1. 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

3. 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

4. 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
patient’s body.
A patient who understands his/her therapy is more inclined
to become an active participant in the management
of the patient’s disease.

5. WHY BE CONCERNED ABOUT HOW DRUGS WORK?
PEACE OF MIND!
Knowledge of how a drug works increases the therapist’s
confidence that the drug is being used appropriately.

6. 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

7. 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

8. 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 drug’s effect.
Most receptors are proteins that have undergone various
post-translational modifications such as covalent
attachments of carbohydrate,
lipid and phosphate.

9. 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.

10. 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

11. 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

12. 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

13. 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.

14. 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.

15. 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®])

16. 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.

17. 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

18. 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

19. 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

20. 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.

21. 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.

22. 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®])

23. HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Active Enzyme
Substrate
Product
Cellular Function

24. HOW DO DRUGS WORK BY INHIBITING ENZYMES?
Inactive Enzyme
Substrate
Bound Enzyme
Inhibitor (Drug)

25. 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.

26. 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®])

27. HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
Ions (e.g., Ca++, Na+, K+)
Open Ion Channel
Intracellular
Compartment
[Ions]
Cellular Response

28. 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

29. 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.

30. 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®])

31. Cellular Response HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane Impermeable Solute
Active Transporter
Membrane Impermeable Solute
Cellular Response
Intracellular
Compartment

32. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane
Impermeable Solute
Inactive Transporter
Drug that Inhibits Transporters
Membrane
Impermeable Solute
Intracellular
Compartment

33. 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.

34. 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®])

35. 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

36. 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

37. 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.

38. 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

39. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?
Agonists of Cell Surface Receptors
Agonists of Nuclear Receptors
Enzyme Activators
Ion Channel Openers

40. HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?
Extracellular
Compartment
Cell Membrane
Inactive Cell Surface Receptor
Intracellular
Compartment

41. 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

42. 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.

44. 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®])

45. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?
Inactive Nuclear Receptor
In Cytosolic Compartment
DNA
Nucleus
Intracellular
Compartment
Inactive Nuclear Receptor
In Nuclear Compartment

46. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?
Active Nuclear Receptor
Bound Exogenous Agonist
of Receptor (Drug)
DNA
Nucleus
Modulation of
Transcription
Intracellular
Compartment

47. 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.

49. 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
(hydrocortisone[Cortef®]; dexamethasone [Decadron®])

50. HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Inactive Enzyme
Substrate

51. HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Active Enzyme
Substrate
Product
Enzyme Activator
(Drug)
Cellular Function

52. 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.

53. 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®])

54. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Binding Site on Ion Channel
Ions (e.g., Ca++, Na+)
Closed Ion Channel
Binding Site on Ion Channel
Ions (e.g., K+)
Intracellular
Compartment

55. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Drug That Opens Ion Channel
Ions (e.g., Ca++, Na+, K+)
Open Ion Channel
Drug That Opens Ion Channel
[Ions]
Cellular Response
Intracellular
Compartment

56. 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.

57. ARE DRUGS THAT OPEN ION CHANNELS CLINICALLY USEFUL?
Some important examples:
Potassium Channel Openers for hair regrowth
(minoxidil [Rogaine®])
GABAAChloride Channel Openers for anxiety
(alprazolam[Xanax®]; midazolam [Versed®])

58. Disrupters of Structural Proteins Drugs that Are Enzymes
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

59. Drugs that Are Nutrients
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

60. DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS? Some important examples:
Vinca Alkaloids for cancer
(vincristine [Oncovin®]; vinblastine [Velban®])
Colchicine for gout

61. ARE SOME DRUGS ENZYMES? Some important examples:
Thrombolytic therapy for acute myocardial infarction
(alteplase [Activase®])

62. DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES?
Some important examples:
DNA alkylating agents for the treatment of cancer
(cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])

63. 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)

64. 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-α for rheumatoid arthritis
(infliximab [Remicade®]; etanercept [Enbrel®])

65. ARE SOME DRUGS NUTRIENTS? Some important examples:
Vitamins, minerals, lipids, carbohydrates, aminoacids

66. 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)

67. 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

68. ARE SOME DRUGS ANTIGENS? Some important examples:
Vaccines

69. IS THE MECHANISM OF ACTION OF SOME DRUGS UNKNOWN?
Some important examples:
Inhalation Anesthetics for general anesthesia
(Isoflurane [Forane®]; Sevoflurane [Ultane®]

70. HOW DO DRUGS WORK?
Now you know!!