December 9

more chapter 10

• 10.5 Discussion of Aspirin
  • good example of how drug targets specific sites
  • good example of how one can design molecules to function as drugs
  • of course, aspirin use predates this information
    • aspirin was shown to work empirically
  • the details do not need to be remembered

• Body -- chemical messenger agents
  • that perform tasks :
• enzymes--catalysts
  • generally small proteins
    • make materials we need
    • remove materials we don't need
    • break down materials (food)
  • liver, for example, produces many essential
    • enzymes for digestive process
  • enzymes are amazingly selective

• class of compounds: hormones
  • primarily to control activity
    • middle management-- don't really do anything themselves
• secreted by glands: endocrines
  • endocrine is hormone secreting (circular definition)
  • high or low level lead to abnormal physiology
    • sometimes a metabolic illness
    • sometimes deliberate response to condition
• prostaglandins...
  • produce fever
    • (elevated temperature is a body defense mechanism)
  • produce swelling (change distribution of water)
  • cause blood vessels to dilate less
    • (reduce blood supply)
  • increase sensitivity of pain receptors
    • (more responsive)
  • increase stomach acidity
    • sounds bad, but often beneficial

• Aspirin and other NAIDS
  • Non-steroidal Anti Inflammatory Drugs
  • block specific enzyme (cyclooygenase, COX)
  • this enzyme gives rise to prostaglandins
  • blocking will reduce fever, swelling, pain
  • more soluble in membranes than rest of tissue
    • so aspirin selectively targets pain receptors

• Actually two (more) COX's
  • COX-1
    • (desirable: maintain kidney, protect stomach)
  • COX-2
    • (here: main cause of inflammation)
• All NAIDS are tough on stomach
  • the COX-2 inhibitors are much less so
  • equally effective with pain, swelling
  • (swelling often puts pressure on nerves--so reducing
  • inflammation could reduce pain)

Drugs and Active Site

• (see text, earlier notes)

• Mirror Images
  • many molecules exist in right-hand/left-hand models
  • 4 different atoms on a carbon do this
    • two forms, mirror images
    • chiral is word (ki-ral pronunciation)
  • Example: Cars US and GB
  • US cars have driver on the left
  • Gas fillers usually on that side
  • Streets place driver near center of road
  • Gas stations laid out to accommodate
  • Rotaries (traffic circles) are clockwise
  • Pedestrians look left for oncoming traffic
  • You should walk facing oncoming traffic
  • Same in England, but reversed
  • Right hand drive
  • Rotaries are counterclockwise
  • Pedestrians reminded to look to the right
• Both systems are equivalent
  • Equally good by themselves
  • No effect (fuel economy, pollution, road wear)
  • But not superimposable
  • US cars and drivers don't fit well in England
• Two molecules with mirror images
  • same bonds, same bond energies
  • same reactions, same heat evolved
  • most tests can't tell the difference
    • unless... reacting with other "chiral" molecules
    • might not fit if wrong mirror version
• Biologically, most enzymes, hormones, vitamins are chiral
  • wrong form is ineffective
  • known for probably 80-100 years

• Chemically important: make the form that works
• Most chemical reactions produce 50% of each type
  • Could make both, prescribe at double dose
  • (50% ineffective, but harmless)
• Nobel Prizes, 2001

Off label Use of Prescription Drugs

• Strange feature of the law on prescription drugs
• To be approved drug goes through severe testing
  • Must be safe (side effects must be minimal)
  • Must be effective in specific problem
  • Attention to drug interactions
    • (effect of combinations)
• Once approved, physician can prescribe
  • for any reason he/she chooses
  • in combination with other drugs
• Can be used for purposes
  • untested, no evidence of effectiveness
  • no evidence of drug compatibility
  • no evidence of safety in this application
• Subject to extreme malpractice only

Thalidomide Is An Informative Case Study

• This was a drug that looked promising
• especially useful in side effects of pregnancy
• In Europe, began use after moderate testing
• In US, the testing standards
  • were more severe and slower

• Thalidomide had a slow, but serious effect
  • It interfers with proper development of fetus
  • Typically, interrupted growth of the limbs
  • Leads to birth defects
  • Called teratogen