Bound

Site of ActionDosage EffectsPlasma

Concen.

Pharmacokinetics Pharmacodynamics

Bound Free Free Bound

LOCUS OF ACTION“RECEPTORS”

TISSUE RESERVOIRS

SYSTEMIC CIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION

WHY BE CONCERNED ABOUT HOW DRUGS WORK?

• FDA Approved and Unapproved Uses

• Interactions with Other Drugs

• Adverse Effects and Contraindications

AIDS MEMORIZATION OF:


• 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:


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

patient’s body.

AIDS PATIENT-DOCTOR RELATIONSHIP:

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

of the patient’s disease.


Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

PEACE OF MIND!

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 withendogenous proteins:

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

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

Definition of RECEPTOR:

Most receptors are proteins that have undergone various post-translational modifications such as covalent

attachments of carbohydrate, lipid and phosphate.

A receptor that is embedded in the cell membrane and functionsto receive chemical information from the extracellular

compartment and to transmit that information to the intracellular compartment.

Definition of CELL SURFACE RECEPTOR:

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 the

receptor and cannot trigger a response.

• The compound is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.


Cell Membrane

Unbound Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment


Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor



Cellular Response


Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor



Bound Antagonist of Receptor (Drug)

Footnote:

Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent

endogenous 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)



Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Receptor



Bound Antagonist of Receptor

Allosteric Inhibitor

Active Receptor

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®])

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Unbound Endogenous Activator (Agonist) of Nuclear Receptor

Inactive Nuclear ReceptorIn Cytosolic Compartment


Nucleus

DNA

Inactive Nuclear ReceptorIn Nuclear Compartment



Nucleus

DNA

Modulation ofTranscription

Active Nuclear Receptor

Bound Endogenous Activator (Agonist) of Nuclear Receptor


Displaced Endogenous Activator (Agonist) of Nuclear Receptor


Nucleus

DNA

Bound Antagonist of Receptor (Drug)

Inactive Nuclear ReceptorIn Cytosolic Compartment

Inactive Nuclear ReceptorIn Nuclear Compartment

ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORSCLINICALLY USEFUL?

• Mineralocorticoid Receptor Antagonists for edema due toliver cirrhosis and for heart failure

(spironolactone [Aldactone®])


• Estrogen Receptor Antagonists for the prevention and treatment

of breast cancer (tamoxifen [Nolvadex®])

HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Inactive Enzyme

Substrate

Bound Enzyme Inhibitor (Drug)

HOW DO DRUGS WORK BY 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 theeffects of enzyme inhibitors.

ARE DRUGS THAT INHIBIT ENZYMESCLINICALLY 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®])

ARE DRUGS THAT BLOCK ION CHANNELS

CLINICALLY USEFUL?

• Calcium Channel Blockers (CCBs) for angina and high blood pressure

(amlodipine [Norvasc®]; diltiazem [Cardizem®])


• Sodium Channel Blockers to suppress cardiac arrhythmias

(lidocaine [Xylocaine®]; amiodarone [Cordarone®])

ARE DRUGS THAT INHIBIT TRANSPORTERSCLINICALLY 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®])

• 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?

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)

HOW DO CHEMICALS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

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.

HOW DO CHEMICALS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION?

• Disrupting of Structural Proteins e.g. vinca alkaloids for cancer, colchicine for gout

• Being Enzymese.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 Atomse.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

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 Antigens e.g. vaccines

• Having Unknown Mechanisms of Actione.g. general anesthetics

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

NH4+-CH2(n)-NH4

+

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)

k1D + R <=> DR

k2By Law of Mass Action: [D]•[R]•K1= [DR]•K2

Therefore K2 /K1= Kd = [D]•[R]/[DR]

If RT = total # of receptors, thenRT = [R] + [DR]

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

RT Kd + [D]=

OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS

EFFECT

effect

Max. effect=

Kd

effect [DR] [D]

Max. effect RT Kd + [D]

==When [D] = Kd

[DR] RT

= 0.5

[D]

[DR

]/RT

0 5 10 15 200.00

0.25

0.50

0.75

1.00

Receptor Binding

The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

% B

ound

Concentration of Ligand

Kd

[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=1kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Receptor

Competitive Noncompetitive

Types of Receptor Antagonists

[D] (concentration units)

% M

axim

al E

ffect

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.

Drug (D)

Ri

DRi DRa

Ra

CONFORMATIONAL SELECTION

HOW TO EXPLAIN EFFICACY?

The relative affinityOf the drug to either conformation will determine the effect of the drug

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 energy landscape. TiPS 1996;17:190-191.

Spare Receptors

Receptor Regulation• Sensitization or Up-regulation

1. Prolonged/continuous use of receptor blocker2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation

• Desensitization or Down-regulation1. Prolonged/continuous use of agonist2. Inhibition of degradation or uptake of agonist

Homologous vs. HeterologousUncoupling vs. Decreased Numbers

From Nies A and Speilberg SP. Principles of Therapeutics. in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th edition, 1996. Pages 43-62.McGraw Hill,

GRADED DOSE-RESPONSE CURVE

ED50

ED50

QUANTAL DOSE-RESPONSE CURVE

Frequency Distribution

CumulativeFrequency

Distribution

Morphine

Aspirin

THERAPEUTIC INDEX – AN INDEX OF SAFETY

Hypnosis Death

Margin of Safety = LD1

ED99

ED50AED99A

LD1A

Causes of Variability in Drug Response

Those related to the biological system1. Body weight and size2. Age and Sex3. Genetics - pharmacogenetics4. Condition of health5. Placebo effect

Causes of Variability in Drug Response

• Those related to the conditions of administration1. Dose, formulation, route of administration.2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy3. 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.

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