1. 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.

2. 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.

3. 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®])

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

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

6. 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.

7. 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®])

8. 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.

9. 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

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

11. 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.

12. 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.

13. 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®])

14. 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.

15. 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.

16. 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®])

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

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

19. 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.

20. 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®])

21. 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

22. 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

23. 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.

24. 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®])

25. 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

26. 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

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

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

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

30. 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)

31. 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®])

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

33. 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)

34. 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