january 25, 2015 introduction to pharmacology · january 25, 2015 introduction to pharmacology...

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January 25, 2015

Introduction to Pharmacology

Edward Fisher, Ph.D., R.Ph.

Professor and Associate Dean for Academic AffairsDirector MS Clinical Psychopharmacology

University of Hawaii at HiloCollege of [email protected]

Ligands

• Ligand: a molecule, or a molecular group that binds to another chemical entity to form a larger complex. In the field of pharmacology, it is a molecule, as a hormone or a drug, which binds to a receptor

• Molecules that carry signals for cellular communication

– Endogenous ligands

– Exogenous ligands

• Toxins

• Drugs

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Pharmacology: the study of substances that interact with living

systems through chemical processes.

Medical pharmacology – therapeutic application

Toxicology – undesirable effects of chemicals on living systems

Pharmacodynamics: the actions of the drug on the body.

Biochemical effects, mechanism of action (MOA)

Drug classification

Pharmacokinetics: the actions of the body on the drug.

Absorption, distribution, metabolism, & excretion

Involved with the time course of the drug in the body

How the drug affects you

How you affect the drug

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DRUG ADMINISTRATION

PHARMACOKINETICS

1.

2.

PHARMACODYNAMICS3.

Effects of the body on drugs:

• Absorption

• Distribution

• Elimination

• Metabolism

Effects of drugs on the body:

• Receptor-mediated responses


• Receptor: part of an organism or cell (macromolecule) that interacts with a ligand (drug, endogenous molecule) causing a chain of biochemical events leading to an observable response.

Active states vs. inactive states

• Inert Binding Site: a component of the biologic system to which a drug binds without changing any function

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Drug: any substance that brings about a change in biologic

function through its chemical actions.

Endogenous – synthesized in the body (hormones)

Xenobiotics – chemicals not synthesized by the body

Drug: Pharmacy definition: Articles intended for use in the

diagnosis, cure, mitigation, treatment or prevention of disease in

man or other animals

.

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Principles Of Drug-Receptor Interaction

Drugs generally exert their effects by:

1) Mimicking the actions of endogenous chemicals at receptors

Example: Activation of mu opioid receptors by opioid analgesics (“pain killers”) such as morphine, codeine, and meperidine

Mu Opioid Receptor

ANALGESIA

Endogenous Opioids

(enkephalins,

endorphins)

Opioid Drug

(e.g., morphine)

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2) By blocking the actions of endogenous chemicals at receptors

Example: Blockade of the dopamine receptors by the antipsychotic drug Haloperidol

D2 Dopamine Receptor Haloperidol

Dopamine

extracellular

intracellular

Psychotic Symptoms


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3)By Inhibiting enzymes

• Examples

– Monoamine oxidase inhibitor phenelzine (Nardil®)– COX2 (cyclooxygenase-2) inhibitor – celecoxib –

treatment of inflammatory disorders


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4) By modulating the function of membrane transporters

• Examples – NE transporter (NET) – adrenomimetic drugs (Ephedrine,

Amphetamines)

– Serotonin transporter – antidepressants (Paroxetine)

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Activation of the same type of receptor can produce a variety of different physiological effects depending on its location

Example: Activation of beta2 adrenergic receptors in the lungs vs. liver

Relaxation of bronchial

smooth muscleBreakdown of glycogen

Beta2 Adrenergic

Receptors

EpinephrineLungs Liver


Inhibition of the same type of receptor can produce a variety of different physiological effects depending on its location

• Example: Haloperidol - Potent D₂ blockade

nigrostriatal causes EPS - Dopamine-mesolimbic treats positive symptoms

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Receptor Activation =

Biochemical Response

chemical

structure

DRUG

binding site

RECEPTOR

Estrogen

Estrogen

Receptor

Drug-receptor Binding

The “Lock and Key” Model


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Drug targets – biomolecules that have a role in the disease

process and are considered to be the site of action for drug

therapy (receptors, enzymes, DNA, ion channels, transport

proteins)


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Agonist: a drug that binds to and activates a receptor which

brings about an effect.

Albuterol – β2-selective adrenoceptor agonist


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Antagonist: a drug that binds to a

receptor and prevents agonists from

binding; do not activate receptor;

blockers.

No direct effect, the antagonistic effect

results from the prevention of agonist binding

and activation of the receptor

Atropine – antagonist for muscarinic

cholinoceptors

Curare - antagonist for nicotinic

cholinoceptors

Generally they are structurally bulky to

prevent receptors from going back to active

confirmation, and so that they have more sites

for receptor interaction


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Partial Agonist: a drug that binds to a receptor and activates it,

but the effect is not as great as with a full agonist.

Are agonists if no full agonist is present; are antagonists if a full

agonist is present

Pindolol – partial β receptor agonist

Inverse Agonist: a drug that binds to a receptor and stabilizes it

in the inactive conformation.

Constitutively active receptors – active without binding to agonist

Many drugs that act as competitive

antagonists are really partial agonists

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An Antagonist

No ActivationActivation

State A

Receptor X

A Full Agonist A Partial Agonist

Activation

State B

Receptor X

Maximal Effect No Effect Sub-maximal Effect


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Regulation of the

activity of a receptor

with conformation-

selective drugs

Two-state Model

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Rinactive Ractive

10 Rinactive 10 Ractive


Add 8 INVERSE AGONISTS that bind to

inactive receptor molecule and stabilize it


New equation


4 Active Receptors are converted to 4 inactive


Fewer active receptors with constitutive activity

A Little Background on Drugs

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A drug is a substance that brings about a change

in biologic function through its chemical actions.

Sources

Endogenous

Exogenous (xenobiotics)

States

Solids

Liquids

Gases

Size

Vast majority of drugs have a MW between 100 – 1000

MW 100 helps achieve selective receptor binding

MW 1000 inhibits diffusion-mediated distribution

= Chemicals foreign to the biological

system in question

Drugs do not create effects they modulate

function

Drug Receptors & Pharmacodynamics

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Receptors:

1.) Determine the quantitative relations between dose or

concentration of drug and pharmacologic effects

receptor number in various target tissues

2.) Are responsible for selectivity of drug action

Affinity – determined by chemical forces that cause drug

to bind to the receptor

Efficacy – change in confirmation toward the active state

Intrinsic activity – ability to evoke maximal effect after

binding

3.) Mediate the actions of both pharmacologic agonists and

antagonists

receptor classes, subtype, and isoforms

Receptor:

Class α β

Subtype α1 α2

Isoforms α1a α1b

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A Closer Look at Selectivity

• Selectivity is a number of receptor types with

which a drug will interact

• Lower selectivity = increased incidence of

adverse effects

A Therapeutic Effect and a Adverse EffectTherapeutic Effect Only

Drug A – More Selective

Receptor X Receptor X Receptor Y

Drug B – Less Selective

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A Closer Look At Affinity

• The affinity of a drug for a receptor describes

how readily and tightly that drug binds to its

receptor

– High affinity = good drug-receptor interaction;

LESS drug needed to produce a response

– Low affinity = poor drug receptor interaction;

MORE drug needed to produce a response

Example:

Affinity for mu opioid receptor:

fentanyl > morphine > meperidine

Dose typically used for analgesia:

fentanyl: 0.1 mg; morphine: 10 mg; meperidine: 100 mg

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Intrinsic activity describes the ability of a drug to activate a receptor and produce a physiological response when it binds to a receptor

•Agonists: bind to the receptor and activate it, producing a physiological response

–Have intrinsic activity•Antagonists: Receptor antagonists bind to the receptor but do not change its function. However, they prevent activation by endogenous chemicals or other drugs

–Do not have intrinsic activity

A Closer Look At Intrinsic Activity

Some drug’s MOA do not involve receptors:

antacids, osmotic diuretics

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Types of Receptors

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Regulatory Proteins:

Mediate actions of most drugs and endogenous chemicals

(neurotransmitters, hormones, autocoids)

Best characterized

Enzymes:

Usually through inhibition

Methotrexate inhibits dihydrofolate reductase

Transport Proteins:

Digoxin inhibits Na+, K+ ATPase

Structural Proteins:

Colchicine inhibits tubulinPrevents polymerization of microtubules

Aspects of Drug Receptor Function

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Relationship between drug concentration (dose) &

pharmacologic response

Relationship Between Dose & Response

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Concentration – Effect curves = Dose – Response curves

From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), © 2007 McGraw-Hill Companies

Hyperbolic curve; concentration-effect reflects concentration-

receptor binding

Occupation theory

Magnitude of pharmacological effect is proportional to percentage of

receptors occupied

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EMAX – maximal response that can be produced by drug

EC50 – concentration of drug that produces 50% maximal effect

Kd – concentration of free drug at which there is 50% maximal binding

equilibrium dissociation constant; measure of affinity

low Kd – high affinity – slow dissociation

high Kd – low affinity – rapid dissociation


From Receptor


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Sigmoidal curve

Expands region of

low drug

concentration

Linear mid-portion

Compresses higher

portion


• Receptor-Effector Coupling: Transduction process between occupancy & drug response

Coupling efficiency based on

1.) extent of conformational change (full agonist-full response, partial agonist-partial response) and

2.) biochemical events that transduce occupancy into response

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42From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.),

© 2007 McGraw-Hill Companies

Competitive Antagonist:

Reversibly competes with agonist for receptor binding

Antagonism can be overcome by concentration of agonist

Effect is influenced by:

Concentration of antagonist

Concentration of agonist that is

competing for binding to receptors

Propranolol vs. Norepi

Effects vary widely in

individuals due to differences

in clearance

Exercise can overcome effect


43From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.),

© 2007 McGraw-Hill Companies

Irreversible (noncompetitive) Antagonist:

Antagonism cannot be overcome by concentration of agonist

Dependent on own rate of elimination

Phenoxybenzamine

irreversible α adrenoceptor

antagonist

control hypertension due to

pheochromocytoma

in case of overdose, cannot

competitively activate receptor


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Full agonist at

single

concentration

Full agonist at

single

concentration


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Allosteric Antagonist:

Binds to another part of the molecule

Chemical Antagonist:

A drug may bind to and inactivate another drug

Protamine used to counteract heparin

Desferrioxamine chelates iron

Physiological Antagonist:

One type of functional antagonism – agonists that oppose via action

on a different receptor or system

Use of a separate endogenous regulatory pathway

Glucocorticoids vs. insulin in controlling blood glucose

Effects are less specific & more difficult to control

Aspects of Drug Receptor Function

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Relationship between dose and clinical response

Relationship Between Dose & Clinical Response

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Maximal benefit with minimal toxicity

Graded dose-response relationship:

Potency – EC50 or ED50 (dose needed for 50% of drug’s maximal

effect)

Dependent on affinity (Kd) and

Efficiency of coupling response

Maximal efficacy – limit of the dose-response relationship;

important for clinical effectiveness

Dependent on ability to reach relevant receptors

Route of administration, absorption, site of action


49From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), ©

2007 McGraw-Hill Companies

• Drugs A & B are more potent than

drugs C & D

• The pharmacologic potency of A

is less than that of B

• Drug A has a larger maximal

efficacy than drug B

• Drugs A, C, & D have equal

maximum efficacy which is greater

than the maximum efficacy of B

Potency = dose needed for 50% of drug’s maximal effect


• A very steep curve implies:

Cooperative actions of different systems

Need great majority of receptors to be occupied

Narrow therapeutic range

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More

potent

Less

potent

More Less

Log dose

Inte

nsit

y o

f re

sp

on

se

50%

1 100

A Closer look at Potency

Potency:

• Describes the amount of a drug required to produce a specific effect

• Represented by the ED50

• The lower the ED50, the more potent the drug

• Determines the drug dose that will be used clinically

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Efficacy:

• Describes the maximal effect that a drug can produce

• Represented by the Emax

• The greater the EMAX, the more efficacious the drug

• Determines clinical effectiveness

1

Inte

ns

ity o

f re

sp

on

se

Log dose

More

Less

More

efficacious

Less

efficacious

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A Closer Look At Efficacy


• Therapeutic index – TD50 /ED50

– Digoxin – narrow

– Benzodiazepines and antipsychotics - wide

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Cumulative Quantal Dose-response Curve and Drug Safety Indices

• Therapeutic window – the range of doses of a

drug or of its concentration in a bodily system

that provides safe and effective therapy

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Narrow vs. wide therapeutic

window

The clinically acceptable risk of toxicity depends critically on the

severity of the disease being treated

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Variation in drug responsiveness:

Clinical response in individual patients

Idiosyncratic – infrequently observed in most patients

Genetic differences in metabolism

Immunological differences

Hypersensitivity – true allergy (uncommon)

Hyperreactive – intensity of effect is increased vs. that in most

individuals

Hyporeactive – intensity of effect is decreased vs. that in most

individuals

Tolerance – responsiveness decreases as a consequence of

continued drug administration

Tachyphylaxis – decreased responsiveness that occurs rapidly

after administration of a drug


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Four mechanisms contribute to

variation in drug responsiveness

1.) Alteration in concentration of drug that reaches receptor

2.) Variation in concentration of endogenous receptor ligand

3.) Alteration in number or function of receptors

4.) Change in responsiveness distal to receptor

1.) Alteration in concentration of drug that reaches receptor

Dose

ADME

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2.) Variation in concentration of endogenous receptor ligand

• Saralasin – weak partial agonist at angiotensin II receptors

• Angiotensin II is a potent vasoconstrictor– What would be its effect on blood pressure up or down?

• What would be the effect on blood pressure of giving saralasin to a patient with high levels of angiotensin?

• What would be the effect on blood pressure of giving saralasin to a patient with low levels of angiotensin?

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• Up-regulation (thyroid hormone increases receptors in heart; antagonists like -blockers also do this)

– Stop antagonist – increase in receptor number - response to endogenous ligand (need to wean)

• Down-regulation

– Stop agonist – may have too few receptors to get effective stimulation

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Pharmacogenomics (or pharmacogenetics) is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug.

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4.) Change in responsiveness distal to receptor

• Largest and most important class of mechanisms that cause variation in responsiveness to drug therapy

• Age

• General health

• Severity & pathophysiology of disease

• Wrong diagnosis

• Compensatory mechanisms - (baroreceptor reflex after administration of an anti-hypertensive agent)

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Clinical selectivity: beneficial vs. toxic effects of drugs:

Same receptor-effector mechanism,

direct pharmacological

extension

Same receptor, different effectors /

different tissues

Different receptor-effector

mechanisms


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Strategies for lowering adverse effects:

Use lowest dose possible

Add an adjunctive drug that acts on a different receptor mechanism

Anatomical selectivity – refine administration to get more drug to site

of action

No drug causes only a single, specific effect

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Drugs are selective, not specific

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january 25, 2015 introduction to pharmacology · january 25, 2015 introduction to pharmacology...

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