Chapter 10 -- Drugs, Medicine, etc.

Start with Overview--

• history, new drugs, drug industry
• medicinal use (not drugs of abuse)

Historically, treatment of illness

• depends on theory of illness
• demons, devils, sin and possession
  • how do you drive out an evil spirit?
  • how do you avoid illness?
  • how do you diagnose illness?
• even today, treatment, diagnosis are theory driven
  • some peoples (and governments) refuse to connect AIDS and HIV
  • dispute about drug and alcohol addiction: illness, genetic origin, character weakness
• we recognize various types of disease
  • (fit model/theory)
  • (typically treated differently)
  • infections (bacteria, virus, protozoa, worms)
  • autoimmune diseases (allergies)
  • cancer (some may have an infectious origin)
  • failure of internal regulation
  • ....

• (one of the Monty Python crew, but a serious physician)

• Being ill is a conscious decision-- a state of mind
  • so a psychosomatic illness is a real illness
  • having a disease is different from a recognition of illness
• what if tests show...
  • high trigycerides, cholesterol, high blood pressure
    • no physical symptoms, hard to get motivated
    • higher probability of getting disease
    • are you ill? do you seek treatment?
  • not rare-- perhaps half of all medication today

Some primitive medical treatment works

• some traditional folk medicine works
• most disease is self limiting
  • (people get well despite the medicine)
  • placebo effect : (people with faith in a treatment do better)
    • [current study: placebo effect vastly overestimated]

Here, we focus on diseases treated with medicine

• chemical species-- digested, ingested, injected...

• Historically, drugs began as herbal / plant extracts (and a few minerals)
  • probably trial and error over a long period
  • established as folk lore
    • generally a mixture of myth and reality
    • often tied to shape, color-- not results
  • eating ____ is helpful in cases of _____.
  • people who eat __ rarely seem to be afflicted with ____.

Digitalis-- heart medicine

• extracted from foxglove (a flower)
• concentrated = lethal
• weaker = helpful
  • known to mediaeval healers

Poppy-- sap from flower bud

• extract with alcohol
• produces pain relief, sleep
• opium (a narcotic = sleep inducer)
  • US Law distorts word narcotic to mean a prohibited drug ; e.g., it classifies marijuana as narcotic
  • major species is morphine
  • can be isolated as a more potent drug
• Opium widely used in ancient Orient, then Europe (1200)
  • in wide unreagulated use though early 1900's
    • is effective (was only effective painkiller)
    • is addictive

Bark-- slippery elm tree

• rich in salicylic acid
• chewing bark = gentle pain killer
  • active part of North American Indian medical lore
• (aspirin = derivative, slowly releases salicylic acid)
• (cheaper to synthesize than to isolate)

Quinine--

• Bark of a tree can overcome malaria symptoms
• can isolate quinine as active component
  • (malaria was major disease in Wood Co Ohio through 1890's-- probably affected 70% population)

Worth Noting:very few medicines cure a disease

• some provide relief from symptoms
  • painkillers, antihistamines
• some counteract a medical condition
  • reduce cholesterol or high blood pressure
  • drugs that control stomach acid production
  • condition returns if discontinue medication
• some provide a needed species
  • insulin (diabetics who can no longer manufacture insulin)
  • vitamins (when diet is deficient)
• some drugs stimulate body's natural processes
  • other diabetes drugs regulate insulin production
• sometimes the body heals itself
  • drugs provide needed support during that process
  • ulcer of stomach may heal if acid level is kept low

few examples of real medicinal cures

• antibiotics
  • actually attack, kill bacteria causing a disease
  • true cure-- discontinue medication
  • penicillin was the first antibiotic (1940's)
  • really important-- minor wounds, simple diseases often became fatal
• antiviral agents
  • actually kill, cure
  • fewer good agents (no cure for cold, flu)
• some chemotherapy
  • can selectively attack and kill cancer cells
  • can lead to remission and even to cure
• a few chemical disease fighters
  • sulfa drugs (1930's)

Economics of the Drug Industry

• drugs that cure = 10-100 pills per patient
• drugs that stabilize = 300-600 pills/year for next 10-40 years per patient
  • which drug would you invest in?

• drugs that attack cancer, heart disease, obesity
  • (20-40% of population; wealthy societies)
• drugs for malaria (mainly in poor countries)
• drugs for "orphan diseases"
  • might only sell to 1000 patients a year
• drugs that fight hair loss, wrinkles
  • real market
• programs to convince people of new "diseases"
  • active youngsters, anxiety

pharmaceutical industry

Drug development is going through a dramatic change

• up to 20 years ago... drug development
  • look for chemicals in nature
    • test any local legends
    • (link plant and disease)
    • test as many exotic plants as possible
      • trail and error (many target diseases)
  • in laboratory, make many new chemicals
    • test for medical possibility
    • screen for any possible value
  • infect mice with diseases
    • test with chemicals
    • look for any evidence of effectiveness
    • 10 mice, 100 diseases, 100 test compounds
    • low probability of finding a hit
  • anything that's promising
    • make 100 chemical derivatives
    • test to see if they are any better
  • if encouraging
    • better tests with more mice
    • extend to other test animals
  • if really encouraging
    • gradually test on humans

• seldom a good idea of why one chemical works
  • if drug works, may find out why
  • seldom an effective way to plan testing

• Continual testing --
  • modify or approximate existing drugs: make analogs
  • partly to avoid patents
  • partly to improve properties
    • solubility, reduce body's excretion rate
    • actual effectiveness
    • reduce side effects
  • Heroin is a minor modification of morphine
    • developed as a more potent narcotic (good)
    • turned out to be more additive (bad)
    • had very brief medicinal use

Drug development now (1990's and beyond)

• generally focus first on the details of the disease
  • cause, initiation stages
  • try to find molecular basis
  • look for genetic basis of disease (if inherited)
  • look at the genetic makeup of infection agents
    • look for active site or receptor site
    • where the biological activity occurs or should occur

• target drug design at specific molecular activity
• more likely to make molecules on computer first
  • drug must be shaped to fit the active site
  • drug needs polarity to bind into the active site
• first screening tests likely to be in test tubes
  • phrase: in vitro (in glass)
  • used for nonanimal tests in general
• targeted at one specific disease
  • these tests can be done on 1-5 mg of substance
  • (animal tests might need 100-1000 grams)
    • in vitro testing (in living organisms)

• one treatment is to take species out of circulation
• another is to make it fight for sites where it works
  • design a drug to tie up that species
  • design a drug to ties up an active site
  • design drug to block synthesis site
    • (dosage to do it at appropriate level)
    • total blockage would be fatal

Go back to history and drug regulations

• medicinal formulations were done by
  • doctors
  • herb healers
  • businessmen
• often no real medicinal value
  • most patent medicines = alcohol, opium
    • rarely tested
    • many were potentially lethal
    • no laws that regulated such products
• in 1915 U. S. Introduced laws regulating foods , drugs
  • FDA (Food and Drug Administration)

• Requires evidence of effectiveness and safety
  • has very elaborate and detailed testing
  • considerable attention to side effects
  • regulates when human testing is allowed
• Must approve new drug before it can be sold
  • approval process may take 8-10 years
  • testing and approval costs many million $
• Continually monitors
  • can withdraw an approved drug
• Most drugs available by prescription
  • many are approved for OTC
  • Over the Counter sales
  • (self prescribed, administered)

Patents, Name Brands and Generic Drugs

• Inventor (of a drug) is issued a patent
  • for new material or a new use
  • has exclusive rights to make , sell that species for 20 years (was 17 years)

• if development is 8-12 years (typical)
  • patent is useful for 8-12 years
  • then, any other manufacturers can make the material
  • during this time, no direct competition exists
    • usually other comparable drugs exist

• Name Brands are Trademarked
  • holder of trademark: exclusive rights to the name
    • trade marks may be renewed indefinitely

• Generic Drugs
  • same chemical material as a name brand drug
  • FDA doesn't require new testing
  • FDA does regulate packaging, manufacture, quality testing
  • no large development cost
    • seldom possible until Patent expires
    • then no significant barriers

• Although complex, international patent and trademark treaties exist

Drug Prices are a serious issue

The most rapidly expanding cost in health care

• Most drugs during patent lifetime
  • sell for 10²-10⁶ times the cost of manufacture
  • cost of drugs sold must cover long development
  • successfully drugs must cover losses on false leads
  • (however, much of the expensive development is funded by the government)
    • Drug pricing typically varies by 2-100 fold as you cross national boundaries
    • Often half if you travel to Windsor

• Governments (US included) may force patent holder
  • to license patent to others (for reasonable fee)
  • to restore competition if none exists
  • to assure adequate production
    • (if patent holder can't)
    • US does this for truck engines, but not for drugs

• Serious Problems: AIDS drugs and Third World
  • Drug company prices are too high to be useful
  • Key drugs are patent protected
  • Several countries (Brazil, Thailand) have overridden Patents
    • allowed under international law
  • AIDS drugs available at manufacturing costs
• US has applied extensive pressure to protect drug company profits
  • Threatens total economic embargo
  • withdrawal of World bank development funds
  • Sometimes results in massive price breaks /donations by manufacturers

• Drug manufacturers prefer prescription approach
  • customers shop prices on OTC drugs
  • less likely to price shop prescription drugs

• often, try to get FDA OTC approval 1-2 years before patent expires
  • allows brand name to establish w/o competition

• interesting case now, others trying to convert several allergy drugs
  • from prescription to OTC
  • sponsored by Insurance Companies
  • opposed by manufacturers
    • know prices drop when product goes OTC