Module II
The Basics of the Brain, the Body and Drug Actions
Segment B
General Principles of Drug Actions
– The Foundation of Drug Actions
in the CNS
Kim Edward Light, Ph.D.
Professor, College of Pharmacy
University of Arkansas for
Medical Sciences
1
Objectives
1.
2.
3.
4.
5.
6.
7.
Identify the various perspectives for understanding drug
actions.
Describe the pharmaceutical and pharmacokinetic
phases of drug actions.
Describe the pharmacodynamic, therapeutic, and toxic
phases of drug actions.
Identify ADME and the important aspects of each.
List the major routes of drug administration and
elimination.
Identify the role of distribution and biotransformation in
drug actions.
What is the importance of dose-response relationships
in drug action?
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Objectives
8.
9.
10.
11.
12.
Identify the difference between quantal and graded
dose-responses.
Differentiate between potency and efficacy in regards to
drug actions?
Define agonists, antagonists, partial agonists and how
their presence in combination impacts the resulting drug
effects.
Identify the difference between competitive and noncompetitive antagonist drug actions.
Identify the importance of signal transduction and how
the type of receptor determines the transduction
process.
3
Aspects of Drug Actions
Pharmaceutical
Pharmacokinetic
Pharmacodynamic
Therapeutic
Toxic
4
Pharmaceutical aspects
Drug
absorption.
Routes of administration
» Oral
» Injection (iv, im, ia)
» Topical
» Inhalation
» Rectal
5
Pharmacokinetic Aspects
6
Absorption
TRANSDERMAL
CAPSULE
AEROSOL
TABLET
SUB-LINGUAL
SYRUP
IV
IM
SUPPOSITORY
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Distribution
Delivery of the drug to tissues
Blood flow
Most drugs “like” fat (lipophilic)
Plasma protein binding
Apparent “barriers”
Blood-Brain Barrier
Synovial barrier
Placental Barrier
Breast milk
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Metabolism
Biotransformation
 To render the drug more water-soluble
 Liver, GI tract, lungs, kidneys, brain
 Cytochrome P450 (CYP) / mixed function
oxidases
 Split molecular O2 to oxidize drug
X + O2 +
CYP + 2NADPH
X-O + H2O
CYP + 2NADP+
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Metabolism
Biotransformation
 Specialized forms of CYP enzymes
CYP3A4 >50% of drugs
CYP2D6 many CNS and cardiovascular drugs
Other enzyme systems:
alcohol dehydrogenase
plasma esterase enzymes
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Elimination or Excretion
 Filtration by the kidneys
 Eliminated in urine
 Some passed into the bile
 After liver metabolism
 Other important routes:
 breath,
 sweat,
 saliva,
 milk,
 hair,
 finger/toe nails
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Plasma
Concentration
Time Course of Drug Actions
12
Pharmacokinetic Terminology
Clearance
the total time to completely
eliminate the drug from the body
Half-life (T½)
the amount of time for the
concentration to decrease by half
13
Half-Lives
 For example, for a drug with an T½ of 6 hours
 @ 0 hours = 100 mg/ml in the plasma
 @ 6 hours = 50 mg/ml
 @ 12 hours = 25 mg/ml
» Note: each T½ decreases the previous concentration by half
Two half-lives
Three half-lives
Four half-lives
Five half-lives
One half-life
 This type of elimination is called FIRST-ORDER
since the amount of drug eliminated per unit time is
dependent on one variable – concentration
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Pharmacodynamics
 Dose-Response Relationships
 Drug actions are related to dose
 More drug = more actions
 Two perspectives
 response of a population of subjects to a given drug
(i.e. how many respond)
 The response magnitude (or graded response)
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Dose Responses in Populations
Cumulative % of subjects
100
75
50
25
0
1
3
5
6
7
8
9
10 11 12 13 14 15
Dose
 Relates the number (or %) of subjects that respond in a specific
manner (i.e. sleep).
 Large numbers of individuals increases accuracy.
 Clinical trials in new drug testing
 If tested population is too small or not diverse then the results will
not be translatable to all individuals.
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Graded Dose Responses
Dose that produces
50% of Maximal
Response
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Receptor Drug Interactions
 Affinity
How well the receptor and drug are attracted to each
other
 Efficacy
How much response is produced by drug-receptor
interaction
 Potency
Comparative measure of how much drug is required
to produce a certain magnitude of response
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Graded Dose Responses
 Types of drug actions
 Agonist = bind and produce a
response
» Affinity and efficacy (Drug A or B)
 Antagonist = bind but don’t
produce response (block
agonist, however)
» Affinity but no efficacy (Drug D)
 Partial Agonist = bind and
produce weak response
» Affinity and weak efficacy (Drug C)
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Understanding Drug Actions
 A fundamental principle of pharmacology is that
drugs do not produce effects that are new or
novel to the physiological system.
 Drugs act within the physiological system to alter
responses
 How drug actions are produced is essentially a
question of how physiological systems are
designed.
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Drug Mechanisms
Agonist
direct = a drug that binds to
and activates specific
receptors
» affinity and efficacy
indirect = a drug that results
in an increase in the
presence and ability of the
endogenous transmitter’s
binding to the receptor
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Drug Mechanisms
 Antagonist
direct = a drug that binds
to but does not activate
specific receptors
» Affinity no efficacy
indirect = a drug that
results in a decrease in the
presence or ability of the
transmitter to bind with the
receptor
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Drug Mechanisms
Partial Agonist
 Affinity and weak efficacy
 Therefore, it may sometimes act as an agonist or antagonist.
If no agonist is present,
then partial agonist
produces some response.
If agonist and partial agonist are present
then less agonist can bind so total
response is less – like antagonist
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Pharmacodynamic Principles
Tolerance
 the ability of the body to adapt to
the presence of a drug that alters
physiological functioning.
 subsequent exposure will require
higher doses to produce the
same magnitude of response
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Pharmacodynamic Principles
Withdrawal
adverse physiological symptoms
produced by the absence of a drug
physiological alterations to oppose
drug actions
removal of the drug results in the
expression of the physiological
alterations
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Pharmacodynamic Principles
Dependence
 physiological state characterized
by the presence of adverse signs
and symptoms that occur when the
drug or treatment is withdrawn.
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Pharmacodynamic Principles
withdrawal
Homeostasis (balance)
drug
adaptation
adaptation
dependence
drug
 Drug effects to alter the system
 System responds to oppose drug effects (tolerance)
 Absence of drug results in expression of the system’s
adaptations (withdrawal)
 Drug presence is necessary to balance the system’s
adaptations (dependence)
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Summary
 Perspectives of drug actions
Pharmaceutics, kinetics, dynamics, etc.
 ADME
 Dose-response relationships
 Drug Actions
agonists, partial agonists, antagonists
 Pharmacodynamic principles
(affinity, efficacy, tolerance, dependance, etc.)
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