HOW DO DRUGS WORK?

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HOW DO DRUGS WORK?
2
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 drugs work by interacting with endogenous
proteins

• Some drugs antagonize, block or inhibit
  endogenous proteins
• Some drugs activate endogenous proteins
• A few drugs 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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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
Definition of RECEPTOR
A macromolecular component of the organism that
binds the drug and initiates the drugs 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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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE
RECEPTORS?
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?
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. However, antagonists may bind to
remote site on receptor and cause allosteric
effects that displace endogenous agonist or
prevent endogenous agonist from activating
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 drugs bind to cell surface receptors, yet
  do not activate
• the receptors to trigger a response.
• When cell surface receptors bind the drug
  molecule,
• the endogenous chemical cannot bind to the
• receptor and cannot trigger a response.
• The drug is said to antagonize or block the
  receptor and
• is referred to as a receptor antagonist.

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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?
Definition of NUCLEAR RECEPTOR
A receptor that exists in the intracellular
compartment and upon activation binds to
regulator regions in the DNA and modulates gene
expression.
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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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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR
RECEPTORS?
Footnote Most antagonists attach to binding
site on receptor for endogenous agonist and
sterically prevent endogenous agonist from
binding. However, antagonists may bind to
remote site on receptor and cause allosteric
effects that displace endogenous agonist or
prevent endogenous agonist from activating
receptor.
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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR
RECEPTORS? KEY CONCEPTS

• Nuclear receptors exist to mediate the effects
  of intracellular,
• endogenous chemicals on gene expression.
• Some drugs bind to nuclear receptors, yet do not
  activate
• the receptors to translocate to the nucleus, bind
  DNA
• and alter gene expression.
• When nuclear receptors bind the drug molecule,
• the endogenous chemical cannot bind to the
• receptor and cannot alter gene expression.
• The drug is said to antagonize or block the
  receptor and
• is referred to as a receptor antagonist.

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ARE DRUGS THAT ANTAGONIZE NUCLEAR
RECEPTORS CLINICAL 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 WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate
Product
Cellular Function
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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
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 WORK BY BLOCKING ION CHANNELS?
Ions (e.g., Ca, Na, K)
Open Ion Channel
Intracellular Compartment
Ions
Cellular Response
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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Ions (e.g., Ca, Na)
Blocked Ion Channel
Drug that Blocks Ion Channels
Ions (e.g., K)
Intracellular Compartment
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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? KEY
CONCEPTS

• Ion channels allow ions to transverse the cell
  membrane
• through a pore and down an electrochemical
  gradient.
• Some drugs bind to ion channels and physically
• block the pore or cause an allosteric change
• that closes the pore.
• Changes in the intracellular concentration of
  ions mediates
• the effects of inhibitors of ion channels.

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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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HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane Impermeable Solute
Active Transporter
Membrane Impermeable Solute
Cellular Response
Intracellular Compartment
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HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane Impermeable Solute
Inactive Transporter
Drug that Inhibits Transporters
Membrane Impermeable Solute
Intracellular Compartment
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HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS? KEY
CONCEPTS

• Transporters bind to and shuttle membrane
  impermeable
• solutes across the cell membrane.
• Some drugs bind to transporters and cause
  allosteric changes
• that prevent proper functioning of the
  transporters.
• Changes in the intracellular concentration of
  specific solutes mediates
• the effects of inhibitors of transporters.

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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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HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS? (Some overlap with enzyme
inhibitors)
Extracellular Compartment
Bound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Active Cell Surface Receptor
Intracellular Compartment
Multiple Signal Transduction Proteins (each is a
potential drug target)
Cellular Response
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HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS? (Some overlap with enzyme
inhibitors)
Extracellular Compartment
Bound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Active Cell Surface Receptor
Intracellular Compartment
Blockade or Augmentation of Signal Transduction
Pathway by Drug
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HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS? KEY CONCEPTS

• Signal transduction proteins transmit a chemical
  signal
• from a receptor to the final biological target.
• Some drugs bind to and inhibit key signal
  transduction proteins.
• Inhibition of key signal transduction proteins
  may block or
• augment the signal transduction pathway and this
• mediates the effects of the drug.

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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
• Agonists of Nuclear Receptors
• Enzyme Activators
• Ion Channel Openers

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HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE
RECEPTORS?
Extracellular Compartment
Cell Membrane
Inactive Cell Surface Receptor
Intracellular Compartment
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HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE
RECEPTORS?
Extracellular Compartment
Bound Exogenous Agonist of Receptor (Drug)
Cell Membrane
Active Cell Surface Receptor
Intracellular Compartment
Cellular Response
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HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE
RECEPTORS?
Footnote Most agonists attach to binding site
on receptor for endogenous agonist and trigger a
response. However, agonists may bind to remote
site on receptor and cause allosteric effects
that increase the ability of an
endogenous agonist to bind to or activate the
receptor.
43
HOW DO DRUGS 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 drugs bind to cell surface receptors and
  trigger a response.
• Drugs in this group are called receptor
  agonists.
• Some drug agonists are actually the endogenous
  chemical signal,
• whereas other drug agonists mimic endogenous
  chemical signals.

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ARE DRUGS THAT ACTIVATE CELL SURFACE
RECEPTORS CLINICALLY USEFUL?
Some important examples

• Alpha1-Adrenoceptor Agonists for nasal congestion
  
• (oxymetazoline Afrin phenylephrine
  Neosynephrine)

• Opioid Receptor Agonists for analgesia
• (morphine meperidine Demerol)

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HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS?
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 ACTIVATING NUCLEAR RECEPTORS?
Active Nuclear Receptor
Bound Exogenous Agonist of Receptor (Drug)
DNA
Nucleus
Modulation of Transcription
Intracellular Compartment
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HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS?
Footnote Most agonists attach to binding site
on receptor for endogenous agonist and trigger a
response. However, agonists may bind to remote
site on receptor and cause allosteric effects
that increase the ability of an
endogenous agonist to bind to or activate the
receptor.
48
HOW DO DRUGS WORK BY ACTIVATING NUCLEAR
RECEPTORS? KEY CONCEPTS

• Nuclear receptors exist to mediate the effects
  of intracellular,
• endogenous chemicals on gene expression.
• Some drugs bind to nuclear receptors and trigger
  a response.
• Drugs in this group are called receptor
  agonists.
• Some drug agonists are actually an endogenous
  chemical,
• whereas other drug agonists mimic an endogenous
  chemical.

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ARE DRUGS THAT ACTIVATE NUCLEAR
RECEPTORS CLINICALLY USEFUL?
Some important examples

• Estrogen Receptor Agonists for hormone
• replacement therapy in postmenopausal
• women (conjugated equine estrogens Premarin)

• Glucocorticoid Receptor Agonist for inflammation
  
• (hydrocortisoneCortef dexamethasone
  Decadron)

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HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Inactive Enzyme
Substrate
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HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Active Enzyme
Substrate
Product
Enzyme Activator (Drug)
Cellular Function
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HOW DO DRUGS WORK BY ACTIVATING ENZYMES? KEY
CONCEPTS

• Enzymes catalyze the biosynthesis of products
  from substrates.
• Some drugs bind to enzymes and increase their
  enzymatic activity.
• Increased biosynthesis of product mediates the
• effects of enzyme activators.

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ARE DRUGS THAT ACTIVATE ENZYMES CLINICALLY USEFUL?
Some important examples

• Activators of Guanylyl Cyclase for angina
• (nitroglycerin isosorbide dinitrate Isordil)

• Reactivators of Cholinesterase after poisoning
  with nerve gas
• or organophosphate pesticide
• (pralidoxime Protopam)

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HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca, Na)
Closed Ion Channel
Binding Site on Ion Channel
Ions (e.g., K)
Intracellular Compartment
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HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca, Na, K)
Open Ion Channel
Drug That Opens Ion Channel
Ions
Cellular Response
Intracellular Compartment
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HOW DO DRUGS WORK BY OPENING ION CHANNELS? KEY
CONCEPTS

• Ion channels allow ions to transverse the cell
  membrane
• through a pore and down an electrochemical
  gradient.
• Some drugs bind to ion channels and
  allosterically open
• the ion channel or allosterically render the
• channel more readily opened by
• other endogenous chemicals.
• Changes in the intracellular concentration of
  ions mediates
• the effects of drugs that open ion channels.

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

• Potassium Channel Openers for hair regrowth
• (minoxidil Rogaine)

• GABAAChloride Channel Openers for anxiety
• (alprazolamXanax midazolam Versed)

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HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS
OF ACTION?

• Disrupters of Structural Proteins
• Drugs that Are Enzymes
• Drugs that Covalently Link to Macromolecules
• Drugs that React Chemically with Small Molecules
• Drugs that Bind Free Molecules or Atoms

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HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS
OF ACTION (Continued)?

• Drugs that Are Nutrients
• Drugs that Exert Actions Due to Physical
  Properties
• Drugs that Work Via an Antisense Action
• Drugs that Are Antigens
• Drugs with Unknown Mechanisms of Action

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DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS?
Some important examples

• Vinca Alkaloids for cancer
• (vincristine Oncovin vinblastine Velban)

• Colchicine for gout

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ARE SOME DRUGS ENZYMES?
Some important examples

• Thrombolytic therapy for acute myocardial
  infarction
• (alteplase Activase)

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DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES?
Some important examples

• DNA alkylating agents for the treatment of
  cancer
• (cyclophosphamide Cytoxan chlorambucil
  Leukeran)

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DO SOME DRUGS REACT CHEMICALLY WITH SMALL
MOLECULES?
Some important examples

• Antacids that neutralize gastric acid
• (various preparations containing Al(OH)3, Mg(OH)2
  or CaCO3)

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DO SOME DRUGS BIND FREE MOLECULES OR ATOMS?
Some important examples

• Bile-Acid Sequestrants for hypercholesterolemia
• (cholestyramine Questran)

• Chelating Agents for heavy metal poisoning
• (dimercaprol penicillamine)

• Proteins that bind TNF-a for rheumatoid
  arthritis
• (infliximab Remicade etanercept Enbrel)

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ARE SOME DRUGS NUTRIENTS?
Some important examples

• Vitamins, minerals, lipids, carbohydrates,
  aminoacids

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DO SOME DRUGS EXERT ACTIONS DUE TO PHYSICAL
PROPERTIES?
Some important examples

• Bulk Laxatives for constipation
• (psyllium Metamucil polycarbophil Fibercon

• Osmotic Diuretics for edema
• (mannitol)

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DO SOME DRUGS WORK VIA AN ANTISENSE ACTION?
An important example

• Antisense Deoxyoligonucleotides for
  cytomegalovirus retinitis
• in patients with AIDS
• (fomivirsen Vitravene

• This is a major focus of drug development

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ARE SOME DRUGS ANTIGENS?
Some important examples

• Vaccines

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IS THE MECHANISM OF ACTION OF SOME DRUGS UNKNOWN?
Some important examples

• Inhalation Anesthetics for general anesthesia
• (Isoflurane Forane Sevoflurane Ultane

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HOW DO DRUGS WORK?
Now you know!!