Bound

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LOCUS OF ACTION RECEPTORS
TISSUE RESERVOIRS
Bound
Free
Free
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ABSORPTION
EXCRETION
Free Drug
SYSTEMIC CIRCULATION
Bound Drug
BIOTRANSFORMATION
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
AIDS MEMORIZATION OF

• FDA Approved and Unapproved Uses
• Interactions with Other Drugs
• Adverse Effects and Contraindications

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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
AIDS EVALUATION OF MEDICAL LITERATURE

• Better assessment of new modalities for using
  drugs
• Better assessment of new indications for drugs
• Better assessment of new concerns regarding
  risk-benefit

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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
AIDS PATIENT-DOCTOR RELATIONSHIP
The patient has more respect for and trust in a
therapist who can convey to the patient how the
drug is affecting the patients body.
A patient who understands his/her therapy is more
inclined to become an active participant in the
management of the patients disease.
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WHY BE CONCERNED ABOUT HOW DRUGS WORK?
PEACE OF MIND!
Knowledge of how a drug works increases the
therapists confidence that the drug is being
used appropriately.
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HOW DO DRUGS WORK?
Most work by interacting with endogenous proteins

• Some antagonize, block or inhibit endogenous
  proteins
• Some activate endogenous proteins
• A few have unconventional mechanisms of action

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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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Definition of RECEPTOR
A macromolecular component of the organism that
binds the drug and initiates its effect.
Most receptors are proteins that have undergone
various post-translational modifications such as
covalent attachments of carbohydrate, lipid and
phosphate.
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Definition of CELL SURFACE RECEPTOR
A receptor that is embedded in the cell membrane
and functions to receive chemical information
from the extracellular compartment and to
transmit that information to the intracellular
compartment.
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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 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.

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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
Extracellular Compartment
Unbound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Inactive Cell Surface Receptor
Intracellular Compartment
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
Extracellular Compartment
Bound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Active Cell Surface Receptor
Intracellular Compartment
Cellular Response
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
Displaced Endogenous Activator (Agonist) of
Receptor
Extracellular Compartment
Bound Antagonist of Receptor (Drug)
Cell Membrane
Inactive Cell Surface Receptor
Intracellular Compartment
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
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)
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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
Displaced Endogenous Activator (Agonist) of
Receptor
Extracellular Compartment
Bound Antagonist of Receptor
Cell Membrane
Inactive Receptor
Active Receptor
Intracellular Compartment
Allosteric Inhibitor
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ARE DRUGS THAT ANTAGONIZE CELL SURFACE
RECEPTORS CLINICALLY USEFUL?
Some important examples

• Angiotensin Receptor Blockers (ARBs) for high
  blood pressure,
• heart failure, chronic renal insufficiency
• (losartan Cozaar valsartan Diovan)

• Beta-Adrenoceptor Blockers for angina,
  myocardial infarction,
• heart failure, high blood pressure, performance
  anxiety
• (propranolol Inderal atenolol Tenormin)

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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR
RECEPTORS?
Unbound Endogenous Activator (Agonist) of
Nuclear Receptor
Inactive Nuclear Receptor In Cytosolic Compartment
DNA
Nucleus
Intracellular Compartment
Inactive Nuclear Receptor In Nuclear Compartment
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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR
RECEPTORS?
Active Nuclear Receptor
Bound Endogenous Activator (Agonist) of Nuclear
Receptor
DNA
Nucleus
Modulation of Transcription
Intracellular Compartment
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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR
RECEPTORS?
Displaced Endogenous Activator (Agonist) of
Nuclear Receptor
Bound Antagonist of Receptor (Drug)
Inactive Nuclear Receptor In Cytosolic Compartment
DNA
Nucleus
Intracellular Compartment
Inactive Nuclear Receptor In Nuclear Compartment
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ARE DRUGS THAT ANTAGONIZE NUCLEAR
RECEPTORS CLINICALLY USEFUL?
Some important examples

• 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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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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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate
Product
Cellular Function
Inactive Enzyme
Substrate
Bound Enzyme Inhibitor (Drug)
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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 the
• effects of enzyme inhibitors.

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ARE DRUGS THAT INHIBIT ENZYMES CLINICALLY USEFUL?
Some important examples

• Cyclooxygenase Inhibitors for pain relief,
• particularly due to arthritis (aspirin ibuprofen
  Motrin)

• HMG-CoA Reductase Inhibitors for
  hypercholesterolemia
• (atorvastatin Lipitor pravastatin
  Pravachol)

• Angiotensin Converting Enzyme (ACE) Inhibitors
  for
• high blood pressure, heart failure, and
• chronic renal insufficiency
• (captopril Capoten ramipril Altace)

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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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ARE DRUGS THAT BLOCK ION CHANNELS CLINICALLY
USEFUL?
Some important examples

• 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)

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ARE DRUGS THAT INHIBIT TRANSPORTERS CLINICALLY
USEFUL?
Some important examples

• Selective Serotonin Reuptake Inhibitors (SSRIs)
  for the
• treatment of depression
• (fluoxetine Prozac fluvoxamine Luvox)

• Inhibitors of Na-2Cl-K Symporter (Loop
  Diuretics) in
• renal epithelial cells to increase urine and
  sodium
• output for the treatment of edema
• (furosemide Lasix bumetanide Bumex)

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ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION
PROTEINS CLINICALLY USEFUL?
Some important examples

• 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

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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 Activators
• e.g. nitroglycerine (guanylyl cyclase),
  pralidoxime
• Ion Channel Openers
• e.g. minoxidil (K) and alprazolam (Cl)

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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.

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HOW DO CHEMICALS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION?

• Disrupting of Structural Proteins
• e.g. vinca alkaloids for cancer, colchicine for
  gout
• Being Enzymes
• e.g. streptokinase for thrombolysis
• Covalently Linking to Macromolecules
• e.g. cyclophosphamide for cancer
• Reacting Chemically with Small Molecules
• e.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 Nutrients
• e.g. vitamins, minerals
• Exerting Actions Due to Physical Properties
• e.g. mannitol (osmotic diuretic), laxatives
• Working Via an Antisense Action
• e.g. fomivirsen for CMV retininitis in AIDS
• Being Antigens
• e.g. vaccines
• Having Unknown Mechanisms of Action
• e.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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OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS
k1 D R ltgt DR k2 By Law of Mass
Action DRK1 DRK2 Therefore K2 /K1 Kd
DR/DR If RT total of receptors,
then RT R DR Replace R by (RT-DR)
and rearrange
EFFECT
DR D RT
Kd D
effect


Max. effect
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effect DR D
Max. effect RT Kd D
When D Kd DR RT


0.5
1.00
0.75
T
DR/R
0.50
0.25
0.00
0
5
10
15
20
D
Kd
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Receptor Binding
Bound
Kd
Concentration of Ligand
The dose-response relationship (from C.D.
Klaassen, Casarett and Doulls Toxicology, 5th
ed., New York McGraw-Hill, 1996).
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Compounds Have Different Affinities for the Same
Receptor
1.00
Kd0.5
Kd1
kd5
0.75
T
DR/R
0.50
0.25
0.00
0.01
0.10
1.00
10.00
100.00
D
(concentration units)
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Types of Receptor Antagonists
Competitive
Noncompetitive
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PARTIAL AGONISTS - EFFICACY Even though drugs may
occupy the same of receptors, the magnitude of
their effects may differ.
Full Agonist
1.0
Partial agonist
0.8
0.6
Partial agonist
Maximal Effect
0.4
0.2
0.0
0.01
0.10
1.00
10.00
100.00
1000.00
D
(concentration units)
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HOW TO EXPLAIN EFFICACY?
Drug (D)
The relative affinity Of the drug to either
conformation will determine the effect of the drug
Ri
Ra
DRi
DRa
CONFORMATIONAL SELECTION
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R
R2
R1
R3
R2
R1
R
R
R2
R1
R3
R3
From Kenakin, T. Receptor conformational
induction versus selection all part of the same
energy landscape. TiPS 199617190-191.
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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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From Nies A and Speilberg SP. Principles of
Therapeutics. in Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 9th
edition, 1996. Pages 43-62.McGraw Hill,
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ED50
GRADED DOSE-RESPONSE CURVE
ED50
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Cumulative Frequency Distribution
QUANTAL DOSE-RESPONSE CURVE
Frequency Distribution
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Morphine
Aspirin
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THERAPEUTIC INDEX AN INDEX OF SAFETY
Death
Hypnosis
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ED99A
ED50A
LD1A
LD1
Margin of Safety
ED99
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Causes of Variability in Drug Response

• Those related to the biological system
• 1. Body weight and size
• 2. Age and Sex
• 3. Genetics - pharmacogenetics
• 4. Condition of health
• 5. 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.