pharmacodynamics new

8/8/2019 Pharmacodynamics New

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Bound Free Free Bound

LOCUS OF ACTION

RECEPTORS

TISSUE

RESERVOIRS

SYSTEMICCIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION


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WHY BE CONCERNED ABOUT

HOW DRUGS WORK?

FDA Approved and Unapproved Uses

Interactions with Other Drugs

Adverse Effects and Contraindications

AIDS MEMORIZATION OF:


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HOW DRUGS WORK?

Better assessment of new modalities for using drugs

Better assessment of new indications for drugs

Better assessment of new concerns regarding risk-benefit

AIDS EVALUATION OF MEDICAL LITERATURE:


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HOW DRUGS WORK?

The patient has more respect for and trust in a therapist whocan convey to the patient how the drug is affecting the

patients body.

AIDS PATIENT-DOCTOR RELATIONSHIP:

A patient who understands his/her therapy is more inclinedto become an active participant in the management

of the patients disease.


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HOW DRUGS WORK?

Knowledge of how a drug works increases the therapists

confidence that the drug is being used appropriately.

PEACE OF MIND!


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HOW DO DRUGS WORK?

Some antagonize, block or inhibit endogenous proteins

Some activate endogenous proteins

A few have unconventional mechanisms of action

Most work by interacting with

endogenous proteins:


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HOW DO DRUGS ANTAGONIZE, BLOCK OR

INHIBIT ENDOGENOUS PROTEINS?

Antagonists of Cell Surface Receptors

Antagonists of Nuclear Receptors

Enzyme Inhibitors

Ion Channel Blockers

Transport Inhibitors

Inhibitors of Signal Transduction Proteins


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A macromolecular component of the organism thatbinds the drug and initiates its effect.

Definition ofRECEPTOR:

Most receptors are proteins that have undergone various

post-translational modifications such as covalent

attachments of carbohydrate, lipid and phosphate.


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A receptor that is embedded in the cell membrane and functions

to receive chemical information from the extracellularcompartment and to transmit that information to

the intracellular compartment.

Definition ofCELL SURFACE RECEPTOR:


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HOW DO DRUGS WORK BY

ANTAGONIZING CELL SURFACE RECEPTORS?

KEY CONCEPTS:

Cell surface receptors exist to transmit chemical signals from

the outside to the inside of the cell.

Some compounds bind to cell surface receptors, yet do not

activate the receptors to trigger a response.

When cell surface receptors bind the molecule,

the endogenous chemical cannot bind to thereceptor and cannot trigger a response.

The compound is said to antagonize or block the receptor

and is referred to as a receptor antagonist.


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HOW DO DRUGS WORK BY ANTAGONIZING

CELL SURFACE RECEPTORS?

Cell Membrane

Unbound Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Extracellular

Compartment

Intracellular

Compartment


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Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Extracellular

Compartment

IntracellularCompartment

Cellular Response


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Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Extracellular

Compartment


Bound Antagonist of Receptor (Drug)


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Footnote:

Most antagonists attach to binding site on receptor for

endogenous agonist and sterically preventendogenous agonist from binding.

If binding is reversible - Competitive antagonists

If binding is irreversible - Noncompetitive antagonists

However, antagonists may bind to remote site on receptor and

cause allosteric effects that displace endogenous agonist

or prevent endogenous agonist from

activating receptor. (Noncompetitive antagonists)


ANTAGONIZING CELL SURFACE RECEPTORS?


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Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Receptor

Extracellular

Compartment


Bound Antagonist of Receptor

Allosteric Inhibitor

Active Receptor


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ARE DRUGS THAT ANTAGONIZE

CELL SURFACE RECEPTORS

CLINICALLY USEFUL?

Angiotensin Receptor Blockers (ARBs) for high blood pressure,heart failure, chronic renal insufficiency

(losartan [Cozaar]; valsartan [Diovan])

Some important examples:

Beta-Adrenoceptor Blockers for angina, myocardial infarction,heart failure, high blood pressure, performance anxiety

(propranolol [Inderal]; atenolol [Tenormin])


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NUCLEAR RECEPTORS?

Unbound Endogenous Activator

(Agonist) of Nuclear Receptor

Inactive Nuclear Receptor

In Cytosolic Compartment

Intracellular

Compartment

Nucleus

DNA


In Nuclear Compartment


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NUCLEAR RECEPTORS?

Intracellular

Compartment

Nucleus

DNA

Modulation of

Transcription

Active Nuclear Receptor

Bound Endogenous Activator



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NUCLEAR RECEPTORS?

Displaced Endogenous Activator


Intracellular

Compartment

Nucleus

DNA

Bound Antagonist

of Receptor (Drug)


In Cytosolic Compartment


In Nuclear Compartment


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ARE DRUGS THAT ANTAGONIZE

NUCLEAR RECEPTORS

CLINICALLY USEFUL?

Mineralocorticoid Receptor Antagonists for edema due to

liver cirrhosis and for heart failure

(spironolactone [Aldactone])


Estrogen Receptor Antagonists for the prevention and

treatment

of breast cancer (tamoxifen [Nolvadex])


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Enzyme Inhibitors





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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Inactive Enzyme

Substrate

Bound Enzyme

Inhibitor (Drug)


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INHIBITING ENZYMES?

KEY CONCEPTS:

Enzymes catalyze the biosynthesis of products from substrates.

Some drugs bind to enzymes and inhibit enzymatic activity.

Loss of product due to enzyme inhibition mediates the

effects of enzyme inhibitors.


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ARE DRUGS THAT INHIBIT ENZYMES

CLINICALLY USEFUL?

Cyclooxygenase Inhibitors for pain relief,

particularly due to arthritis (aspirin; ibuprofen [Motrin])


Angiotensin Converting Enzyme (ACE) Inhibitors for

high blood pressure, heart failure, and

chronic renal insufficiency

(captopril [Capoten]; ramipril [Altace])

HMG-CoA Reductase Inhibitors for hypercholesterolemia

(atorvastatin [Lipitor]; pravastatin [Pravachol])


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Enzyme Inhibitors





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ARE DRUGS THAT INHIBIT TRANSPORTERS

CLINICALLY USEFUL?

Selective Serotonin Reuptake Inhibitors (SSRIs) for thetreatment of depression

(fluoxetine [Prozac]; fluvoxamine [Luvox])


Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) inrenal epithelial cells to increase urine and sodium

output for the treatment of edema

(furosemide [Lasix]; bumetanide [Bumex])


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Tyrosine Kinase Inhibitors for chronic myelocytic leukemia

(imatinib [Gleevec])


Type 5 Phosphodiesterase Inhibitors for erectile dysfunction

(sildenafil [Viagra])

This is a major focus of drug development

ARE DRUGS THAT INHIBIT SIGNAL

TRANSDUCTION PROTEINS

CLINICALLY USEFUL?


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HOW DO DRUGS WORK BY ACTIVATING

ENDOGENOUS PROTEINS?

Agonists of Cell Surface Receptors(e.g. alpha-agonists, morphine agonists)

Agonists of Nuclear Receptors(e.g. HRT for menopause, steroids for inflammation)

Enzyme Activatorse.g. nitroglycerine (guanylyl cyclase), pralidoxime

Ion Channel Openerse.g. minoxidil (K) and alprazolam (Cl)


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HOW DO CHEMICALS WORK BY ACTIVATING


KEY CONCEPTS:

Cell surface receptors exist to transmit chemical signals from

the outside to the inside of the cell.

Some chemicals bind to cell surface receptors and

trigger a response.

Chemicals in this group are called receptor agonists.

Some agonists are actually the endogenous chemical signal,

whereas other agonists mimic endogenous chemical signals.


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HOW DO CHEMICALS WORK BY

UNCONVENTIONAL MECHANISMS OF ACTION?

Disrupting of Structural Proteinse.g. vinca alkaloids for cancer, colchicine for gout

Being Enzymes

e.g. streptokinase for thrombolysis

Covalently Linking to Macromoleculese.g. cyclophosphamide for cancer

Reacting Chemically with Small Moleculese.g. antacids for increased acidity

Binding Free Molecules or Atoms

e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)


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HOW DO DRUGS WORK BY UNCONVENTIONAL

MECHANISMS OF ACTION (Continued)?

Being Nutrientse.g. vitamins, minerals

Exerting Actions Due to Physical Propertiese.g. mannitol (osmotic diuretic), laxatives

Working Via an Antisense Actione.g. fomivirsen for CMV retininitis in AIDS

Being Antigense.g. vaccines

Having Unknown Mechanisms of Actione.g. general anesthetics


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Characteristics of Drug-

Receptor Interactions

Chemical Bond: ionic, hydrogen,

hydrophobic, Van der Waals, and covalent.

Saturable

Competitive

Specific and Selective

Structure-activity relationships

Transduction mechanisms


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NH4+-CH2(n)-NH4

+


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Receptor Transduction

Mechanisms Ion channel linked receptors e.g. Ach nicotinic

(Na+) and GABA (Cl-)

Second messenger generation,

adenylate cyclase stimulation or inhibition - cAMP,

guanylate cyclase - cGMP,

phospholipase C - IP3, DAG

Some receptors are themselves protein kinases Intracellular receptors (e.g. corticosteroids, thyroid

hormone)


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k1

D + R DRk2

By Law of Mass Action: [D][R]K1= [DR]K2

Therefore K2

/K1

= Kd

= [D][R]/[DR]

If RT = total # of receptors, then

RT = [R] + [DR]

Replace [R] by (RT-[DR]) and rearrange: [DR] [D]

RT Kd + [D]=

OCCUPATION THEORY OF DRUG-

RECEPTOR INTERACTIONS

EFFECT

effect

Max. effect=


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Kd

effect [DR] [D]

Max. effect RT Kd + [D]

==When [D] = Kd[DR]

RT= 0.5

[D]

[DR]/ R

T

0 5 10 15 200.00

0.25

0.50

0.75

1.00


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Receptor Binding

The dose-response relationship (from C.D. Klaassen, Casarett and Doulls Toxicology, 5thed., New York: McGraw-Hill, 1996).

%B

ound

Concentration of Ligand

Kd


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[D] (concentration units)

[DR] /

RT

0.01 0.10 1.00 10.00 100.000.00

0.25

0.50

0.75

1.00

Kd=1

kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Receptor


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Competitive Noncompetitive

Types of Receptor Antagonists


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PARTIAL AGONISTS - EFFICACY


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[D] (concentration units)

%

Maxim

alEffec

t

0.01 0.10 1.00 10.00 100.00 1000.000.0

0.2

0.4

0.6

0.8

1.0

Partial agonist

Full Agonist

Partial agonist

PARTIAL AGONISTS EFFICACYEven though drugs may occupy the same # of receptors, the

magnitude of their effects may differ.


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HOW TO EXPLAIN EFFICACY?


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Drug (D)

Ri

DRi DRa

Ra

CONFORMATIONAL SELECTION

HOW TO EXPLAIN EFFICACY?

The relative affinity

Of the drug to either

conformation will

determine the effect

of the drug

R


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R

R1*

R2*

R3*

R R

R1*

R1*

R2*

R2*

R3*

R3*

From Kenakin, T. Receptor conformational induction versus selection: all part of the same energylandscape. TiPS 1996;17:190-191.

S R t


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Spare Receptors


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Receptor Regulation

Sensitization or Up-regulation

1. Prolonged/continuous use of receptor blocker

2. Inhibition of synthesis or release of

hormone/neurotransmitter - Denervation Desensitization or Down-regulation

1. Prolonged/continuous use of agonist

2. Inhibition of degradation or uptake of agonist

Homologous vs. Heterologous

Uncoupling vs. Decreased Numbers


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GRADED DOSE-

RESPONSE CURVE

ED50

ED50


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QUANTAL DOSE-

RESPONSE CURVE

Frequency

Distribution

Cumulative

FrequencyDistribution


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Morphine

Aspirin

THERAPEUTIC INDEX AN INDEX OF SAFETY


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Hypnosis Death


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Margin of Safety =LD1

ED99

ED50 A

ED99 A

LD1A


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Causes of Variability in Drug

Response

Those related to the biological system

1. Body weight and size2. Age and Sex

3. Genetics - pharmacogenetics

4. Condition of health5. Placebo effect


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Causes of Variability in Drug

Response Those related to the conditions of administration

1. Dose, formulation, route of administration.

2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy

3. Drug interactions:

chemical or physical;

GI absorption;

protein binding/distribution;metabolism (stimulation/inhibition);

excretion (ph/transport processes);

receptor (potentiation/antagonism);

changes in pH or electrolytes.

pharmacodynamics new

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