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- Combination of two official compendia-
- United States Pharmacopeia-National Formulary
- Contains standards for medicine,dosage form, drug substances, excipients, medical devices and dietary supplements.
- Official compendium
- Uniform Standards to ensure quality of drugs and product.
Who publishes International Pharmacopeia?
World Health Organization (WHO)
- Homeopathic Pharmacopeia of United States
- "like cures like"
- United States Pharmacopeia-Drug Information.
- Publication and computer database with info on pharmaceutical products: indications, pharmacology, side effects, dosage help for health care professionals.
- Food and Drug Administration;
- Responsible for drug regulation and control.
- Safety and Effectiveness.
Elixir prepared with diethylene glycol (toxic agent in antifreeze)
- Sedative and Tranquilizer during pregnancy caused phocomelia (short/missing limbs)
- Now treats leprosy
- Investigational New Drug Application.
- Permission to test on Humans.
- FDA 30 days to evaluate drug.
- Sponsor proposes protocol-"plan of study"
- Over the Counter
- safe enough for use by the layman for self treatment; no presciption required.
- Presciption only
- Too dangerous for self medication and useful only after expert diagnosis; "caution: federal prohibits dispensing without presciption."
- Drugs known to be subject to public abuse.
- Regulated by DEA Drug Enforcement Administration.
- 5 schedules: schedule 1: no medical use
- Product must include: DEA symbol "C"
- "Warning: may be habit forming"
How are new drugs discovered?
- Many years of tireless pursuit: -targeted screening
- -molecular modification
- -mechinism-based drug design
Sources of New Drugs
- Animal:Hormones, Serum, vaccines, tissue cultures
- Chemical: synthetic/semi synthetic
- Genetic engineering:
- -recombinant DNA-humulin insulin
- -monoclonal antibody-xolair
- -gene therapy-stem cells
- The ideal drug
- Full theraputic efficacy and no side effects.
- Dose not exist!
- Protocol compound with a fundamental desired pharmcological biologic activity.
- Can be modified.
- Ex: penicilin---Librium (antianxiety)
- Inactive substance requiring metabolic transformation to become pharmacologically active.
- Designed for solubility, absorption, biostability, prolonged release.
- Ex: Enalapril---hydrolysis---Enalaprilat
FDA's definition of NEW DRUG?
- new chemical entity
- new use, even if established drug
- new dosage schedule/regimen
- new route of administration
- new dosage form
- change in formulation
- change in proportion of each drug
number if atoms and their relationship
relative location of each atom (chemical name)
- Generic name
- given by USAN-united states adopted name
- Brand/Trademark Name
- given to manufacturers
First 4 numbers?
Next 4 numbers?
Last 2 numbers?
- National Drug Code. number assigned permanently to a drug product by the FDA.
- 1)indicates manufacturer (Labeler Code)
- 2)indicates drug formulation (Product Code)
- 3)indicates package size and type (Package Code)
5 Steps for New Drug Approval Process (FDA)
- 1)Biological Characterization of drug-pharmacology, metabolism, toxicology
- 2)Formulation Studies -dosage form design
- 3)INDA-reviewed and approved to test on humans-clinical investigation:3phases
- 4)NDA-review clinical trials
- 5)Post marketing surviellance-Medwatch "phase 4"
Components in Drug Development?
- Time consuming
- Word done in diverse fields
- Disease process research
- short term
- toxic side effect
- safe dosage range
- if too toxic, abandoned
- Institutional Review Board
- "ethics committee"
- responsible to review and monitor biomedical research
A drug for rare disorders with no known cure.
When may foreign studies be used?
- if well designed
- well conducted
- qualified investigators
- Ethical principles applied
clinical trials should include?
- double blind
- placebo control
- Controlled: age, gender,disease state
Phase 1 clinical trials
- up to 100 healthy people
- how drug absorbed, processed and excreted
- effects on organ and tissue
- initial side effects observed
- how much drug recieved
- how often drug should be recieved
- safety precautions
- 13-14 out of 20 pass
Phase 2 clinical trials
- up to several hundred people with disease
- determine drug effectiveness
- clearer picture of side effects/risks
Phase 3 clinical trials
- Up to several thousand patients with disease of different levels
- Long term studiy 3-6 years
- Final safety and efficacy
- find less common side effects
- optimum dosage
- 5-6 out of 20 pass
- New Drug Application
- Behavior in Body
- Results of all testing
- Manufacturing process
- Current Good Manufacturing Practice
- established by FDA
- Domestic and Foreign
- Provide for systems that assure proper design, monitoring and control of manufacturing processes and facilities.
Current Good Compounding Practice
All drug products distributed in US must meet labeling requirement.
How long must records be maintainted for?
Maintained 1 year following expiration date of product batch...needed if recalled.
- National Association of Boards of Pharmacy
- The good compounding practices applicable to state licensed pharmacist.
excipeint or inactive ingredient
What is the reason for dosage forms?
- appropriate dose
- administration by different routes
- protection of drug
- age of patient
- liquid products of substances that are insoluble or unstable in desired vehicle
- rate controlled drug action
mixture of two solides=melt
crystal and amorphous
How can you attain solubility?
- salt/ester form
- Particle size
- Dissolution:rate limiting step in absorption
- Membrane permeability-passive, active, facilitated
- Partition coefficient-ratio of lipid/water solubility
- PKa dissociation constant-degree of ionization
What are destructive processes?
mixing drugs with other chemicals to help dissolve/ protect degradation of first pass ex: metals
reduce particle size
How can you reduce Hydrolysis?
- waterproof protective coating
- use substitute of liquid: glycerin, alcohol, veggie oil
- preparation of suspension:non aqueous vehicle
- dry powder for reconsitution
- pH control-buffering agent
How can you reduce oxidization?
- Air replacement of airspace within container-adding nitrogen gas (inert)
- chelating agents:complexation of trace metals
- light resistant (opaque) container
- cool place
- pH control
what percent can drug potency decrease by USDA?
rate reaction: zero order
drug loss independent of the concentration
rate reaction: first order
drug loss directly proportional to concentration remaining with respect to time
- shelf life estimation
- to assign expiration date of product
pharmaceutic ingredients importance?
- establish primary features of product
- appearance: contribute to physical form
- taste-palatability=flavoring, sweetening agents,coloring agents, preservatives (glycerin)
- overall appearance
- study of the time course of drug concentration in the blood and tissues
- Study rate and extent of absorption and excretion
- Disintegration: tablet to granule
- Deaggregation: granule to fine particle
- Wetting: fine particle get wet in body fluid
- Dissolution: The rate limiting step fine particles diffuse into liquid
1st pass effect
- first pass metabolism
- phenomenon of drug metabolism wherby the concentration of a drug is greatly reduced before it reaches the systemic circulation.
Factors affecting rate of dissolution
- surface area: inversely proportional to particle size
- crytal vs. amorphous form (dissolve faster) exception penicillin crytal form more stable and chloremphenical most active in crystal form.
- salt forms
- state of hydration
- GI tract pH
- ficks first law
- driven by concentration gradient
- difference in drug concentration on both sides of the membrane
measurement of solubility of lipid/water solubility
against concentration gradient
similar to active but driven by concentration gradient
rate and extent of absorption and availability of drug at the site of action
- comparison of bioavailabilities
- Brand vs. Generic
- original product compared to new one must work in same manner
- rate and extent of absorption do not show significant differnece from that of the pioneer drug.
cross over design study
Tablet to liquid
apporved drug products with therapeutic equivalence evaluations, published and updates by FDA.
maximum drug concentration in blood
time of maximum concentration
area under the curve (blood/serum concentration time)
minimal toxic concentration
minimal effective concentration
Main routes of Drug Administration?
- Parenteral: IV, IM, SC, ID, etc
- Transdermal,Epicutaneous (topical)
- Intraocular, intranasal, intra-aural
- Rectal, Vaginal, urethral
- free to leave the circulation for tissues and cellular sites
Factors influencing metabolism
- Disease State
- Other drugs
- termination of drugs activity and presence in the body
- Kidney #1 organ to get rid of drugs
- Sweat glands
- Breast milk
- time required for a drugs blood concentration to decrease by half
- Help determine dosage regimen
- removal of drug from body
- hepatic clearance
- Renal clearance
- total body clearance