MIDW 125

Introduction to Pharmacology,
Pharmacodynamics and
Pharmacokinetics

January 6-13, 2015

Welcome and introduction

Dr. Jennifer Shabbits ([email protected])

Office: LSC 1542 / 604-822-9729
• PhD (Pharm Sci, UBC)
• BSc (Biochem, SFU)
• Senior Instructor, MD Undergraduate Program &
Pharmacology Department

No set office hours – happy to meet anytime

Send me an email to make arrangements

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Additional *optional* pharmacology texts

All on reserve at Woodward library

Overview of next 3+1 lectures

Part 1: Introduction
What are drugs?

Part 2: Pharmacodynamics
What do drugs do to the body?

Part 3: Pharmacokinetics
What does the body do to drugs?

Part 4: Drug Dosing

How do we design drug dosing regimens?

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 Part 1: Introduction to
Pharmacology

Some definitions

What is Pharmacology? pharmakon = drug

logos = the study of

 Pharmacology = the study of drugs

 what they do and how they do it

≠ Pharmacy: the health

profession that deals with the
preparation and dispensing of
(prescription) medications

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“Drug” has many definitions

Webster’s Dictionary:
“a substance intended for use in the diagnosis, cure,
mitigation, treatment or prevention of disease”

More broadly:
“any substance that brings about a biological
change or effect on the body”

Drugs come from many sources

Plants

Foxglove → Digoxin

Animals
Pregnant mare urine
↓
Premarin®

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 Drugs come from many sources

Minerals – Lithium Synthetic – Sulfa drugs

Natural ≠ Safe!

“Caffeine-loaded energy drinks have now crossed the line from

beverages to drugs delivered as tasty syrups,” the Canadian Medical
Association Journal says.
~Vancouver Sun, July 27, 2010

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 • Health Canada’s
recommended daily intake of
retinol for women is 700 mcg

• One 547mL Fuze Vitalize

bottle contains 3000 mcg

• Increased risk of liver damage

• Potentially harmful for

pregnant women –
increased risk of birth
defects

~Vancouver Sun, January 24, 2011

One drug…many names

1. Chemical Name:
Identifies the chemical elements and compounds that are found in
the drug – most important to chemists, pharmacists and
researchers who work with the drug at a chemical level.

2. Generic or Non-proprietary Name:

The universally accepted name of a drug. It appears on all drug
labels, resource guides and publications. Generic names often
follow similar patterns for drugs of the same class or mechanism.
(ex: lidocaine, procaine)

3. Brand or Trade or Proprietary Name:

The copyrighted and trademarked name given by the drug
company – restricts the use of the name.

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One drug…many names

Chemical name: ()-2-(p-isobutylphenyl) propionic acid

Generic name: Ibuprofen
Brand names: Advil®, Motrin®

Chemical name: Ethyl 4-(8-chloro-5,6-dihydro-11H-

benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-
piperidinecarboxylate
Generic name: Loratadine
Brand name: Claritin®

Pharmacology has 2 arms

Pharmacodynamics
“what the drug does to the body”
• the study of the effect(s) of drugs on body processes

Pharmacokinetics
“what the body does to the drug”
• the study of the movement of drugs in the body (how it
reaches and leaves its site of action and at what
concentration)

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The PK – PD relationship

Dosage [DRUG] - Plasma Pharmacological

Regimen Effects

How much? How

often? How long?
What form?
[DRUG] - Receptors
at Target Site

Part 2: Pharmacodynamics

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Simplification of drug action

Drug

Receptor Drug – Biologic

receptor alteration
complex
Pharmacologic
effect(s)

What are receptors?

• Receptors are
macromolecules that mediate
a biological change following
ligand (drug) binding

• Most receptors are proteins

with:
• 1° aa sequence
• 2° regular sub-structures
• 3° 3-D structure
• sometimes 4° multi-protein
complexes

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 Where are receptors?
• Receptors are located on the surface of or within cells

The drug-receptor complex

• Van der Waals forces, hydrogen and ionic bonds in the
active (binding) site typically mediate formation of the
drug-receptor complex → receptor affinity

(DRUG)

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An exception to the rule

• a few drugs work via non-receptor mechanisms, for

example:

Antacids - purely chemical basis via acid

neutralization in the stomach

Osmotic diuretics - promote urine

excretion by altering water flow in the
kidney independent of receptors

There are 4 main classes of receptors

Na+

Na+

Change in membrane Intracellular 2nd Intracellular Altered transcription

potential or [ion] messengers phosphorylation

INTRACELLULAR EFFECTS

PHARMACOLOGIC EFFECTS

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What binds to the receptors?

• Most receptors have naturally occurring (endogenous)

molecules that bind to them
• Exogenous (foreign) molecules can be designed to
bind to the same receptor  rational drug design

Example ~
Endorphins (endogenous)
Bind opiate receptors
Morphine (exogenous)
in brain

EUPHORIA

Drugs can be agonists

AGONISTS have:
1. AFFINITY for the receptor (they bind to it)
2. INTRINSIC ACTIVITY (binding elicits a response)

Agonists can be either

1. Endogenous (ex: adrenalin) Both  rate
2. Exogenous (ex: dobutamine)

Effect

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Drugs can be antagonists

ANTAGONISTS (aka receptor blockers or inhibitors)

1. have AFFINITY (bind the receptor)
2. LACK intrinsic activity (no response)

No
Effect

Antagonist example

Claritin®: an antagonist that blocks histamine receptors

→ allergy treatment

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Pharmacologic effects – side effects

“A drug without side effects isn’t really a drug”

Side Effects/Adverse Effects

Mild, tolerable, subside Potentially life-

on their own threatening & sustained
(ex: GI disturbances) (ex: seizures)

Risks vs benefits must be carefully

weighed → Therapeutic Index

Side effect or not? A matter of perspective

“may cause drowsiness”

When taken for When taken as a

seasonal allergies sleep aid
 

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 The pharmacologic effect is related to dose

Drug dose-response curves

hypotension
≥5 mmHg decrease (fainting)
in diastolic BP

% %
individuals individuals
responding responding

Median Effective Dose Median Toxic Dose

log drug dose log drug dose

Therapeutic index: a measure of drug safety

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Therapeutic index: a measure of drug safety

Narrow TI Drugs
• Digoxin
• Lithium
• Phenobarbital
• Vancomycin
• Warfarin

Routes of drug administration

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Which route to use? 3 factors to consider

1.
• size, water vs lipid solubility, pH stability

2.
• consciousness, ability to follow instructions,
age, other medications

3.
• urgency of situation, local vs systemic effects

Enteral administration (systemic effect)

• involves the gastro-intestinal (GI) tract

 oral (po) – most common
 sublingual (sl)
 rectal (pr)

Advantages: convenient, inexpensive, safe

Disadvantages: possible1st-pass metabolism,
pH stability, variable absorption

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Parenteral administration (systemic effect)

• does not involve the GI tract (usually injections)

 intravenous (iv)
 subcutaneous (sc, subQ)
 intramuscular (im)
Advantages: immediate – no Disadvantages: discomfort,
absorption (iv), avoids stability potential for infection
concerns, unconscious OK

Other routes

Inhalational (systemic or local effect)

• metered dose inhalers, general anesthetics, nasal
decongestants

Topical (local effect)

• cream, ointment, drops

Transdermal (systemic effect)

• patch

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The drug is now in the body…what next?

“Pharmacokinetics”

Part 3: Pharmacokinetics

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Claritin monograph

What words or phrases in the drug

monograph are unfamilar to you?

Source: Compendium of
Pharmaceuticals and Specialties (CPS)

Claritin monograph

• pharmacokinetics • bioavailability
• elimination • active metabolite
• half-life • unchanged drug
• Cmax • conjugated drug
• Tmax • clearance
• steady state

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The PK – PD relationship

Pharmacokinetics Pharmacodynamics

Dosage [DRUG] - Plasma Pharmacological

Regimen Effects

How much? How

often? How long?
What form?
[DRUG] - Receptors
at Target Site

Pharmacokinetics – the ADME processes

A gets drug into the blood

D where it goes in the body
M what happens to it
E how it gets out

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Absorption
 The movement of drug from site of administration
into the blood  occurs by passive diffusion

Influencing Factors:

 concentration Drug
gradient (hi → low)

 drug size (must be

less than 1 kDa) Blood

 lipid solubility / pH

Membrane permeability – effect of lipid solubility

• Only uncharged, hydrophobic drugs can passively

diffuse across lipid bilayers (membranes)

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Membrane permeability – effect of pH

• Most drugs are weak acids or weak bases – exist

in equilibrium between protonated &
unprotonated, charged & uncharged species

weak acid drug weak base drug

HA  H+ + A- B + H+  BH+

• pH of environment and pKa of drug dictate which

of the two forms predominates

Weak acid and weak base drugs

Total weak acid drug = HA + A- =

99% 1%
50% 50%
12% 88%

Total weak base drug = BH+ + B =

99% 1%
50% 50%
12% 88%

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Membrane permeability – effect of pH
• Only the uncharged (unionized) species will cross
the membrane (ie be absorbed)

Weak acid Weak base

Predicting absorption/diffusion

• We can use the Henderson-Hasselbalch equation

to predict the extent to which this will occur

pH = pKa + log unprotonated form

protonated form

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Practice calculation 1
Piroxicam is a weak acid (pKa=1.8) that is used to
relieve arthritic pain. How much of it will diffuse
across the gastric mucosal barrier and into the blood
(plasma) when taken orally?

Practice calculation 2

The first dose provides temporary pain relief but

also causes stomach upset. The person decides to
take a ‘Tums’ with her next dose.

After this her stomach is no longer upset, but now

her pain won’t go away. Why?

(Tums raises the stomach pH by 2 units)

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Bioavailability (fraction absorbed, F)

 the fraction of drug that reaches systemic

circulation unchanged

amount of drug in systemic circulation

F= amount of drug administered

What can you do to ensure a drug is 100%

bioavailable (F=1)?
• non-iv dosage recommendations take fractional
absorption into account
• useful for comparing routes of administration

Question…

When comparing the iv vs po routes of

administration, which would require a larger
dose of the same drug in order to achieve the
same effect? Why?

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How does the drug know where to go?

drug circulates throughout body

in the blood

encounters receptors for which
it has affinity

binds

pharmacological response

Distribution
 The process by which drug reversibly leaves
the bloodstream
• drug moves between body compartments
• drug reaches the site of action (receptors)

Influencing Factors:

 conc. gradient
 drug size
 lipid solubility / pH
→ blood flow
→ protein binding

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Distribution – effect of blood flow
• Drug is delivered to tissues in relation to perfusion

Distribution – effect of protein binding

• Drugs reversibly bind plasma (blood) proteins
(protein + drug  drug-protein complex)

• Proteins are large – sequester (trap) drug in blood

 drug can’t distribute to target receptors
 protein bound drug is pharmacologically inactive

• Concentration of free drug in blood 

 less pharmacologically active drug

Most drug dosing regimens take protein binding into account

BUT there are situations where protein profiles are altered
(pregnancy; disease) and dosing needs to be adjusted

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Effect of protein binding

Weakly protein bound drug Highly protein bound drug

Volume of distribution (Vd)

 Administration: dose or amount (mg, g)

 Plasma analysis: concentration (mg/L, g/mL)

Concentration = dose
Vd

Which volume do we use?

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 Volume of distribution (Vd)
There are several physiological fluid
compartments into which hydrophilic
drugs can distribute
2/3 1/3
Total body water (TBW)
= 70kg x 1L/kg x 0.6 = 42L
hypothetical density of body ~60%
PK man water water

Examples:
Heparin = 3L → Plasma 2/3 1/3
Gentamicin = 18L → ECF
Ethanol = 38L → TBW

A clinical example

A 30mg dose of the antidepressant Nortriptyline

is administered to a patient iv and a plasma
concentration of 25g/L is subsequently measured.

What is the volume of distribution of this drug?

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A clinical example ~ solution

What is volume of distribution?

• NOT a real, physiological volume but rather a
proportionality constant that relates the amount of
drug in the body to its concentration in the blood

• The magnitude of Vd indicates the extent of drug

distribution in the body, but not the location

Large Vd (>42 L): drug distributes outside blood and body

fluids into tissues
Small Vd (≤42 L): drug has limited distribution, typically
restricted to blood or physiological fluids

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Distribution notes in pregnancy

1. Plasma protein levels are DECREASED in

pregnancy ~ what affect will this have on drug
activity?
2. The placenta is NOT a barrier to drug transport –
small (<500 Da) MW, lipophilic, un-ionized drugs
passively diffuse
3. P-glycoprotein (Pgp)
drug transporter pumps
drugs from fetal to
maternal side

Metabolism

 the irreversible biotransformation of drug

• makes it more polar to ↑ renal (urinary)
excretion

Occurs primarily in the liver via 2 (usually sequential)

enzyme-catalyzed processes:
• Phase I oxidation/reduction/hydrolysis
• Phase II conjugation

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Phase I: cytochrome P450 enzymes
A superfamily of related enzymes that add on or
uncover small polar groups (–OH, –NH2, –COOH) to 
water solubility
Phase 1
Metabolite Parent Drug
P450 Enzymes

P450 enzyme induction and inhibition

• some P450 enzymes can be induced or inhibited by
other drugs, foods, pregnancy or disease

Induction:  metabolic activity of enzymes

 [Drug] (ex: alcohol)

Inhibition:  metabolic activity of enzymes

 [Drug] (ex: grapefruit juice)

 Primary cause of drug interactions

 Requires drug dosing to be increased or decreased
 P540 enzyme profile changes in pregnancy:
 in CYP 2D6, 3A4 and 2C9  in CYP 1A2 and 2C19

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Practice problem
Relative to a non-pregnant woman, how would
drug dosing need to be altered ( or ) for
the following drugs in pregnancy:
1. Erythromycin (metabolized by Cyp3A4)

2. Omeprazole (metabolized by Cyp2C19)

3. Paroxetine (metabolized by Cyp2D6)

4. Ibuprofen (metabolized by Cyp2C9)

5. Caffeine (metabolized by Cyp1A2)

Phase II: conjugative enzymes

Mediated by various non-P450

liver enzymes
• covalently add large, polar, Phase I
P450
endogenous molecules to
Phase I metabolite phenytoin

• ensures that metabolite is ready

for excretion Phase II
glucuronyl
p-OH-phenytoin
(glucuronide, glutathione, sulfate, transferase

acetate, amino acids etc)

phenytoin-ether-glucuronide

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Drug metabolism
Metabolite + Receptor
• usually inactivates the drug ≠ MR complex
• is required to activate prodrugs

CYP2D6

Drug metabolism
• may be harmful if the metabolite(s) are toxic
Tylenol® = Acetaminophen

Phase II

Phase I Phase II
CYP2E1 metabolites
Induced by 
alcohol urine

Phase II
Toxic
semiquinone

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First pass metabolism

Most drugs absorbed from the GI tract are delivered to

the liver before reaching the systemic circulation

IV Drug delivered to target receptors

 oral doses > iv

Some drug is
doses to account metabolised
Oral

for loss due to (lost)

metabolism

Drug

Drug metabolism in the gut

Some drugs undergo significant metabolism by bacterial
enzymes in the gut (ex: digoxin)

What effect might a course of antibiotic therapy

have in a person taking digoxin?

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 Metabolism notes in pregnancy
1. P450 enzymes are altered in pregnancy (see previous)

2. The placenta is capable of metabolizing drugs, but

this is of little relevance to the mother (ie it does
not significantly impact the maternal drug
concentration)

3. However, placental metabolism can protect the

fetus from drug exposure (some P450 and
conjugation)

4. The fetal liver is capable of metabolizing drugs by

oxidation reactions only (all other enzymes are not
yet developed)

Excretion – kidney (renal excretion)

 The irreversible loss of drug from the body

Blood Proximal tubule
1. Passive Glomerular Filtration
Afferent
diffusion of small drugs <20kDa arteriole

2. Active Tubular Secretion

transport systems for large drugs Drug in
blood
*Pgp acts here

3. Passive Tubular Reabsorption

concentration gradient may drive Efferent
arteriole
uncharged drug back into blood
*urine pH is key
Urine

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 Absorbed or Excreted?

Weak acid: HA ⇋ H+ + A-

Weak base: B + H+ ⇋ BH+

Changing urine pH to treat an overdose

 increasing urine pH shifts equilibrium to

promote excretion of weak acid drugs (ex: aspirin)
• iv sodium bicarbonate raises pH from 6-8

HA  H+ + A-
Ionized form is water
soluble  excreted in urine

*Remember:  pH =  [H+]

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Changing urine pH to treat an overdose

How would you modify the urine pH to treat an

overdose of a weak base drug?

B + H+  BH+

Excretion – bile/feces (aka biliary excretion)

 Drugs and/or metabolites actively secreted into
biliary tract – delivered
to duodenum via common
bile duct *Pgp acts here

 Carrier-mediated
process protein binding
& ionization are not
limiting factors

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 Excretion – breast milk

1. Breast milk is a relatively minor route of drug

excretion from mother’s perspective

2. Potentially significant for nursing baby

3. Breastmilk pH < plasma (7.2 vs 7.4)

 what group of drugs will concentrate (be
trapped) in breastmilk – weak acids or bases?

4. Drugs of concern: CNS depressants,

sedatives, anticancer drugs

Summary

Administration of
agonist or antagonist

Drug binds
receptor(s)

Response

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