Pharmacodynamics Flashcards
drug targets that are proteins
- receptors
- ion channels
- enzymes
- carriers
ion channels
- when activated will open and form pores in cells and allow ions in and out
- blockers
- modulators
blockers
- permeation blocked
modulators
- increased or decreases opening probability
enzymes
- inhibitors
- false substrate
- pro-drug
inhibitors
- normal reaction inhibited
false substrate
- abnormal metabolite produced
pro-drug
- active drug produced
carriers
- molecules that transport molecules from one side of a membrane to another
- normal transport
- inhibitor
agonist drugs
- mimic the effects of the endogenous agonists
antagonist drugs
- block the effects of endogenous agonists
Kd
- the concentration of the drug at which 50% of receptors are occupied
- direct reflection of the affinity of the drug for the receptor
low Kd means
- greater affinity
all reactions between agonist and receptor
- reversible
dependence of agonist binding to receptors
- concentration dependent
Hill Langmiur equation
Y = [D]
Kd + [D}
[D] = dose of drug Kd = dissociation constant
the lower the Kd
- the more potent the drug
- further to the left
efficacy
- how much effect the drug can produce
- looking for 100% therapeutic effect
what determines potency
- how tightly the drug binds to the receptor
what determines effectiveness
- what that drug does to the receptor after it is bound to it
which y axis tells you the Kd
- has to say receptor occupancy
relationship between receptor occupancy and therapeutic effect
- no relationship
- possible to achieve a full therapeutic effect while only occupying a certain percent of receptors
signal amplification
- maximal cellular response at less-than-maximal receptor occupancy
receptor reserve
- receptors that are available for agonist binding but are not necessary for maximal effect
competitive antagonist
- binds for same binding site as the endogenous agonist
non-competitive agonist
- endogenous agonist and antagonist bind at different sites
- can be reversible or irreversible
how competitive agonist affects dose curve
- decrease in potency
- Kd shifts right
- need more substrate to outcompete the antagonist
how non-competitive agonist affects dose curve
- decrease in efficacy
- you have knocked out receptors so you can’t get the same effect
full agonist
- elicits maximal response from its receptor
- may be an endogenous molecule or a drug
how is maximal response defined
- defined based on natural agonist that exists in your body
partial agonist
- elicits a submaximal response from its receptor
- doesn’t elicit response to the same level
- you may not want a drug to be a full agonist
neutral antagonist
- reduces effect of an agonist but has no effect itself
- inhibits normal agonist from producing any response
inverse agonist
- receptors have a low level of signaling even when there is nothing bound to them
- inhibits basal activity of a receptor in the absence of the normal agonist
- may be competitive antagonists if they bind to the same receptor site as the endogenous agonist
why don’t we consider inverse agonists to be antagonists?
- they aren’t competing with the endogenous agent
clinically relevant inverse agonists/antagonists
- metoprolol
- losartan
- famotidine
- risperidone
- naloxone
- MFLRN
- mutha fuckas lit right now
full agonist example
- endorphins
- morphine
- heroin
partial agonist example
- bupenorphine
- Nalbuphine
neutral antagonist example
- naltrexone
inverse agonist example
- naloxone
what are drug response curves useful for
- describing effects that are continuous
example of continuous effects
- reduction of pain
- reduction of BP
- reduction of BP
what do you do with dose response curves when the variable isn’t quantal
- you describe a population of people instead of an individual
ED50
- effective dose at which 50% of patients are benefitting
TD50
- toxic dose at which 50% of patients are suffering toxicity
LD50
- concentration at which 50% of patients die
therapeutic window
- the range of drug concentration between the minimum effective dose and the minimum toxic dose
- TD-ED
minimum effective dose
- dose at which drug is minimally effective
minimum toxic dose
- dose at which toxicity starts in the patients
big therapeutic window
- far apart curves
- you want therapeutic dose to have good benefit with little to no toxicity
therapeutic index
- measure of the safety of a drug
- not always the best measurement
therapeutic index formula
- TILE
TD50/ED50 OR LD/50
do you want therapeutic index to be high or low?
- high
- you want toxic dose to be extremely high
- and effective dose to be low
why might dose response curves look different?
- dependent on drug binding to the same receptor or not to exert its effects
what does the curve look like on a drug binding to different receptors
- share a point of origin and then spread apart
off-target toxicity
- produce toxic effects by binding to a different receptor
mechanism based toxicity
- drug binds to the same receptor for therapeutic and toxic/lethal effects
certain safety factor
- LD1/ED99
what value do you want for the certain safety factor?
- HIGH
- you want the lethal dose that kills 1% of people to be high
- you want the effective dose that helps 99% of people to be low
drug antagonistic relationship
- two drugs together produce less than additive effect
drug additive relationship
- two drugs together produce additive effect
drug synergistic relationship
- two drugs together produce more than additive effect
potentiation
- when one drug has therapeutic effect and a second drug helps it
potentiation example
- cephalosporins and probenecid
cephalosporins and probenecid
- probenecid has no effect of its own
- potentiates the effect of antibiotics
- increased serum concentration of drug and prolonged therapeutic effect
tolerance/desensitization
- reduced effect with continued use of a drug
short term tolerance/desensitization
- tachyphylaxis
receptor inactivation
- after a receptor has been bound to an agonist for a period of time or after multiple times
- it can become inactivated
- will turn off and no longer produce effect
receptor internalization
- once it binds to the agonist,
- it get internalized into the cell
- and then becomes recycled
receptor down regulation
- receptor binds to agonist
- becomes internalized
- then degraded
- cell has to resynthesize a new receptor
fewer active receptors but still enough to give 100% of a response
- shifts right on dose response curve
fewer active receptors but NOT enough to give 100% response
- decrease % effect
- may shift left
- you have deactivated some of the receptors to help you get that effect
