rapid inactivation of drug prior to entry into the systemic circulation.
- Drugs absorbed in GI tract enter the portal circulation. Therefore they are
exposed to the liver (and its rich drug metabolizing enzymes) prior to
distribution to the rest of the body.
• Major consideration for
drugs taken orally.
• Certain drugs (i.e.
morphine, nitroglycerin,
buprenorphine) are
subject to such an
extensive first pass effect
that they must be given
via alternative routes.
Absorption - Bioavailability (F)
Bioavailability:
Fraction of unchanged drug that reaches the systemic
circulation.
This fraction will be reduced by incomplete absorption and by
hepatic metabolism (first-pass effect)
A (i.v)
Concentration
F = AUC po  dose absorbed
AUC iv  dose administered
AUC = area under curve
AUC = body’s total exposure to the drug. It a function of
the dose that enters the systemic circulation via the
administration route and drug clearance
B (oral)
Time
Absorption - Bioavailability
F = AUC dose absorbed
AUC dose administered
IV administration F=1
(100% of drug reaches the systemic circulation)
Other routes of administration, F is usually <1 due to
many factors that affect bioavailability: +/-food, drug
interactions, intestinal motility, first pass effect, efflux
transporters….
Bioavailability- Sample Question 1
• “Pete Mitchell” is an experimental drug used on Russian MiGs.
For a 70kg male the IV AUC from a 200 mg dose is 150 mg.hr/L.
The Oral AUC from a 200 mg dose is 13.2 mg.hr/L. What is the
bioavailability of this drug?
• What other conclusions might we draw from these data.
F = AUC po  dose absorbed
AUC iv  dose administered
F= 13.2/150
F=0.088 or 8.8%
With such a low bioavailability this
drug would be better administered
parenterally.
Bioavailability- Sample Question 2
• ShermerHighDetention is a new drug used for the treatment of
rebellious students. Its oral bioavailability is ≈80%. The standard IV
dose is 40mg. What dose would need to be administered orally to
achieve the same plasma concentration as the IV dose?
Q. What dose will result in 40 mg of circulating ShermerHighDetention if
only 80% is absorbed?
F= dose absorbed/dose administered
0.8=40/X
[X] x 0.8= 40 mg
40/0.8= [X]
[X] = 50 mg
PHARMACOKINETICS- Distribution
Distribution– Movement of drug through the body and to its site of action
(generally via vascular system).
Speed of drug distribution (equilibration with plasma) depends on the
nature of the compartment it is distributing to
Central compartments
- Heart, liver, brain, kidney, bloodstream.
- Highly perfused tissues, rapid equilibration
- Rapid clearance upon drug removal
Peripheral compartments - Organs with less or more variable perfusion
-i.e. adipose tissue, skeletal muscle
- Slower clearance upon drug removal
PHARMACOKINETICS- Distribution
• Movement of drug between compartments (distribution) may be rapid
or slow.
• Single compartment distribution- drug distribution between
compartments is immediate (behave as one)
• Multiple compartment distribution-drug distribution is slow,
• Certain drugs can partition selectively to individual compartments (i.e.
lipophyllic drugs in adipose tissue)
• Can impact on the amount of drug needed
• Can impact on the clearance of a drug
PHARMACOKINETICS- Distribution
Single Compartment
- Distribution is instantaneous
- Reductions in plasma
concentrations due to
elimination
Two Compartments
- Distribution is slow
- Reductions in plasma
concentrations first due to
distribution to peripheral
compartments and then due to
elimination
Drugs can segregate to body fluid compartments
drugs
acetaminophen
theophylline
warfarin
Apparent volume of distribution (Vd)
• Hypothetical volume of liquid required to account
for the observed drug concentration initially
measured in the body
Vd = amount in body / plasma concentration
• Useful term for understanding where drug is being
distributed in the body and in calculating
experimental doses needed to achieve a given
plasma concentration
Apparent Volume of Distribution
therapeutic plasma concentration = dose / Vd
Volume of distribution is useful in that it gives some
indication of drug concentration (therapeutic levels) to be
expected after a given dose
Vd1 = dose / plasma concentration
1
Vd values can even be above the total water content in body
Drug-protein binding
Compartmental sequesteration (i.e. lipid soluble drugs in fat tissue)
Volume of Distribution- Sample Problem
1000 mg of a drug called “JohnMcLane” is given to a 79 kg
male named Hans Gruber for psychotic behaviour.
Immediately after absorption/distribution his plasma
concentration is 2 mg/L.
What is the apparent volume of distribution?
What does the Vd suggest about the distribution of this drug?
Vd = dose / plasma concentration
Vd= 1000 mg/2 mg/L
Vd= 500 L
The drug appears to be partitioning out of the plasma and into a
separate body compartment.
Distribution- Exiting the Vascular System
Typical capillary beds
• In most capillary beds,
“large” gaps exist between
the cells that comprise the
capillary wall.
• Drugs and other molecules
can pass fairly easily into
and out of the bloodstream
through these gaps.
• Lipid-soluble compounds
can also pass directly
through the cells of the
capillary wall.
Distribution- Exiting the Vascular System
The Blood Brain Barrier
• Vascular structure in the
brain differs from other
tissue beds.
• Tight junctions exist
between the cells that
comprise capillaries in
the central nervous
system
• Serves as a barrier to
many drugs
• Only drugs that are
lipid soluble or that
have a transport system
can cross the bloodbrain barrier to a
significant degree
DISTRIBUTION: PLACENTAL BLOOD
TRANSFER
 The placenta is a multi-layer barrier of
cells which serve to block the diffusion
of substances from the maternal to
uterine circulations.
 Protects the developing fetus.
 Placental membrane does NOT
constitute an absolute barrier to the
passage of drugs.
 Generally speaking, small lipid soluble
drugs are more likely to cross placental
barrier.
Drug distribution- placental transfer
 Due to a poorly developed metabolism system and differentiating
tissues, developing fetus is a greater risk of damage due to drug
exposure.
 Teratogen- A drug that causes improper development/malformation of
an embryo
Thalidomide
• Sedative once used as a treatment for
sleeplessness and morning sickness in
pregnant women
• Marketed from late 50s-early 60s
(Canada- 1959-1962)
• Quickly discovered to be a teratogenassociated with neuritis, limb abnormalities and
other birth defects
• Pulled from market in 1962 (3 months after
UK/Germany)
DISTRIBUTION: PROTEIN BINDING
 Drugs bind reversibly with
various blood proteins, most
importantly albumin
 Albumin is a large molecule
(molecular weight of 69,000
– most drugs are < 500)
and always remains within
the bloodstream
Binding of drug to proteins may:
• Facilitate the distribution of drugs (if it normally would sequester)
• Retard the excretion of a drug
• Impair therapeutic activity
DISTRIBUTION: PROTEIN BINDING
 Only free drug can reach an
extravascular site of action
 Similar proteins can compete for the same protein binding sites
(altered pharmacokinetics- amount of free drug at a given dose is
increased).
 Amount of albumin and/or binding capacity may be altered in
liver and kidney disease (also cancer, heart failure, sepsis, and
certain inflammatory diseases).
(altered pharmacokinetics- amount of free drug at a given dose is
increased).
Until Next Time
Questions?
dburger@uottawa.ca
RGN 2513