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USP-NF
- Combination of two official compendia-
- United States Pharmacopeia-National Formulary
- Contains standards for medicine,dosage form, drug substances, excipients, medical devices and dietary supplements.
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Pharmacopeia
- Official compendium
- Uniform Standards to ensure quality of drugs and product.
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Who publishes International Pharmacopeia?
World Health Organization (WHO)
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HPUS
- Homeopathic Pharmacopeia of United States
- "like cures like"
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USP-DI
- United States Pharmacopeia-Drug Information.
- Publication and computer database with info on pharmaceutical products: indications, pharmacology, side effects, dosage help for health care professionals.
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FDA
- Food and Drug Administration;
- Responsible for drug regulation and control.
- Safety and Effectiveness.
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Sulfanilamide
Elixir prepared with diethylene glycol (toxic agent in antifreeze)
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Thalidomide
- Sedative and Tranquilizer during pregnancy caused phocomelia (short/missing limbs)
- Now treats leprosy
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INDA
- Investigational New Drug Application.
- Permission to test on Humans.
- FDA 30 days to evaluate drug.
- Sponsor proposes protocol-"plan of study"
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OTC
- Over the Counter
- safe enough for use by the layman for self treatment; no presciption required.
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Legend Drug
- Presciption only
- Too dangerous for self medication and useful only after expert diagnosis; "caution: federal prohibits dispensing without presciption."
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Schedule Drug
- 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"
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How are new drugs discovered?
- Randomly.
- Many years of tireless pursuit: -targeted screening
- -molecular modification
- -mechinism-based drug design
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Sources of New Drugs
- Botanical:Taxol
- Animal:Hormones, Serum, vaccines, tissue cultures
- Chemical: synthetic/semi synthetic
- Genetic engineering:
- -recombinant DNA-humulin insulin
- -monoclonal antibody-xolair
- -gene therapy-stem cells
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Goal Drug
- The ideal drug
- Full theraputic efficacy and no side effects.
- Dose not exist!
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Lead compound
- Protocol compound with a fundamental desired pharmcological biologic activity.
- Can be modified.
- Ex: penicilin---Librium (antianxiety)
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Prodrug
- Inactive substance requiring metabolic transformation to become pharmacologically active.
- Designed for solubility, absorption, biostability, prolonged release.
- Ex: Enalapril---hydrolysis---Enalaprilat
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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
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Empirical Formula
number if atoms and their relationship
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Systematic Name
relative location of each atom (chemical name)
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Nonpropriety Name
- Generic name
- given by USAN-united states adopted name
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Propriety Name
- Brand/Trademark Name
- given to manufacturers
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NDC?
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)
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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"
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Components in Drug Development?
- Complex
- Time consuming
- Word done in diverse fields
- Disease process research
- Money
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Animal Studies
- short term
- toxic side effect
- safe dosage range
- if too toxic, abandoned
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IRB
- Institutional Review Board
- "ethics committee"
- responsible to review and monitor biomedical research
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Orphan Drug
A drug for rare disorders with no known cure.
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When may foreign studies be used?
- if well designed
- well conducted
- qualified investigators
- Ethical principles applied
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clinical trials should include?
- randomization
- double blind
- placebo control
- Controlled: age, gender,disease state
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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
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Phase 2 clinical trials
- up to several hundred people with disease
- determine drug effectiveness
- clearer picture of side effects/risks
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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
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NDA
- New Drug Application
- Composition
- Toxicology
- Behavior in Body
- Results of all testing
- Manufacturing process
- Labeling
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cGMP
- 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.
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cGCP
Current Good Compounding Practice
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Labeling requirement
All drug products distributed in US must meet labeling requirement.
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How long must records be maintainted for?
Maintained 1 year following expiration date of product batch...needed if recalled.
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NABP
- National Association of Boards of Pharmacy
- The good compounding practices applicable to state licensed pharmacist.
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Pharmaceutic
excipeint or inactive ingredient
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What is the reason for dosage forms?
- appropriate dose
- administration by different routes
- protection of drug
- taste/odor
- age of patient
- safety
- liquid products of substances that are insoluble or unstable in desired vehicle
- rate controlled drug action
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phase rule
mixture of two solides=melt
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Polymorphism
crystal and amorphous
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How can you attain solubility?
- salt/ester form
- Particle size
- PH
- Co-solvents
- Dissolution:rate limiting step in absorption
- Membrane permeability-passive, active, facilitated
- Partition coefficient-ratio of lipid/water solubility
- PKa dissociation constant-degree of ionization
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What are destructive processes?
- Hydrolysis
- Oxidation
- Polymerization
- Decarboxylation
- Deamination
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Complexation
mixing drugs with other chemicals to help dissolve/ protect degradation of first pass ex: metals
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Micronization
reduce particle size
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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
- refrigeration
- pH control-buffering agent
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How can you reduce oxidization?
- Antioxidants
- Air replacement of airspace within container-adding nitrogen gas (inert)
- chelating agents:complexation of trace metals
- light resistant (opaque) container
- cool place
- pH control
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what percent can drug potency decrease by USDA?
10%
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rate reaction: zero order
drug loss independent of the concentration
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rate reaction: first order
drug loss directly proportional to concentration remaining with respect to time
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Q10 method
- shelf life estimation
- to assign expiration date of product
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pharmaceutic ingredients importance?
- establish primary features of product
- appearance: contribute to physical form
- texture
- stability
- taste-palatability=flavoring, sweetening agents,coloring agents, preservatives (glycerin)
- overall appearance
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ADME studies
- Absorption
- Distribution
- Metabolism
- Excretion
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pharmacokinetics
- study of the time course of drug concentration in the blood and tissues
- Study rate and extent of absorption and excretion
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Absorption (DDWD)
- 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
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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.
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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
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Passive diffusion
- ficks first law
- driven by concentration gradient
- difference in drug concentration on both sides of the membrane
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partition coefficient
measurement of solubility of lipid/water solubility
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Active transport
against concentration gradient
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facilitated diffusion
similar to active but driven by concentration gradient
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Bioavailability
rate and extent of absorption and availability of drug at the site of action
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Bioequivalence
- 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.
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cross over design study
Tablet to liquid
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orange book
apporved drug products with therapeutic equivalence evaluations, published and updates by FDA.
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cMAX
maximum drug concentration in blood
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Tmax
time of maximum concentration
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AUC
area under the curve (blood/serum concentration time)
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MTC
minimal toxic concentration
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MEC
minimal effective concentration
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Main routes of Drug Administration?
- Oral
- Sublingual
- Parenteral: IV, IM, SC, ID, etc
- Transdermal,Epicutaneous (topical)
- Intraocular, intranasal, intra-aural
- Intrarespiratory
- Rectal, Vaginal, urethral
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Unbound drug
- active
- free to leave the circulation for tissues and cellular sites
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Factors influencing metabolism
- Species
- Age
- Diet
- Disease State
- Other drugs
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Excretion
- termination of drugs activity and presence in the body
- Kidney #1 organ to get rid of drugs
- Bile
- GI
- Lungs
- Sweat glands
- Saliva
- Breast milk
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Half life
- time required for a drugs blood concentration to decrease by half
- Help determine dosage regimen
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Clearance
- removal of drug from body
- hepatic clearance
- Renal clearance
- total body clearance
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