Test 1 Part V Flashcards
what is the fx of the transferase enzyme during a phase II biotransformation reaction
catalyze the coupling of an activated endogenous substance and a drug
which biotransformation reaction occurs faster, the P450 reaction of phase I or the conjugation reaction of phase II
conjugation (phase II)
which reaction/enzyme of phase II biotransformation is microsomal
glucuronide conjugation
which enzymes/reactions of a phase II biotransformation is non-microsomal
acetic acid
sulfate
glutathione
methyl
why does a toxic dose of tylenol cause liver failure?
CYP (phase I) works great, but the glutathione required for conjugation of phase II is depleted faster than it can be regenerated –> toxic metabolite build up in liver –> liver failure
__________________ is based on genetic inheritance of P450s
allergic reactions
what is a genetic polymorphism
the occurrence of a variant allelle of a gene at a population frequency of >/= 1% resulting in altered expression or functional activity of the gene product or both
___________________ results in altered efficacy of drug therapy or adverse drug reactions
genetic polymorphism
what is the phase II biotransformation genetic difference that is found in 50% of blacks and whites in the US causing longer time to metabolize certain drugs
slow acetylator
genetic differences causing changes in biotransformation and drug metabolism is predominately a ___________________ trait
autosomal recessive
slow acetylators are seen in _____________ of blacks and whites in the US, and there is an increased incidence in ____________________ living in high northern latitudes
50%; europeans
slow acetylation is less common in which people
asians and eskimos
in what age groups of people are there an increased pharmacologic and toxic activity
very young; very old
who metabolize certain drugs (ethanolol, propranolol, benzos, estrogens, and salicylates) faster men or women
men
your patient states in a genetic test they had done they are a slow acetylator, this means you would do what to their benzodiazepine dose prior to entering the OR
lower it
what diseases can affect drug metabolism
- acute or chronic disease of the liver
- cardiac disease
- thyroid dysfunction
- pulmonary disease
- infections (bacterial or viral)
- cancer
- inflammation
how does cardiac disease cause impairment of drug metabolism?
limits the blood flow to the liver, thus impairing the metabolism of the drugs that are flow limited or flow dependent
how does bacterial infections, viral infections, cancers, and inflammatory processes impair the metabolism of drugs?
causes release of inflammatory mediators impairing the function of P450
what is the first step in drug development
discovery/synthesis of a new drug compound or a new target (receptor)
in the U.S. ______________ and ____________ of drug must be defined before marketing can legally begin
safety; efficacy
in the US _______ - _______ % of healthcare money is spent on prescription drugs
10; 12
less than ____________ of drugs tested in clinical trials make it to market
1/3
what is teh approximate cost of developing a new drug
150 million to several billion
where do most drugs orginate?
private sector (universities, research institutes)
of the new drugs that achieve marketing approval, ____________% are drugs with significant advances in safety and efficacy; the rest are molecular varient compounds that are already in circulation
10-15
only _______ out of 10 drugs produce a return on investment
2
what is the purpose of “drug screening”
to define the pharmacologic profile of the drug at the molecular, cellular, organ, organ system, and organism level
they type and number of initial drug screening tests depends on what factors?
the pharmacologic and therapeutic goal of a new potential drug
drug screening results must be ______________ and ____________ to develop a pharmacologic profile
reliable; reproduceable
drug screen at the molecular level
screen for activity on the target receptor
effects evaluated on P450 enzymes
which level of the drug screen determines whether the drug is an antagonist, agonist, partial agonist, or inverse agonist at the target receptor
cellular level drug screen
what part of the drug screen is the new drug characterized by its pharmacologic activity and selectivity
organ drug screen
what part of the drug screen is the drug tested in animal studies?
organ system
what information is derived from the organ system drug screen?
duration of action and efficacy after oral and IV administration
drug screen at the level of the organism examines what?
signs and sx of adverse effects on all major organ systems
what drug screen level is there an estimation of tolerance and/or abuse potential, physical or psychological dependence, and drug-drug interaction information obtained
organism level
successful drug screening leads to the development of a ________________
lead compound
what is a lead compound
A compound demonstrating a property that is likely to be therapeutically useful (through drug screening)
when can someone apply for a patent on a new drug they are developing
after drug screening
__________________________ is an essential step in the drug development process where limiting toxicities, therapeutic index, and risk and benefits are identified
preclinical safety and toxicity testing
what is the goal of preclinical safety and toxicity testing
- ID potential human toxicities
- design tests to further define the toxic mechanisms
- predict the most relevant toxicities to be monitored during clinical trials
- quantitative dose estimates (used to calculate initial dose for human trials)
in preclinical safety and toxicity testing what is the no-effect dose?
the max dose at which a specific toxic effect is not seen in animals
what quantitative estimate dose from preclinical safety and toxicity testing is used as the start dose for human trials
1/10th - 1/100th of no-effect dose
what is the minimal lethal dose that is obtained from preclinical safety and toxicity testing
smallest dose that is observed to kill any experimental animal
what is the medial lethal dose obtained from preclinical safety and toxicity testing?
the dose that kills approx 50% of animals, estimated from the smallest number of animals possible
what are the limits to preclinical safety and toxicity testing?
- time consuming and expensive
- large numbers of animals needed
- data from animal studies may not translate all potential toxicities in humans
- rare adverse effects are unlikely to be detected
how long does preclinical safety and toxicity testing potentially take before a drug is ready for human testing?
2-6 years
what are the 3 major confounding factors in human evaluation of a new drug
- variable natural hx of diseases
- presence of other diseases and risk factors
- subject and observer bias
if the FDA approves a drug or food as “safe and effective” is does NOT mean ___________________________
free of side effects
the pure food and drug act of 1906 is a response to what?
unsanitary and unethical practices in the meat packing industry
