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61 Cards in this Set

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how do nonsynthetic reactions differ from synthetic reactions in their type?
both are determined by functional group

there are a limited number of synthetic reactions, but a wide variety of nonsynthetic reactions

synthetic reactions are relatively predictable, whereas nonsynthetic reactions are unpredictable
how do the metabolites differ between synthetic and nonsynthetic reactions?
synthetic - almost always less lipid soluble, almost always pharmacologically inactive

nonsynthetic - usually less lipid soluble, may have less/equal/greater/different activity
what biotransformations are catalyzed by nonmicrosomal enzymes (occur in the cytoplasm)?
synthetic - all except glucuronidation

nonsynthetic - most hydrolyses
what biotransformation reactions are catalyzed by microsomal enzymes (occur in the ER)?
synthetic - only glucuronidation

nonsynthetic - most oxidations and reductions
when is the rate of reaction of synthetic reactions affected by drugs?
in the ER, the rate of reaction of microsomal enzymes is stimulated by drugs

in the cytoplasm, the rate of reaction of nonmicrosomal enzymes is not stimulated by other drugs
when is the rate of biotransformation reactions of nonsynthetic reactions stimulated by other agents?
in the ER, the rate of reactions of nonsynthetic reactions is stimulated by many agents

in the cytoplasm, the rate of reactions of synthetic reactions is not stimulated by other drugs
what are the classic enzyme inducers?
barbiturates
define enzyme induction
process in which a drug induces (enhances rate of synthesis or reduces degradation of) an enzyme

important enzyme for our discussion - P-450
how do toxins affect metabolism of drugs?
can damage the tissue where the enzymes are located leading to an irreversible inhibition of activity
how does age affect metabolism/excretion of drugs?
in the elderly, generally expect to see a decreased excretion rate
what is a bimodal distribution?

why does isoniazid have a bimodal distribution?
continuous probability distribution with two local maxima

in a plot of number of patients vs. plasma [isoniazid], there is a bimodal distribution because some people are genetically programmed to acetylate efficiently, and others do it inefficiently
how is isoniazid metabolized?
acetylated
what are first order kinetics?
a first-order reaction depends on the concentration of only one reactant
what is an elixir?
mixture of alcohol, a drug, and water; alcohol is used to dissolve the drug
what is a suspension?
preparations containing finely divided drug particles (clumps) distributed throughout a vehicle in which the drug is insoluble
what is used in a suspension to help prevent the drug from settling to the bottom of the container?
thickening agents (often carboxymethylcellulose)

shaking the container before dosing
what is the old way of creating sustained release drug preparations?
clumps of drug particles were coated with coatings differing in their solubility

easily soluble coatings release the drug quickly for immediate absorption, and slowly dissolving coatings release the drug at a later point in time
what is the new way of creating sustained release drug preparations?
drug is contained in a membrane that is semipermeable to water, and has a laser drilled delivery orifice in it

as water enters the membrane, the drug goes into solution and the solution is pushed out the small hole at a controlled rate
how are depository (depot) forms of drug administration used?
IM use (NOT IV)
what is a depository (depot) form of drug administration?
suspension of poorly water-soluble drug is injected into muscle, slowly dissolves, and is absorbed into the plasma
how can a water soluble drug be made into a depository form of drug administration?
a long hydrocarbon chain can be esterified to an OH group, making the complex weakly water soluble

the complex is slowly absorbed and broken apart by enzymes in the plasma, thus liberating free drug
what is bioequivalence?
a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug

if two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same
what three factors are considered by the FDA when approving a generic as bioequivalent to to its brand name counterpart?
peak height concentration

time of peak concentration

area under the serum concentration time curve (yields extent of absorption)
what was the effect of the Pure Food and Drugs Act of 1906?
prohibited interstate commerce of misbranded and adulterated foods, drinks, and drugs, and provided the remedies of seizure and prosecution
what inspired the Pure Food and Drugs Act of 1906?
Upton Sinclair's book, The Jungle
what was the effect of the sherley amendment to the FD&C act of 1906?
prohibited false or fraudulent statements regarding the effectiveness of a drug
what was the effect of the federal food, drug, and cosmetic act of 1938?
drugs must be safe but not necessarily effective

FDA cannot interfere with practice of medicine (approved drugs can be used for unapproved uses)
what was the effect of the 1962 kefauver-harris drug amendments?
drug manufacturers were required to PROVE to the FDA that their product was effective before marketing them

FDA could deny or approve a new drug application based on the studies submitted to them by the majufacturer

FDA required that drug safety be shown to their satisfaction before marketing
what event initiated the Federal Food, Drug, and Cosmetic Act of 1938?
100 die due to ethylene glycol as solvent in elixir of sulfanilamide in 1938
what event initiated the Kefauver-Harris Drug Amendments of 1962?
thalidomide causes severe birth defects in thousands of babies in western Europe in 1962
how does the new mission of the FDA differ from the old mission?
in old mission, FDA was risk averse, focusing solely on safety

new mission puts emphasis on balancing the safety aspect with the potential benefit of the new drug
what is an Investigational New Drug (IND) Application?
request for an exemption from the federal statute that prohibits an unapproved drug from being shipped in interstate commerce

permission to test in humans
what is a New Drug Application (NDA)?
the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S.
what is the purpose of a new drug application (NDA)?
FDA examines:

Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.

Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.

Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.
what is an Abbreviated New Drug Application?
application for a generic drug, in which the company only has to show bioequivalence to the brand name drug (peak concentration, time to peak concentration, area under the curve) in order to sell their generic
what happens in preclinical testing?
testing in animals

IND is filed
what happens in Phase I Clinical Testing?
human testing (first time the drug is used in a human body)

emphasis on safety
what happens in Phase II Clinical Testing?
human testing

emphasis on efficacy

limited number of people (about 100)
what happens in Phase III Clinical Testing?
human testing

emphasis on side effects and long-term use

500-3000 patients

catch early toxicities; miss infrequent/delayed toxicities

NDA is submitted
what is Phase IV of clinical testing?
postmarketing

MD reporting
when does a drug enter phase IV of clinical testing?
after NDA approval
what is the definition of pharmacokinetics?
study of the time course of drug action; involves the factors that influence the appearance and disappearance of the drug in plasma
by what order kinetics are most drugs absorbed and eliminated?
first-order kinetics

(rate is proportional to the concentration of one reactant although the process may have several reactants)
describe zero-order kinetics
process occurs at a constant rate

rate is independent of concentration
describe first-order kinetics
process occurs at a decreasing rate as drug concentration declines

rate is proportional to concentration
why is glucose an exception to the rule that reabsorption is always first-order?
reabsorption of glucose is carrier mediated whereas reabsorption of most drugs, etc. is via passive diffusion
by what order of kinetics does glomerular filtration operate?
ALWAYS first-order
by what order of kinetics does reabsorption operate?
almost always first-order

glucose is different because it is carrier-mediated
by what order of kinetics does tubular secretion operate?
zero-order above the saturation concentration
when are biotransformation/biliary transport first-order?
only if enzymes or transporters are not saturated
why is a first-order elimination process not linear when graphed?
the body is better at getting rid of something when there's more of it
what is a half life?
time required for 50% of the drug to be excreted
what is the rule of thumb for how long it takes to eliminate a drug from the body?
4 half-lives
how long does it take for a drug to reach steady-state?
4 half-lives
why does the level of drug in a patient's system level off after four half-lives?
the rate of absorption of the drug becomes equal to the rate of elimination of the drug
what is the equation for rate of absorption?
Rate of Absorption = [Drug]GI x k
what is the equation for rate of elimination?
Rate of Absorption = [Drug]plasma x k
what is the equation for absorption and elimination at steady state?
[Drug]GI x k = [Drug]plasma x k1

k is not equal to k1
on what factors is the point where a plateau concentration is reached in a drug administration curve dependent?
half life
dosing rate

NOT:
dosage given
how does dosing administration affect peak-trough difference?
the more frequently a dose is given, the smaller the peak-trough difference
what is a peak-trough difference?
difference between drug concentration at peak blood concentration and at minimal blood concentration during a dosing schedule

more doses per half-life means smaller peak-trough differences