toxicology Flashcards
pharmacokinetics is
the study of absorption, distribution, metabolism and excretion of drugs
a hydrophilic medicinal agent has the following property
a low ability to penetrate through the cell membrane lipids
what does the term bioavailability mean
amount of drug reaching the systemic circulation following any route administration
the reason determining bioavailability are?
extent of absorption and hepatitis first pass effect
most of drugs are distributed homogeneously
false
for the calculation of the volume (Vd) one must take into account?
concentration of a substance in plasma: Vd=D/C
D
a small amount of the volume of distribution is common for lipophylic substances easy penetrating through barriers and widely distributing in plasma, interstitial and cell fluids. t/f?
false
stimulation of liver microsomal enzymes can
require a dose increase of some drugs
conjugation of a drug includes the following
glucoronidation- sulfate formation- metylation NOT hydrolysis
half life (T1/2) does not depend on
time of drug absorption
pharmacodynamics involves the study of the following -
- biological and therapeutic effects of drugs
- mechanisms of drug action
- drug interactions
NOT absorption and distribution of drugs
what does affinity mean
a measure of how tightly a drug binds to a receptor
an agonist is a substance that
interacts with the receptor and initiates an effect
a competitive antagonist is a substance that
binds to the same receptor site and inhibits the agonist response
ED50 is a measure of drugs efficacy is
potency
tachyphylaxis is
very rapidly developing tolerance
nitric oxide causes
smooth muscle relaxation
drug that stays mostly in the vascular compartment
has low volume of distribution
drug that stays mostly in peripheral body tissues
has high volume of distribution
guy weighed 70kg was given 2000 mg of a drug, bioavailability was 28.5, what did he end up with?
70?
a man came in with OCD mania and trouble at work- you give him?
SSRI
a woman has a hx of depression and chronic pain from an old car accident- you give her
SNRI
EC50 main reflects a drugs
potency
what would you give to someone with a sleep disorder
hypnotic
a girl came into the ER with an overdose of something- what is the best way to administer the antidote
IV
definition of pharmacokinetics
what the body does with the drug- (KIN AD ME)
- administer, distribute, metabolize, excrete.
definition of pharmacodynamics
what the drug does to the body
what would you give to someone who has hepatic issues because it is primarily excreted through kidneys
lithium
what do opioids do?
open Ca channels- Close Na channels
morphine was given and completely relieved pain, then pentazocine was given and only partially relieved pain, why?
morphine is a full agonist, pentazocine is a partial agonist
a guy tried to quit smoking, had already used nicotine patches and they didn’t work. what do you give
varenicline
Vary Nicotine Line
guy was given a drug with weak acid of 6.5, where in the body would it be absorbed?
would pass through membranes in stomach with pH of 2.5
a drug given acted just as strongly as something else- why?
it is a full agonist
a girl asks you what effect lithium will have when taking it for the first time
hallucinogenic
benzodizepines all have
sedative effects
hypnotics affect sleep how
decreased REM sleep
what drug would you give a kid with ADHD
methylphenidate
M(ethyl is a funny date for a kid_
what route for administration has the most bioavailability
IV administration
If you give a single drug, what happens to the receptors
cascade effect? signal amplification?
drugs bound to albumin are inactive t/f
true
what does methodone do
induce less euphoria- binds to the receptors
what is true about fentanyl
it has 100X the potency of morphine
what is given to reverse opioid overdose
naloxone
narcolepsy is treated by
amphetamine
(I) am phet (up- gonna ) narc (on you)
when antagonists bind reversibly there is
competitive inhibition
what phase I reaction allows a drug to be excreted in urine
glucoronidation
the magnitude of the response is
proportional to the number of drug receptor complexes
antimuscarnic action
antihistamines action and alfa adrenoreceptor- blocking action are all autonomic nervous system effects common for which drugs?
tricyclic antidepressants
a patient with edema would have an increased volume of distribution (Vd) if?
the patient was taking a hydrophilic drug
the prinicipal mechanism of action of antidepressant agents is
blocking epinephrine or serotinin reuptake pumps
what are disadvantages of administering drugs orally
- first pass effect
- low bioavailability
- number of drug receptors, tachyphylaxis, can all do what to the drug?
can affect the effectiveness of a drug.
what is the cost to bring a drug to market?
150-900 million (not including marketing costs)
how many drugs return the research and dev. cost?
3/10
compounds which show potential for therapeutic benefit usually undergo further modification to improve what?
- efficacy, potency and safety prior to formal evaluation
what was the top selling drug in 2004?
lipitor reaching 10 billion dollars
in the US how much of the health care costs were consumed by drugs costs?
10% of health care costs
since 1950 how many lives and at what costs have drugs improved lives?
- 150 million lives saved and cost 140 billion for tb polio CAD and Cerebrovascular dz
while the cost of drug development is high the potential benefit is _____
high
what are some principles of drug discovery?
- ID of a new potential drug target
- rational drug design
- modification of an existing drug/potential drug
- screening of chemicals in libraries
- biotech approach using human genome
- combo of known drugs to get synergistic effects
what is drug screening?
sequence of iterative experimentation and characterization involving biologic assays ranging from the molecular to organism level
the number and type of initial screening tests depends on?
the therapeutic intent
screening also attempts to identify a _________ which can identify potential adverse responses
mechanism of action
what does broad screening procedures allow?
identification and characterization of both suspected and unsuspected toxicities- and sometimes unsuspected therapeutic benefit
rogain increases growth of hair but it was meant for?
hypertension BP
what type of animals are drugs tested on? what are the tests looking for?
-normal animals
-evidence of overall drug safety
- absence ill effects on normal physiology
the end of a drug screening process is called? what kind of “entity” is this?
- the end result of the drug screening process is called a LEAD COMPOUND
- this is a PATENTABLE ENTITY
what is the goal of preclinical studies?
- identifying potential human toxicities
- designing mechanisms to monitor for these toxicities in clinical trials
what could discovery of a sig. toxicity do?
- indicate the need for some drug modification
what is specific testing determined by?
- the proposed therapeutic use of an agent
what are the three doses identified with respect to toxicity?
- no effect
- min. letal dose
- med. lethal dose
this is the max dose showing no toxicity
no effect- dose #1
this is the min. dose resulting in the death of a subject
min. lethal dose
this is the dose killing 1/2 of tested subjects
median lethal dose - LD50
which does is used to calculate the initial dose in human trials?
no effect dose is used to calculate the initial dose used in human trials- usually taken as the following
- 1/100th- 1/10th
how long is toxicity testing time line?
what are some additional limitations to preclinical testing?
-2-6 years to acquire data prior to human testing
- time consuming and expensive
- large number of animals are needed-predictive value is severely limited.
- extrapolation of animal data to humans may not be accurate for all toxicities
- rare adverse effects are unlikely to be detected
how many drugs tested in clinical trials reach market? WHY?
- less than 1/3 of drugs tested in clinical trials reach market.
- human clinical trials have extensive oversight from # of institutions.
- Fed. law has strict rules
- confounding factors
what are confounding factors in clinical trials? What does the study design need to take in account for?
- most dz have a variable clinical course some get better, some get worse and some get better w/o intervention
- study design must account for the natural hx of the dz.
- the presence of other dz and risk factors
- known or unknown dz risk factors may influence clinical study results. Thorough hx and medical evaluation needed.
- subject and observer bias
- study design must account for placebo affect
what is the FDA
-administrative body charged with oversight of the drug evaluation process all drugs must be shown to be safe and effective
- approval for marketing a drug requires FDA approval
- the FDA’s authority to regulate drugs derives from specific legislation
once a drug has been judged ready to be studied in humans what must be filed with the FDA?
IND-( Investigational New Drug) notice of claimed investigational exemption for a new drug must be filed
what does the application IND need to include?
- extensive profile of drug including the mechanism
- of action, formulation and composition of the drug, the proposed clinical plans and protocols, the names and credentials of physicians who will conduct the trials
- this data is made available to investogators and their review boards.
how long does clinical trials usually take?
- 4-6 years with animals of clinical testing to accumulate and analyze all the data
when can human testing begin?
it can begin after sufficient acute and subacute toxicity testing in animals has been completed
what is done concurrently with human trials
chronic safety testing
this document describes the ethical guidelines for human drug testing-
The declaration of helsinki
what are specifics of declaration of helsinki
- the well being of the human subject should take precedence over the interests of science and society
- consent should be in writing
- use caution if participant is in dependent relationship with researcher
- limit use of placebo
- participants benefit from research
-both ____ and _____ must approve all protocols
-clinical trials go through _____ phases.
- FDA
- institutional review boards
- 4 phases
what does phase I trials determine?
- dose-response relationship of the drug
what kind of volunteers are needed for phase I trials?
what is the main goal of phase I trials
-subjects are normally healthy
- the main goal is to identify the max. tolerated dose in the absence of severe toxicity- if a drug is expected to have severe toxicity patient volunteers are used for phase I studies.
- phase 1 trials are done to determine if humans and animals show significantly different toxicities and establish the range of safe dosages.
- pharmacokinetic parameters are determined in these trials
- participants don’t know what they are taking- dose is gradually increased until the first participant develops drug related symptoms
the drug is studied in a small group of patients with the target disease to determine efficacy.
phase 2 trials
-in this trial a single blinded protocol is usually used- often a positive control with the current recommended treatment is included-
-what is a single blinded protocol?
- this is a phase 2 trial
- single blinded protocol - the admin knows who is taking the drug but patients do not.
these trials involve target patients in much larger than phase 2
phase 3 trials
these trials try to establish Safety and Efficacy- these trials are designed to minimize potential confounding factors. Often these test involve DOUBLE BLIND CROSSOVER PROTOCOLS.
phase 3 trials
what is double blind crossover?
both admin and patient do not know who is taking the drug
where is phase 3 trials usually performed?
in a clinical setting similar to that intended for the marketed drug.
phase 3 trials are _____ due to the large number of patients and the masses of data collected and analyzed.
expensive
- the first order kinetics- the enzymatic metabolism of drugs generally follow ?
- in most cases the concentration of drug is much less than?
- the rate of drug metabolism is proportional to?
- generally follow- michaelis-menten kinetic (see pic)
- than Km so…..(see pic)
- proportional to the concentration of free drug, a constant fraction is metabolized per unit time.
regarding renal elimination:
- what is glomerular filtration?
- what happens to the free drug
- what is proximal tubular secretion?
- what are the two energy processes by which secretion into the proximal tubule occurs?
- drugs in the plasma pass through the glomerular capillary plexus.
- free drugs enter Bowmans space as glomerular filtrate.
- drugs are transferred into glomerular filtrate pass to the efferent arterioles surrounding the proximal tubule
- the two energies - one for anions and one for cations- both are non specific and saturable
what does recognition of a drug by receptor trigger?
triggers a biologic response
regarding major receptor families?
- what are the four major types of receptors? (transmembrane signaling mechanisms)
- ligand gated ion channels
- G-protein coupled receptors
- enzyme-linked receptors
- intracellular receptors
regarding ligand gated ion channels:
- what are they responsible for?
- regulation of these channels is done by?
- how fast do these channels respond- (time)
- what can ligand binding open or modify
- what are receptor sites for local aesthetics?
- regulation of the flow of ions through the cell membrane
- activity of these channels is regulated by ligand binding to the ion channel
- ion channel receptors respond rapidly and have a very short duration of effect (millisecond)
- they can open channels or modify the function of ion channels
- voltage gated ion channels in peripheral nerves are receptor sites for local anesthetics
regarding G-protein coupled receptors :
- what happens to the GTP-a subunit
- both subunits do what
- what does stimulation of G-protein coupled receptors result in?
- 2nd messengers proceed….?
- what is a common 2nd messenger generated from this type of receptor?
- it dissociates from the (by) subunit
- they interact with other cellular effectors resulting in the formation of intracellular 2nd messenger
- results in responses lasting form seconds to minutes.
- proceed to modify a number o fintracellular processes.
- cAMP is a common 2nd messenger generated from this type of receptor- phospholipase-C is also activated by this type of receptor
regarding enzyme linked receptors:
- what are the components in this type of receptor?
- what does binding of an extracellular ligand activate?
- what kind of responses are received
- what is the most common enzyme type
- often this results in what type of cascade
- cytosolic enzyme component
- binding of an extracellular ligand to the receptor activates or inhibits the attached enzyme
- these receptors elicit responses minutes to hours in duration.
- the most common enzyme type is a tyrosine kinase which phosphorylates tyrosine residues when activated.
- results in a phosphorylation cascade whereby a small number of activated receptors can generate a large response.
regarding insulin receptor:
- what kind of binding occurs with this receptor?
- subsequent _______ of intracellular proteins _______ or ______ them resulting in a change in cellular processes.
- insulin binding to cells occurs through this type of receptor
- phosphorylation/ activates or deactivates
regarding intracellular receptors:
- how do these receptors differ?
- which hormones pass directly to bind to an intracellular receptor
- what results in altered gene expression
- how long is onset of response
- the ligand passes through the membrane (lipid soluble) and diffuses throughout the cell to bind with a receptor located inside the cell.
- steroid hormones pass directly through the cell membrane binding to an intracellular receptor
- the receptor steroid complex bind to a specific DNA segment resulting in altered gene expression
- because these receptors usually involve new protein synthesis the onset of response is at least 30 minutes but can last for hours to days.
regarding potency:
- define potency?
- how is this determined ?
- drugs producing the same response can be compared for?
- what is a contributing factor to potency?
-
- the amount of drug necessary to produce an effect 50% of an agents maximal effect
- determined using the dose which produces 50% of the max. chosen effect (EC50)
- compared for potency
- is the affinity of a drug for the receptor (Kd)
regarding competitive antagonist:
- many antagonists bind to the same receptor site as agonists but??
- this binding occupies the receptor preventing?
- when antagonists bind reversibly there is ?
- the presence of a competitive antagonist shifts the dose (curve) to what side?
- are unable to elicit transduction- they bind but produce no intracellular response
- preventing the binding of the endogenous ligand or agonists thus blocking the drugs effect.
- there is competitive inhibition- just like in enzyme-substrate interactions
- shifts the response curve to the right
-what is the goal of pharmacogenomics?
-what is it based on
- what has become apparent
- currently what drugs for pharma co analysis is indicated?
- the goal is to predict the response of an individual to various drugs toxin chemicals prior to exposure by analysis of their genome
- this is based on the presence of certain SNPs (single nucleotide polymorphisms) and responses to certain agents.
- the incomplete knowledge of the elements involved in both therapeutic response and metabolism of agents
- warfarin being on the first non-ani-neoplastic agents with the recommendation for genetic analysis prior to treatment at determine the appropriate dose.
