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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.)