Pharmacology

Pharmacology

Pharmacokinetics
Pharmacokinetics
Pharmacodynamics
Pharmacodynamics
Pharmacokinetics
Pharmacokinetics
•• Time
Time course
course of
of drug
drug absorption,
absorption,
distribution,
distribution, metabolism,
metabolism, excretion
excretion

How
How the
the drug
drug
comes
comes and
and goes.
goes.
Pharmacokinetic
Pharmacokinetic Processes
Processes

“LADME” is key

Liberation
Liberation Metabolism
Metabolism

Absorption
Absorption Excretion
Excretion

Distribution
Distribution
Liberation
Liberation
•• Applies
Applies to
to drugs
drugs given
given orally
orally
•• Components
Components
–– Release
Release of
of drug
drug from
frompill,
pill, tablet,
tablet, capsule
capsule
–– Dissolving
Dissolving of
of active
active drug
drug inin GI
GI fluids
fluids

Ex:
Ex: Enteric
Enteric coated
coated
aspirin
aspirin slows
slows absorption
absorption in
in
stomach
stomach vs
vs non-coated
non-coated
Absorption
Absorption
•• Movement
Movement from
from administration
administration site
site into
into
circulation
circulation
Factors
Factors Affecting
Affecting
Liberation/Absorption
Liberation/Absorption
•• Formulation
Formulation factors
factors •• Patient
Patient factors
factors
–– Tablet
Tabletdisintegration
disintegration –– Absorbing
Absorbingsurface
surface
–– Inert
Inertingredient
ingredient// –– Blood
Bloodflow
flow
solvent
solventeffects
effects –– Environmental
EnvironmentalpH pH
–– Solubility
Solubility –– Disease
Diseasestates
states
–– Drug
DrugpH –– Interactions
pH Interactionswith
withfood,
food,
–– Concentration
Concentration other
otherdrugs
drugs
 Membranes
Membranes and
and Absorption
Absorption
Hydrophilic
Lipid Bilayer
Hydrophilic
Heads
Heads Hydrophobic
Hydrophobic
Tails
Tails
Small, H2O, urea,
uncharged Swoosh!
CO2, O2, N2

Large, Glucose DENIED!

uncharged Sucrose
Small
charged H+, Na+, K+,
ions Ca2+, Cl-, DENIED!
HCO3-
LaChatlier’s
LaChatlier’s Principle
Principle

a.k.a.
a.k.a. Mass
Mass Action
Action A
A reaction
reaction at
at equilibrium
equilibrium
responds
responds toto stress
stress in
in aa
way
way to
to best
best return
return to
to
System
System equilibrium
equilibrium
at
at
Equilibrium
Equilibrium

4 Na+ + 4 Cl_ 4 NaCl

 4.
4. System
3. System
System
3.2.
1.
2.
1. returns
System
Stress
System responds
returns
Stress
Systemappliedto
responds
at to equilibrium!
toto
at equilibrium
applied to stress
equilibrium!
to
system
equilibrium stress
system

System
An not
not at
example
System at of
equilibrium!
equilibrium!
LaChatlier’s
Principle
 by 4 4 NaCl 
 by 84
dissociate
84 Na
4 + + 4 Cl-
8 12
4 NaCl
8 NaCl
Ionization
Ionization

Acids
Acids Release/Donate H
Release/Donate H ++

Ionized
Ionized
HA H+ + A- form
form
Bases
Bases Bind/Accept H
Bind/Accept H ++

H+ + B- HB Non-ionized
Non-ionized
form
form
Environmental
Environmental pH
pH and
and
Ionization
Ionization
If
If we
we put
put an
an acidic
acidic drug
drug in in an
an
environment
environment withwith aa lot
lot of
of HH++ (low
(low pH)
pH)
what
what will
will this
this equilibrium
equilibrium do? do?

HA
HA
HA H+ + A -
HA
HA

 System
H ++
fromat
 H from
Non-ionized
System
Non-ionized at Equilibrium
acid
form
acid
form environment
predominates!
Equilibrium
environment
predominates!
A
A real
real live,
live, actual
actual clinical
clinical
question...
question...

Aspirin
Aspirin isis an
an acidic
acidic drug.
drug. In
In the
the
stomach
stomach will
will itit exist
exist mostly
mostly in
in ionized
ionized
or
or non-ionized
non-ionized form? form?

NON-IONIZED
Why?
Why?
How
How will
will this
this affect
affect aspirin
aspirin
absorption?
absorption?
Lipid Bilayer

Ionized
Ionizedform
form
(charged)
(charged)
A-

Ionized
Ionizedform
form
(uncharged)
(uncharged)
HA HA
Moral
Moral of
of the
the story...
story...

Acidic
Acidic drugs
drugs are
are best
best absorbed
absorbed from
from
acidic
acidic environments
environments

Basic
Basic drugs
drugs are
are best
best absorbed
absorbed from
from
basic
basic environments
environments
So...
So...

To  absorption
To absorption ofof an
an acidic
acidic drug…
drug…
acidify
acidify the
the environment
environment

To  absorption
To absorption of
of an
an acidic
acidic drug…
drug…
alkalanize
alkalanize the
the environment...
environment...
Distribution
Distribution
•• Rate
Rate of
of perfusion
perfusion
•• Plasma
Plasma protein
protein (albumin)
(albumin) binding
binding
•• Accumulation
Accumulation in in tissues
tissues
•• Ability
Ability to
to cross
cross membranes
membranes
–– Blood-brain
Blood-brain barrier
barrier
–– Placental
Placental barrier
barrier
Plasma
Plasma Protein
Protein Binding
Binding

warfarin
warfarin (Coumadin)
(Coumadin) isis highly
highly protein
protein
bound
bound (99%).
(99%). Aspirin
Aspirin binds
binds toto the
the same
same
site
site on
on serum
serum proteins
proteins as
as does
does
Coumadin.
Coumadin. If If aa patient
patient on
on Coumadin
Coumadin
also
also takes
takes aspirin,
aspirin, what
what will
will happen?
happen?

1)
1) Why?
The available Coumadin will
Why?
2)
2) Why
Why do
do we
we care?
increase. care?
Blood-Brain
Blood-Brain Barrier
Barrier

The
The blood
blood brain
brain barrier
barrier consists
consists of
of
cell
cell tightly
tightly packed
packed around
around the
the
capillaries
capillaries ofof the
the CNS.
CNS. What
What
characteristics
characteristics mustmust aa drug
drug possess
possess
to
to easily
easily cross
cross this
this barrier?
barrier?

Non-protein bound, non-ionized,

Why?
Why?
and highly lipid soluble
Metabolism
Metabolism
(Biotransformation)
(Biotransformation)
•• Two
Two effects
effects
–– Transformation
Transformation to
to less
less active
active metabolite
metabolite
–– Enhancement
Enhancement of
of solubility
solubility
•• Liver
Liver == primary
primary site
site
•• Liver
Liver disease
disease
–– Slows
Slows metabolism
metabolism
–– Prolongs
Prolongs effects
effects
Hepatic
Hepatic ‘First-Pass’
‘First-Pass’
Metabolism
Metabolism
•• Affects
Affects orally
orally administered
administered drugs
drugs
•• Metabolism
Metabolism of of drug
drug by
by liver
liver before
before drug
drug
reaches
reaches systemic
systemic circulation
circulation
•• Drug
Drug absorbed
absorbed into
into portal
portal circulation,
circulation, must
must
pass
pass through
through liver
liver to
to reach
reach systemic
systemic
circulation
circulation
•• May
May reduce
reduce availability
availability ofof drug
drug
Elimination
Elimination
•• Kidneys
Kidneys == primary
primary site
site
–– Mechanisms
Mechanisms dependent
dependent upon:
upon:
•• Passive
Passiveglomerular
glomerularfiltration
filtration
•• Active
Activetubular
tubulartransport
transport
–– Partial
Partial reabsorption
reabsorption
–– Hemodialysis
Hemodialysis
•• Renal
Renal disease
disease
–– Slows
Slows excretion
excretion
–– Prolongs
Prolongs effects
effects
Active
Active Tubular
Tubular Transport
Transport

Probenecid
Probenecid isis moved
moved into
into the
the urine
urine by
by
the
the same
same transport
transport pump
pump that
that moves
moves
many
many antibiotics.
antibiotics. Why
Why isis probenecid
probenecid
sometimes
sometimes given
given as
as an
an adjunct
adjunct toto
antibiotic
antibiotic therapy?
therapy?
It competes with the
antibiotic at the pump and
slows its excretion.
Urine
Urine pH
pH and
and Elimination
Elimination
AA patient
patient has
has overdosed
overdosed on on
phenobartital.
phenobartital. Phenobarbital
Phenobarbital isis an
an acid.
acid.
If
If we
we ‘alkalinalize’
‘alkalinalize’ the
the urine
urine by
by giving
giving
bicarbonate
bicarbonate what
what will
will happen
happen toto the
the
phenobarbital
phenobarbital molecules
molecules asas they
they are
are
filtered
filtered through
through the
the renal
renal tubules?
tubules?

They will ionize...

How
How will
will this
this affect
affect phenobarbital
phenobarbital
reabsorption
reabsorption byby the
the kidney?
kidney?

Non-ionized Ionized

HA H+ + A -

Decreased
Decreased reabsorption
reabsorption

Increased
Increased elimination
elimination
Elimination
Elimination
•• Other
Other sources
sources
–– Feces
Feces
–– Exhaled
Exhaled air
air
–– Breast
Breast milk
milk
–– Sweat
Sweat
Biological
Biological Half-life
Half-life (t(t 1/2
1/2)
)
•• Amount
Amount of of time
time to
to eliminate
eliminate 1/2
1/2 of of total
total
drug
drug amount
amount
•• Shorter
Shorter tt 1/2 may need more frequent doses
1/2 may need more frequent doses
•• Hepatic
Hepatic disease
disease maymay increase
increase tt1/2
1/2
AA drug
drug has
has aa half
half life
life of
of 10
10 seconds.
seconds. You
You
give
give aa patient
patient aa dose
dose of of 6mg.
6mg. After
After 30
30
seconds
seconds howhow much
much of of the
the drug
drug remains?
remains?

Time
Time Amount
Amount
00 sec
sec 66 mg
mg
10
10 sec
sec 33 mg
mg
20
20 sec
sec 1.5
1.5 mg
mg
30
30 sec
sec 0.75
0.75 mg
mg
Administration
Administration Routes
Routes
•• Intravenous
Intravenous
–– Fastest,
Fastest, Most
Most dangerous
dangerous
•• Endotracheal
Endotracheal
–– Lidocaine,
Lidocaine, atropine,
atropine, narcan,
narcan, epinephrine
epinephrine
•• Inhalation
Inhalation
–– Bronchodilators
Bronchodilators via
via nebulizers
nebulizers
•• Transmucosal
Transmucosal
–– Rectal
Rectal or
or sublingual
sublingual
Administration
Administration Routes
Routes
•• Intramuscular
Intramuscular
–– Depends
Depends on
on perfusion
perfusion quality
quality
•• Subcutaneous
Subcutaneous
–– Depends
Depends on
on perfusion
perfusion quality
quality
•• Oral
Oral
–– Slow,
Slow, unpredictable
unpredictable
–– Little
Little prehospital
prehospital use
use
Pharmacodynamics
Pharmacodynamics
•• The
The biochemical
biochemical and
and physiologic
physiologic
mechanisms
mechanisms of
of drug
drug action
action

What
What the
the drug
drug
does
does when
when itit gets
gets there.
there.
Drug
Drug Mechanisms
Mechanisms
•• Receptor
Receptor interactions
interactions
•• Non-receptor
Non-receptor mechanisms
mechanisms
Receptor
Receptor Interactions
Interactions
Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
Receptor
Receptor Interactions
Interactions

Induced Fit

Receptor

Perfect Fit!
 Receptor
Receptor Interactions
Interactions
Competitive
Inhibition

Antagonist Receptor

Antagonist-Receptor
DENIED!
Complex
Receptor
Receptor Interactions
Interactions
Non-competitive Antagonist
Inhibition

Agonist Receptor

DENIED!
‘Inhibited’-Receptor
Non-receptor
Non-receptor Mechanisms
Mechanisms
•• Actions
Actions on
on Enzymes
Enzymes
–– Enzymes
Enzymes == Biological
Biological catalysts
catalysts
•• Speed
Speedchemical
chemicalreactions
reactions
•• Are
Arenot
notchanged
changedthemselves
themselves
–– Drugs
Drugs altering
altering enzyme
enzyme activity
activity alter
alter processes
processes
catalyzed
catalyzed by
by the
the enzymes
enzymes
–– Examples
Examples
•• Cholinesterase
Cholinesteraseinhibitors
inhibitors
•• Monoamine
Monoamineoxidase
oxidaseinhibitors
inhibitors
Non-receptor
Non-receptor Mechanisms
Mechanisms
•• Changing
Changing Physical
Physical Properties
Properties
–– Mannitol
Mannitol
–– Changes
Changes osmotic
osmotic balance
balance across
across membranes
membranes
–– Causes
Causes urine
urine production
production (osmotic
(osmotic diuresis)
diuresis)
Non-receptor
Non-receptor Mechanisms
Mechanisms
•• Changing
Changing Cell
Cell Membrane
Membrane Permeability
Permeability
–– Lidocaine
Lidocaine
•• Blocks
Blockssodium
sodiumchannels
channels
–– Verapamil,
Verapamil, nefedipine
nefedipine
•• Block
Blockcalcium
calciumchannels
channels
–– Bretylium
Bretylium
•• Blocks
Blockspotassium
potassiumchannels
channels
–– Adenosine
Adenosine
•• Opens
Openspotassium
potassiumchannels
channels
Non-receptor
Non-receptor Mechanisms
Mechanisms
•• Combining
Combining With
With Other
Other Chemicals
Chemicals
–– Antacids
Antacids
–– Antiseptic
Antiseptic effects
effects of
of alcohol,
alcohol, phenol
phenol
–– Chelation
Chelation of
of heavy
heavy metals
metals
Non-receptor
Non-receptor Mechanisms
Mechanisms
•• Anti-metabolites
Anti-metabolites
–– Enter
Enter biochemical
biochemical reactions
reactions in
in place
place of
of normal
normal
substrate
substrate “competitors”
“competitors”
–– Result
Result in
in biologically
biologically inactive
inactive product
product
–– Examples
Examples
•• Some
Someanti-neoplastics
anti-neoplastics
•• Some
Someanti-infectives
anti-infectives
Drug
Drug Response
Response Relationships
Relationships
•• Time
Time Response
Response
•• Dose
Dose Response
Response
Time
Time Response
Response Relationships
Relationships
Maximal (Peak) Effect

Effect/
Response

Latency Duration of Response

Time
Time
Time Response
Response Relationships
Relationships

IV
IM
SC
Effect/
Response

Time
Dose
Dose Response
Response Relationships
Relationships
•• Potency
Potency
–– Absolute
Absolute amount
amount ofof drug
drug required
required toto produce
produce
an
an effect
effect
–– More
More potent
potent drug
drug isis the
the one
one that
that requires
requires lower
lower
dose
dose to
to cause
cause same
same effect
effect
Potency
Potency

A B
Therapeutic
Effect
Effect

A!
Why?
A!
Why?

Dose
Which drug is more potent?
Dose
Dose Response
Response Relationships
Relationships
•• Threshold
Threshold (minimal)
(minimal) dose
dose
–– Least
Least amount
amount needed
needed to
to produce
produce desired
desired effects
effects
•• Maximum
Maximum effect
effect
–– Greatest
Greatest response
response produced
produced regardless
regardless of
of dose
dose
used
used
 Dose
Dose Response
Response Relationships
Relationships
B

A
Therapeutic
Effect
Effect

Dose
Which drug has the lower threshold dose? AA
Which has the greater maximum effect? BB
Dose
Dose Response
Response Relationships
Relationships
•• Loading
Loading dose
dose
–– Bolus
Bolus of
of drug
drug given
given initially
initially to
to rapidly
rapidly reach
reach
therapeutic
therapeutic levels
levels
•• Maintenance
Maintenance dose
dose
–– Lower
Lower dose
dose of
of drug
drug given
given continuously
continuously or
or at
at
regular
regular intervals
intervals to
to maintain
maintain therapeutic
therapeutic levels
levels
Therapeutic
Therapeutic Index
Index
•• Drug’s
Drug’s safety
safety margin
margin
•• Must
Must be
be >1
>1 for
for drug
drug toto be
be usable
usable
•• Digitalis
Digitalis has
has aa TI
TI of
of 22
•• Penicillin
Penicillin has
has TI
TI of
of >100
>100

LD
LD50
50
TI 
TI
ED
ED50
50
Therapeutic
Therapeutic Index
Index

Why
Why don’t
don’t we
we use
use aa
drug
drug with
with aa TI
TI <1?
<1?

ED50
ED50 << LD50
LD50 == Very
Very Bad!
Bad!
Factors
Factors Altering
Altering Drug
Drug
Responses
Responses
•• Age
Age
–– Pediatric
Pediatric or
or geriatric
geriatric
–– Immature
Immature oror decreased
decreased hepatic,
hepatic, renal
renal function
function
•• Weight
Weight
–– Big
Big patients
patients “spread”
“spread” drug
drug over
over larger
larger volume
volume
•• Gender
Gender
–– Difference
Difference in
in sizes
sizes
–– Difference
Difference in
in fat/water
fat/water distribution
distribution
Factors
Factors Altering
Altering Drug
Drug
Responses
Responses
•• Environment
Environment
–– Heat
Heat or
or cold
cold
–– Presence
Presence or
or real
real or
or perceived
perceived threats
threats
•• Fever
Fever
•• Shock
Shock
Factors
Factors Altering
Altering Drug
Drug
Responses
Responses
•• Pathology
Pathology
–– Drug
Drug may
may aggravate
aggravate underlying
underlying pathology
pathology
–– Hepatic
Hepatic disease
disease may
may slow
slow drug
drug metabolism
metabolism
–– Renal
Renal disease
disease may
may slow
slow drug
drug elimination
elimination
–– Acid/base
Acid/base abnormalities
abnormalities may
may change
change drug
drug
absorption
absorption or
or elimination
elimination
Influencing
Influencing factors
factors
•• Genetic
Genetic effects
effects
–– Lack
Lack of
of specific
specific enzymes
enzymes
–– Lower
Lower metabolic
metabolic rate
rate
•• Psychological
Psychological factors
factors
–– Placebo
Placebo effect
effect
Pediatric
Pediatric Patients
Patients
•• Higher
Higher proportion
proportion of
of water
water
•• Lower
Lower plasma
plasma protein
protein levels
levels
–– More
More available
available drug
drug
•• Immature
Immature liver/kidneys
liver/kidneys
–– Liver
Liver often
often metabolizes
metabolizes more
moreslowly
slowly
–– Kidneys
Kidneys may
may excrete
excrete more
more slowly
slowly
Geriatric
Geriatric Patients
Patients
•• Chronic
Chronic disease
disease states
states •• Dietary
Dietary deficiencies
deficiencies
•• Decreased
Decreased plasma
plasma •• Use
Use of
of multiple
multiple
protein
protein binding
binding medications
medications
•• Slower
Slower metabolism
metabolism •• Lack
Lack of
of compliance
compliance
•• Slower
Slower excretion
excretion
Web
Web Resources
Resources
•• Basic
Basic Pharmacokinetics
Pharmacokinetics on
on the
the Web
Web
–– http://pharmacy.creighton.edu/pha443/pdf/Defa
http://pharmacy.creighton.edu/pha443/pdf/Defa
ult.asp
ult.asp
•• Merk
Merk Manual:
Manual: Overview
Overview of
of Drugs
Drugs
–– http://www.merck.com/pubs/mmanual_home/s
http://www.merck.com/pubs/mmanual_home/s
ec2/5.htm
ec2/5.htm
Web
Web Resources
Resources
•• Merk
Merk Manual:
Manual: Factors
Factors Affecting
Affecting Drug
Drug
Response
Response
–– http://www.merck.com/pubs/mmanual_home/s
http://www.merck.com/pubs/mmanual_home/s
ec2/8.htm
ec2/8.htm
•• Merk
Merk Manual:
Manual: Pharmacodynamics
Pharmacodynamics
–– http://www.merck.com/pubs/mmanual_home/s
http://www.merck.com/pubs/mmanual_home/s
ec2/7.htm
ec2/7.htm