1 module ii the basics of the brain, the body and drug actions segment b general principles of drug...
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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 PharmacyUniversity of Arkansas for Medical Sciences
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Objectives
1. Identify the various perspectives for understanding drug actions.
2. Describe the pharmaceutical and pharmacokinetic phases of drug actions.
3. Describe the pharmacodynamic, therapeutic, and toxic phases of drug actions.
4. Identify ADME and the important aspects of each.
5. List the major routes of drug administration and elimination.
6. Identify the role of distribution and biotransformation in drug actions.
7. What is the importance of dose-response relationships in drug action?
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Objectives
8. Identify the difference between quantal and graded dose-responses.
9. Differentiate between potency and efficacy in regards to drug actions?
10. Define agonists, antagonists, partial agonists and how their presence in combination impacts the resulting drug effects.
11. Identify the difference between competitive and non-competitive antagonist drug actions.
12. Identify the importance of signal transduction and how the type of receptor determines the transduction process.
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PharmaceuticalPharmacokineticPharmacodynamic
Therapeutic Toxic
Aspects of Drug Actions
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Pharmaceutical aspects
Drug absorption.Routes of administration
» Oral» Injection (iv, im, ia)» Topical» Inhalation» Rectal
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Pharmacokinetic Aspects
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Absorption
TABLET
CAPSULE
SYRUP
AEROSOL
SUB-LINGUAL
TRANSDERMAL
SUPPOSITORYIV IM
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Distribution
Delivery of the drug to tissuesBlood flow Most drugs “like” fat (lipophilic)Plasma protein binding
Apparent “barriers”Blood-Brain BarrierSynovial barrierPlacental BarrierBreast milk
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MetabolismBiotransformation
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 + X-O + H2O
CYP + 2NADPH CYP + 2NADP+
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MetabolismBiotransformation
Specialized forms of CYP enzymesCYP3A4 >50% of drugsCYP2D6 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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Time Course of Drug ActionsP
las
ma
Co
nc
entr
ati
on
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Pharmacokinetic Terminology
Clearancethe total time to completely
eliminate the drug from the body
Half-life (T½) the amount of time for the
concentration to decrease by half
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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
This type of elimination is called FIRST-ORDER since the amount of drug eliminated per unit time is dependent on one variable – concentration
Half-Lives
One half-lifeTwo half-lives
Three half-livesFour half-lives
Five half-lives
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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)
Pharmacodynamics
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1 3 5 6 7 8 9 10 11 12 13 14 150
25
50
75
100
Dose
Cu
mu
lati
ve %
of
sub
ject
s
Dose Responses in Populations
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
AffinityHow well the receptor and drug are attracted to each
other Efficacy
How much response is produced by drug-receptor interaction
PotencyComparative 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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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
Drug Mechanisms
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Pharmacodynamic Principles
ToleranceTolerance 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
WithdrawalWithdrawal adverse physiological symptoms
produced by the absence of a drugphysiological alterations to oppose
drug actionsremoval of the drug results in the
expression of the physiological alterations
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Pharmacodynamic Principles
DependenceDependence 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
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)
Homeostasis (balance)
adaptationdrug
drug
adaptationwithdrawal
dependence
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Summary
Perspectives of drug actionsPharmaceutics, kinetics, dynamics, etc.
ADME Dose-response relationships Drug Actions
agonists, partial agonists, antagonists
Pharmacodynamic principles(affinity, efficacy, tolerance, dependance, etc.)