802 Exam 1

What was enacted because of the false therapeutic claims?

1912 Sherley Amendment was added to the 1906 Pure Food and Drug Act in response to false therapeutic claims.

How many potential rate limiting steps are there in drug bioavailability?

3

Describe the key traits of pharmacokinetic blood plasma profile.

?

Define the affinity constant.

??

Describe an IND.

A drug sponsor must file an IND with the FDA before a drug may be given to humans. IND approval allows the sponsor to initiate and carry out clinical investigation. IND approval allows the drug to be transported across state lines. Filing an IND protects rights and safety of subjects. Clinical protocol are submitted at this time for 3 phases of clinical trials where a scientifically sound plan is outlined to achieve desired goals.

Describe a drug that is bioequivalent.

A drug with the same amount of API in identical dosage form and has no sig difference in rate/extent of absorption.

Describe the diff between absolute and relative bioavailability.

Absolute F: uses IV comparison. Relative F: uses a secondary standard when IV not poss.

What are Cmax and Tmax dependent on?

Absorption rate.

Calculate bioavailability "F" related to amount of active drug absorbed from a drug product.

Amount of drug absorbed = Dose x F

Describe clockwise hysteresis and give an example drug.

An example of clockwise hysteresis is lipophilic fentanyl which rapidly partitions from plasma compartment into effect compartment which is the fat tissue (K1e), but displays slow receptor binding (Ke0).

Describe mechanism based drug design.

Chemical alteration of a drug designed to interfere specifically with known/suspected biochemical pathway. (Buriamide example) Change fn groups to attain/change traits of the overall compound.

What factors in the Noyes Whitney eq. are initially directly affected if the temp is increased during dissolution?

Cs (saturation solubility) increases. D (diffusion constant) increases.

What is drug safety margin and how do you calculate it?

Drug safety margin is the % increase in a ED99 to become toxic to 1% of the population. DSM = ([LD1/ED99] - 1) x 100

Describe pharmacology related to preclinical drug studies.

Drug selectivity, and efficacy related to specific enzyme systems, organ systems, and whole animals. Basic info to predict safe/effective use in humans.

Who controls ads for OTC and RX drugs?

FDA controls ads for RX FTC controls ads for OTC

What led to the 1906 Pure Food and Drug Act?

False therapeutic claims. USP/NF was designated as government's official standards for drug manufacturing quality, strength, and purity.

Describe the approval process for a drug that has a new route of administration.

Follows essentially the same as normal process. Some pre-formulation and toxicity may be avoided (only with respect to API). All studies that involve the new product must be re evaluated. Can be costly.

Describe a graded response.

For individuals there is a min threshold effect and a max ceiling effect. Everything in between varies with dose.

What can increase dissolution?

Heat Agitation: more exposure to solvent + removal of surrounding dissolved solute Having sink conditions: Removing dissolved solute Increasing volume of solvent: inducing sink conditions Using a more soluble salt/non-crystalline material (amorphous): Reducing or removing crystalline activation energy. Milling/grinding solute: Incr. SA for solvent to act on solute.

Explain why pure drug can't be administered to patients.

High potency is common, patient administering tiny amounts of powders has high degree of error. To protect drug from degradation/after administration. Conceal tastes and control rate of action. Optimal targeting to disease site.

Describe the Biologics Act and its respective year.

Led to the formation of Center for Biologics Evaluation and Research (CBER) now a sub division of the FDA. The Biologics Act of 1902 was initiated bc of contaminated diphtheria antitoxin in St. Louis resulting in 12 kids dead. This act focuses on safety, purity, potency and effectiveness of bio products.

What is MEC?

Minimum effective concentration, the amount of drug required to produce a therapeutic effect

Differentiate between a NDA, Treatment IND, ANDA, SNDA, BLA, and EUA.

NDA: submitted to FDA from drug sponsors after doing phases 1-3. Demonstrated safety/efficacy. FDA reviews then may grant permission for drug to go to market. Treatment IND: Allows patients with serious life threatening diseases access to investigational drugs that might help their condition while the drug is still in clinical trials. ANDA: Filed after patent expires for marketed product. Generic approval omits all clinical and nonclinical studies and must show bioequivalence. SNDA: Sponsor of an approved NDA may request approval for changes to that app. May be for change in formulation, packing, or labeling. BLA: Submitted to the FDA prior to marketing of vaccines, blood products, and toxins EUA: EUA mech provides appropriate participant protections based on the circumstances of the emergency.

Describe properties of a pharmaceutical dosage form.

Phys/chem. stable (preform) Preserved/protected against decomp/contamination. (preform/form) Releases ingredients in proper qty. (form) Efficient administration. (form) Possess features to enhance patient acceptance. (form) Effectively packaged, clearly/completely labeled. (Marketing/safety review).

Describe the various elements of a clinical protocol.

Purpose/objective of study Study design Estimate # of patients involved Basis for subject selection Dosing plan

Describe pharmacokinetics related to preclinical drug studies.

Rate and extent of drug absorption. Distribution of drug throughout the body. Rate of metabolism of drug, pathways of metabolism, and identification of metabolites. Proportion of drug elimination

Describe rate of dissolution.

Rate of dissolution is proportional to the diff. between the instantaneous concentration and the saturation solubility.

Describe the traits of biological membranes and how absorption occurs.

Small polar molecules pass diffuse thru pores. Large polar molecules use active transport/facilitated diffusion. Lipid molecules passively diffuse thru membrane.

What is the law of mass action?

States that velocity of a chemical rxn is proportional to the active masses of reactive substances. Dictates absorption.

List the different routes of drug delivery and dosage forms associated with those routes.

Sublingual: tabs, troches, lozenges Parenteral: solutions, suspensions Transdermal: creams, ointments, powders, lotions, pastes, plasters, aerosols, patches Intraocular/intra aural: solutions, suspensions, creams/ointments Intranasal: solutions, sprays inhalants, ointments Intra respiratory: aerosols Rectal: solutions, ointments, suppositories Vaginal: Solutions, ointments, aerosol foams, isnerts, insufflations, suppositories, sponge. Ureathral: Solutions, suppositories

Differentiate routes for systemic drug delivery and localized drug delivery.

Systemic: Oral, injections, transdermal patches, suppositories, and aerosols. Localized: Creams, ointments, ophthalmic, nasal, aerosol, ear drops, nails.

How do you calculate therapeutic index (TI)? What could cause misleading TI results?

TI = toxic dose/therapeutic dose TI may be misleading if log-dose response curves for effectiveness and toxicity have dif. slopes (not in parallel)

How do you calculate a test dose?

Test dose = relative potency x standard dose

What is the duration of drug action?

The difference between onset time and the time for drug to decline back to MEC.

Define bioavailability

The rate and extent to which the API is absorbed from from a product and becomes available at the site of drug action.

What is the onset time?

Time to reach MEC.

Discuss the various pharmacy laws that led to the formation of the FDA (1820-1912).

There was a need for regulation bc of widespread addictive ingredients in medications. There was public concern with habit forming drugs. The USP first published in 1820 listed highly controlled or illegal substances/habit forming drugs.

Describe how drugs are named.

They are named with USAN guidelines stating that nonproprietary names should be short, distinct, indicate general pharmacologic/therapeutic class, and embody the syllable traits of a related group of compounds.

What did the supreme court ruled regarding 1906 Pure Food and Drug Act?

They ruled that the 1906 Pure Food and Drug Act did not prohibit false therapeutic claims, but only false and misleading statements about the ingredients or identity of a drug.

Describe Upton Sinclair and its respective year.

Upton Sinclair in collaboration with Theodore Roosevelt published on unsanitary conditions in manufacturing in the meat and drug industries. 1901

Discuss bioequivalence testing as required by the FDA.

Uses an FDA estimation of 90% confidence interval. "Is the difference between the test and reference means not more than 20% from the reference treatment mean?" alpha = 0.05 significance levels.

Describe basic PK concepts.

Uses experimental, statistical, and theoretical approaches. PK is the science of drug kinetics (ADME) in the body. Ultimate goal is the design and prediction of optimal dosing regimens.

What factors in the Noyes Whitney eq. are initially directly affected if the stirring rate is increased during dissolution?

h: Stirring removes layers of the stagnant layer thereby reducing its thickness, h.

What are excipients?

inactive ingredients that compose the dosage form i.e. capsule of a liquid gel.

What is MTC?

minimum toxic concentration

Define: Noyes-Whitney Equation

relates the rate of dissolution of solids to the properties of the solid and the dissolution medium. dC/dt = DA/h x (Cs-C) D = diffusion coefficient A = surface area of drug Cs-C = concentration gradient of drug h = thickness of stagnant layer (stirring reduces H)

How do you calculate relative potency?

relative potency = 10^diff.eq.pts.

What are the 7 summary events leading to the formation of the FDA in 1930?

1) 1820 First USP published 2) 1847 AMA Formed 3) 1848 Drug importation act 4) 1901 Upton Sinclair publication 5) 1902 Biologics Act CBER 6) 1906 Pure Food and Drug Act 7) 1912 Sherley Amendment

Describe the theory/assumptions of drug-receptor interaction.

1) Combination/dissociation occurs. 2) It is reversible 3) Only a single specific type of receptor binding.

Describe the approval process for a drug using Section 505(b)2 of the FD&C Act of 1938.

1) Contains full reports of safety and effectiveness (an NDA) 2) Contains full reports but some info comes from studies not conducted by or for the applicant, and for which the applicant has not obtained a right of reference. 3) The proposed product is identical in API, form, strength, route, label, quality, performance, intended use to a prev. approved product.

Describe potential rate limiting steps in drug therapy.

1) Disintegration of the drug product. 2) Dissolution of the drug 3) Absorption across cell membranes 4) Transport to the target

Describe the various pharmacy laws that deal with safety, effectiveness, and the drug approval process. Federal food, drug, and cosmetic act. Durham Humphrey. Kefauver Harris Amendment. Drug listing act. Orphan drug act. Drug price competition and patent restoration act. Drug exports amendments act. Prescription drug marketing act. Revision of IND. Treatment use of INDs. Generic drug enforcement act. Prescription drug user fee act PDUFA. M

1) Federal food, drug, and cosmetic act of 1938 replaced the Pure Food and Drug Act of 1906. 2) 1951 Durham-Humphrey amendment referred to as the "Prescription Amendment" it defined OTC and RX drug products. Made RX drugs required to carry the statement "Caution: Federal law prohibits dispensing w/o prescription. 3) 1962 Kefauver Harris Amendment to the Federal food, drug and cosmetic act of 1938. 4) Drug listing act: required manufacturers to keep inventory of their products. 5) Orphan drug act: rare diseases affecting fewer than 200k ppl are designated orphan status diseases. Led to breakthroughs previously not achieved due to lack of funding. 6) Drug price comp/patent restoration act: Paved to way for generic competition by creating the Abbreviated New Drug Application (ANDA). 7) Drug exports amendment: Reform of drug export laws allows companies to export drugs not approved by the FDA to 37 tier 1 countries. 8) Prescription drug marketing act: Prevent illegal diversion and sale of prescription drugs from legitimate distributors. Requires state licensing of wholesale distributors. Ban on reimportation of products produced in the US. Ban trafficking in or counterfeiting of drugs. Prohibits the resale of rx human drug products. Was developed in response to the rise of a wholesale submarket known as the diversion market for rx drugs.

Describe the desirable characteristics of a "goal drug". (8)

1) Low cost manufacture 2) Pharmaceutically elegant 3) Physically/chemically stable 4) Specific desired effect 5) Administered by the most desired route 6) Optimal onset and duration 7) No side effects 8) Eliminated efficiently, completely, and w/o residual effects

Define a "new drug" that would require FDA approval.

1) New chemical entity (NCE) 2) Change in previously approved drug product's formulation or manufacture 3) New combination of drugs if a question of safety/efficacy is introduced by the change 4) New use for an approved drug 5) New dosage schedule or regimen 6) New route of administration 7) New dosage form

Describe Kefauver-Harris Amendments (Drug Efficacy Amendment) of 1962.

After thalidomide tragedy; drugs had to be proven effective, safe, pregnancy tested, and led to FDA control over drug advertising forcing ads to be more informative ab risks and disallowed marketing cheap drugs as expensive drugs. The purpose was to prevent future similar tragedies.

Describe the definitions used in pharmaceutical substitution.

Chemically equivalent (pharma. equivalent): Means 2 or more drug products contain equal amounts of the same therapeutically API in identical dosage forms. Pharmaceutical alternatives: Drug products that contain the same therapeutic moiety but differ in salt or ester form, in the dosage form or in the strength. Must meet USP/NF requirements.

Describe the biopharmaceutics classification system of solubility/permeability.

Class I: High Sol. High Permeability Class II: Low Sol. High Permeability Class III: High Sol. Low Permeability Class IV: Low Sol. Low Permeability X axis solubility; Y axis permeability

Describe Brodie's D ratio and how it relates to drug absorption

D is a mathematical estimate for drug absorption across a membrane. D = 1+10^(pH1 - pKa)/1+10^(pH2 - pKa) for a weak acid D = 1+10^(pKa - pH1)/1+10^(pKa - pH2) for a weak base

Define: Fick's First Law of Diffusion and how the components affect drug diffusion across a membrane.

Diffusion = -dC/dt = SxDxK/h x fu x CTd

Describe factors affecting bioavailability.

Dosage form, route of administration, drug stability, and metabolism.

For a given drug calculate the change in dose required when patient changes medication.

Dose of new dosage form = amount of drug absorbed from current dosage form/F of new dosage form

Calculate the change in dose for a patient when a drug salt is substituted for weak acid or base drug molecule.

Dose of new dosage form = amount of drug absorbed/S x F S = fraction of active drug

Describe toxicology related to preclinical drug studies.

Drug Safety Evaluation (DSE) Short term toxicity (acute) Long term toxicity (chronic) Potential for organ specific toxicity Mode/type/degree of toxicity Initial dose-response relationships

Describe preformulation related to preclinical drug studies.

Evaluation of a drug's physical/chemical properties that might affect its formulation into stable and useful pharmaceutical product.

Describe the approval process for an Abbreviated New Drug App (ANDA).

Generic drug apps apps are abbreviated bc no need for preclinical studies to prove safe/effective. Instead applicants must scientifically demonstrate their product performs the same as innovator drug. How: show bioequivalence (rate/extent of drug absorp)

Describe high throughput screening.

Involves chemical alteration of a known characterized organic compound for the purpose of enhancing its usefulness as a drug, then checking its effectiveness compared to the original compound.

Discuss drug discovery random screening.

Involves testing of large numbers of synthetic organic compounds or compounds of natural origin for biologic activity.

What is the issue with Mrs. Winslow's soothing syrup?

It is highly addictive because it contained the addictive ingredient sulphate of morphia. Bad thing to give kids.

Describe clinical protocol design.

It needs to include purpose/objectives of study. Involves study design. Estimates number of patients involved. Explain the basis for subject selection. Explain the dosing plan. Contains inclusion/exclusion criteria for subject selection. Dosing plan must include route of admin, doses, freq. of dosing, and duration of exposure.

What is the formula for Kd?

Kd = [R][D]/[R x D]

What was the import drug act of 1848?

Law passed after a senate investigation disclosed that American troops in the Mexican war had been given substandard imported drugs. This law required U.S. Customs Service inspection to stop entry of adulterated drugs from overseas.

Summarize criteria for designing a delivery system.

Non-elastic to pH, fluid vol., food, etc. Reasonable shelf life. Protection from external elements. Organoleptic properties may encourage patient compliance. Cost is reflective of the development stage, manufacturing cost, and composition.

Describe counterclockwise hysteresis with protein binding.

PD response increases rapidly (think why this happens) Ajmaline is plasma protein bound (think why this matters) Effect compartment partitioning is slow (low K1e) Corresponds to high [plasma] before a rapid effect begins (high Ke0)

Identify the various phases of clinical trials.

Preclinical: lab and animal studies Phase 1: First administration of drug to humans. Assess safety, early PK studies, healthy ppl used (20-100) Phase 2: Eval effectiveness, side effects, dose, PK data, and the final formulation is refined. Uses 200-400 ppl. Phase 3: Usefulness of drug in larger patient base, overall benefit : risk profile, varied dosage strengths given, marketing info gathered, uses 2000-4000 ppl.

What did the May 1909: Journal of American Medical Association do?

Print a list of Habit Forming Nostrums. Alcohol, opium, cocaine, chloral, and cannabis.

What is AUC related to?

The EXTENT of drug absorption.

Describe the importance of cGMP in the drug approval process.

cGMP provides assurance for drug quality with well documented procedures. cGMP results in greater confidence of a drug product. Prevents contamination, mix ups, and errors.