Pharmacodynamic Flashcards
receptor
a macromolecule whose biological function changes when a drug binds to it
affinity
measure of propensity of a drug to bind receptors; the force of attraction between drug and receptor
signal transduction
a cascade of events triggered by drug-receptor binding interaction to which target tissue responds
…. bonds are involved in the stereospecific interaction between a receptor and its ligand
multiple
in most cases, binding is…
transient (drug molecule binds, dissociates, binds again, so on)
each binding triggers a…
signal
drugs with a …. conc. will have a greater chance of binding
higher
ka=
k1/k2 (affinity constant)
kd=
k2/k1 (dissociation constant)
the lower the kd….
the more affinity the drug has for the receptor
Emax
maximal effect produced by a drug or efficacy of a drug
dose-response curve or log dose response graph?
log dose response is sigmoidal, compresses dose scale, proportionate doses occur at equal intervals, easier to analyze mathematically
EC50
dose of a drug that produces 50% of maximal (half max) response
efficacy/ intrinsic activity
ability of a bound drug to change the receptor in a way that produces an effect
some drugs posses …. but not….
affinity, efficacy
Kd
conc. of a drug that occupies 50% of the total number of receptors at equilibrium
agonist
a grud which binds to the receptor and produces an effect (has affinity AND intrinsic activity)
partial agonist
has affinity for receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor, therefore lower Emax)
antagonist
a drug which binds, but does not activate the receptor (has affinity but no intrinsic activity)
At the presence of a full agonist, a partial agonist…
acts as an antagonist and blocks the full effect of an agonist
example of a therapeutic use of a partial agonist
buprenorphine
- an opioid analgesic
- lower abuse potential since lower level of physical dependence
- safer than full agonist such as morphine
antagonist properties of a partial agonist
-provide some activity and block endogenous full agonist at the same time
clinical example of a partial agonist acting as an antagonist
pindolol for high blood pressure and abnormal heart rhythms
-reduce excessive stimulation due to norepinephrine in a person with high sympathetic nervous system activity
competitive antagonism
a higher dose of agonist is required to produce the same effect
-can still produce maximal effect
irreversible/non-competitive antagonism
even a higher dose of agonist cannot produce maximal effect
-Emax is depressed
inverse agonist
some receptors have intrinsic activity even when no ligand is bound to them; when a ligand binds to them, their basal activity is reduced
allosteric interaction
when a ligand binds to a site close to the site of an agonist on a receptor and maybe affecting the binding and/or response to the agonist.
-2 ligands on a single receptor
example of an allosteric interaction
Benzodiazepine drugs potentiate the response to game aminobutyric acid (GABA) when they bind to GABA receptor
If an antagonist binds to the same site as the agonist, but does so IRREVERSIBLY or PSEUDOIRREVERSIBLY…
it causes a shift of the dose-response curve to the right with progressive depression of the maximal response as [I] increases
It is easier to treat overdose or poisoning caused by…
a competitive (reversible) receptor blocker as opposed to an irreversible inhibitor
quantal dose response curve
indicates sensitivity of a given population to the doses of a drug for a given effect
frequency distribution
each bar shows the # of people responding to that dose and excludes people responding to lower doses
cumulative frequency
each bar shows the # of people responding to that dose and to lower doses
therapeutic index =
TD50/ED50 or LD50/ED50
a therapeutic index that has a …. ratio, the safer the drug
higher
therapeutic window
reflects a plasma conc. range that provides efficacy without unacceptable toxicity; difference between minimum effective conc. for desired response and an adverse response
ED50
effective dose in 50% of people
TD50
toxic dose in 50% of people
LD50
lethal dose in 50% of people
4 fundamental signal transduction mechanisms
- g protein coupled receptor systems (fast, half of all known drugs work through GPCR)
- ion channel receptors (fastest)
- enzyme receptors (meh)
- nuclear receptors (slowest)
g protein coupling uses energy in the form of..
GTP
3 second messengers activated by GPCRs
- cAMP
- IP3
- DAG
enzyme receptors
- receptor is a pair of separate proteins
- an agonist cause them to interact and form a dimer
- interaction phosphorylates tyrosine and receptor becomes an active enzyme
- active receptor enzyme activates a number of other enzymes that interact with the active tyrosine
ion channel receptors
- receptor is a protein with a channel in the centre
- agonist causes channel to open and allow specific ions to cross cell membrane to other side
ion channel receptor examples
- nicotinic acetylcholine receptor (conducts Na+ ions which muscle depolarization and contraction)
- GABA receptors (conduct Cl- ions which inhibit neurotransmission)
nuclear receptors
- receptors are mostly in the cell cytosol
- agonist enters cell and binds to receptor
- drug-receptor complex enters nucleus and stimulates even transcription which leads synthesis of new proteins and enzymes
examples of nuclear receptors
steroid, retinoids, and thyroid hormones
homologous desensitization
when a desensitization to one agonist desensitizes other agonists at the SAME receptor
heterologous desensitization
when a desensitization to one agonist in one receptor causes desensitization of to other agonists at a different receptor
agonists tent to… receptors
desensitize
antagonists tens to …. receptors
up regulate (sensitize)
how do antagonists up regulate receptors?
-they cause a withdrawal rebound effect when antagonist treatment is stopped suddenly (when more receptors become available for the agonist)
