Federal Pure Food and Drug Act – 1906 

Food must be free of adulterants (unwanted food additive, illicit drug, or poinson)

  Food, Drug and Cosmetic Act – 1938

• People died who took antibiotic, d/t  (filler) ingredients were toxic
• Required all new drugs undergo testing for toxicity

Kefauver-Harris Amendments – 1962

• Brought on by thalidomide – (European sedative), pregnant women & babies lacked legs/limbs
• Now require proof of effectiveness/safety

Controlled Substances Act – 1970

• 1^st law to strictly control manufacturing & dispense of drugs that have potential for abuse
• Classified Drug Schedules (I-V)

Orphan Drug Act – 1983

a drug (a drug for a disorder affecting fewer than 200,000 people in the United States) may sell it without competition for seven years. May get Tax incentives

1992 – fast track drugs that treat certain diseases 

For diseases like aids or cancers

Food and Drug Admin Modernization Act – 1997

• Added more disease that we could fast track
• Also had to do more drug testing on women and children
• Also have to notify people if company going to discontinue a drug

• Stages (preclinical/clinical)
• Incorporate (controls, placebo, blinding, randomization)
• Costly $$$$$

Limitations and challenges of the drug development process 

ü  Women – childbearing women excluded for fetal safety. Ths don’t know if beneficial/adverse effects would be same as men, if affect menstrual cycle, or if MEAD will be the same.

ü  Children – been excluded from trials, therefore there is little info on how kids will react to drugs. 

Preclinical testing of a drug

ü  Stages of drug development (remember costs are 200-800 million/drug)

ü  Preclinical testing (Animals) (1-5 years)

o   Parameters evaluated are

§  Toxicity

§  Pharmacokinetic (how it is MEAD)

§  Biological effects

Clinical Testing (Whole process 2-10 years)

Phase I

• Healthy adult volunteers (except antineplastic drugs)
• Evaluation metabolism, pharmacokinetics’, biological effects
• Determination of effects on humans
  • Toxicity, MEA, preferred route of admin, safe dose

Clinical Testing

Phase II

ü  Phase II (patients 500-5000, on drug 3-6 yr)

o   Small select group of patients to determine potential use of the drug with respect to the disease

o   Compare results with Phase I for

§  Therapeutic utility and dosage range in diseased patients

Clinical Testing

Phase III

ü  Phase III (patients 500-5000, on drug 3-6 yr)

o    after effective dose range estb’l, drug studied using large # of pts, multicenters using below techniques…

§  Double Blind

§  Crossover

§  Matched Adult Subjects

o   Apply for FDA for “New Drug Application”

Clinical Testing

Phase IV

• Post MARKETING Surveillance
• With conditional approval form FDA, drug company controls release of the drug
• Can be used by general population
• New side effects may be discovered
• Voluntary reporting by health professionals is essential

ü  Chemical: Description and nomenclature of chemistry

ü  Generic (Non Propriety Name): assigned by the U.S. Adpobted Names Council or Pharmocopoeia (one generic name/drug)

ü  Trade (Propriety or Brand Name) : intended to make it easier for consumer/providers to remember, given by the company

o   1 drug has 1 generic name, but multiple trade names

Prescription vs non-prescription

ü  Prescription (need a physician order)

ü  Non-prescription (Over The Counte)

o   most illness (60% to 95%) initial therapy consists of self-care, including self med with an OTC drug

o   The average home medicine cabinet contains 24 OTC preperations

Controlled vs non-controlled substances

ü  •Non-controlled substances

ü  •Controlled substances

o   Prescription drugs with high potential for drug dependence, abuse, ie barbiturates, morphine, amphetamines

o   These drugs are classified in schedule 1-5

o   Highest pain meds we use are schedule 2

o   Lower you go down (ie 5) hardly ever abusive

Advantages & disadvantages of oral medication packaging

Tablets

ü  Pro – can be delivered orally

ü  Cons – fillers can cause difference in disintegration, thus bioavailability. 2 tablets w/same amt of drug can differ in intensity/onset of effect

ü  Pro – coating allows dissolution in intestine not the stomach

ü  Cons – absorption can be even more variable than tablets, because gastric emptying can vary from minutes to 12 hours, coating can even allow NO dissolution

Advantages & disadvantages of oral medication packaging

Sustained Release

ü  Pro – spheres dissolve at various rates, allows for reduced # of daily doses

ü  Cons – high $$$$ and potiential variable absporption

 2 tablets contain same amount of identical chemical coupound

Bioavailability: 

Preparations are considered equal in bioavailability if the drug they contain is absorbed at the same rate and to the same extent.

Absorption 

Ways to prevent absorption of oral meds

ü  Induce Vomiting

ü  Use of activated charcoal

ü  Induce catharsis 

-liver may produce significant decrease in amount of circulating drug due to liver biotransformation (Hepatic metabolism) – Extensive first pass effect

o   enteral route (GI tract) stomach, small intestine, large intestine must go through the LIVER via the hepatic portal vein before getting to the heart to circulate

Need to be aware of how dosing changes in regards to route (higher orally, lower IV)

• Rectal
• IV
• Intramuscular
• Inhalation
• Sublingual
• Buccal

Routes of Administration (pros/cons)

PO, Oral

ü  Pros:

o   Oldest, safest, most convenient, most economical

o   Usual site of absorption is the small intestine - only a few drugs including ethanol are significantly absorbed from the stomach

ü  Cons:

o   Emesis: d/t irritant chemicals (take w/food to decrease irritation)

o   Variability: absorption highly variable

o   Destruction: (insulin destructed by enzymes)

o   Poor Absorption: d/t food interaction

o   Full Stomach: slow absorption= delayed emptying, decrease delivery to SI

o   Cooperation: patient has to be able to swallow

ü  Pros

o   Rapid

o   Bypass hepatic destruction (a.k.a first pass) – utilizes venous return via veins to the heart rather than portal circulation to the liver

ü  Cons: Not useful for irritating/unpleasant tasting drugs

ü  Pros:

o   Local and Systemic effects (transdermal adhesive patches)

o   Topical drugs can utilize mucosal membranes as a site of administration

ü  Cons: Irritating to the skin

ü  Pros

o   Useful when patient vomiting or unconscious, or pt has colon disease

o   By pass portal ciculation

ü  Cons:  Irritation of rectal mucosa; irregular/incomplete absorption, stigma

ü  drug admin into IV (usually small amount ie pain killer) via IV

ü  Pros: Rapid & uniform absorption

ü  Cons: No time to reverse, Less amount of time to dilute into the plasma

o   IV drugs given too rapidly can result in è Uncessary side effects

Routes of Administration

IM, IV, Sub Q

ü  Pros: More rapid and uniform absorption (is 100%)

o   Better/accurate dosage

o   Use in unconscious/uncooperative patient

o   Can use large volumes of fluid

o   Can give drugs which are irritants

ü  Cons

o   High Cost, Difficulty & Inconvenience (special training) of Administration

o   Irreversibility (inject slowly if possible)

o   Fluid Overload (bad for pt with HTN, ESRD, CHF)

o   Infection (from contaminated drug or infection of site)

Embolism (injure venous wall causing a thrombus (clot))

Routes of Administration (Pros/Cons)

IV Piggyback

ü  drug (in a separate mini bag) diluted in a prescribed amount of fluid and infused IV over an appropriate amount of time (15-30 min), Frequently used to administer IV antibiotics

ü  Pros: Uniform absorption

ü  Cons: IV drugs given too rapidly can result in è Uncessary side effects

Route of Administration (Pros/Cons)

Epidural

ü  NOT IV,  above the dura, NOT into CSF, affects spinal roots as they exit/enter dural

ü  Not IV, but used to administer meds straight into the brain

ü  Pros: avoid the blood brain barrier, direct ot CSF

ü  Pro: Large surface area to administer to & is extremely vascularized

o   Systemic achieve effects (ie give O2, or anesthesia)

ü  Con: hard to regulate in those that smoke (thickened scarring)