Lecture 6: Pharmacodynamics Flashcards
pharmacodynamics
the study of what drugs do to the body
dissociation constant
Kd; equilibrium constant that measures propensity of larger object to separate (dissociate) reversibly into smaller components. the drug concentration (in moles) at which half of the receptors are bound to the drug
dissociation constants for drug-receptor or transmitter-receptor interactions can be in ___
nM to muM range
definition of receptor
large molecule; site where naturally-ocurring signaling molecules produce biological effect
agonistic action
binding to the site of the normal endogenous neurotransmitter which initiates a similar cellular response
allosteric action
binding to nearby site can facilitate transmitter binding
antagonistic action
binding to receptor site can block access of transmitter to normal binding site
4 types of receptor structure
- ionotropic
- metabotropic
- carrier proteins (transporters)
- degradative enzymes
3 steps of ionotropic receptor binding
- NT molecules bind to protein sites in receptor channel
- binding causes channel to open immediately
- when channel opens, ions are able to move into or out of the neuron
what does GABA stand for?
gamma aminobutyric acid
two broad classes of GABA receptors and types
GABAa (ionotropic)
GABAb (metabotropic)
how many protein subunits does the GABAa receptor have?
5
names of GABAa receptor subunits
gamma2
beta2 (2)
alpha1 (2)
how many membrane spanning domains does a subunit have?
4 - helices
polypeptides
amino acids linked by peptide bonds
4 important parts of GABAa receptor
- chloride channel
- GABA site
- barbiturate site
- benzodiazepine site
metabotropic receptors
G protein-coupled receptors (GPCRs)
metabotropic receptors induce the release of ___ which can trigger ___
intracellular protein
second messengers
what are 3 of the 5 examples of processes metabotropic receptors control?
- ion channel function
- energy metabolism
- cell division/differentiation
- neuron excitability
- gene expression
when G proteins bind ___ they are on, and when they bind ___ they are off
guanosine triphosphate (GTP) guanosine diphosphate (GDP)
4 steps in G protein activation of an ion channel
- NT molecule binds to GPCR
- transmitter binding activates GPCR
- activated subunit of GPCR moves to nearby ion channel
- when G protein subunit attaches to ion channel, it opens, allowing ion flow
two major processes/enzymes triggered by G protein activation
- phospholipid hydrolysis
2. adenylyl cyclase
phospholipid hydrolysis second messengers
- DG
2. IP3
major adenylyl cyclase 2nd messenger
cAMP (cyclic adenosine monophosphate)
consequence of presynaptic change in channel activity
change in amt of NT released
consequence of postsynaptic change in channel activity
change in firing pattern of neuron or cell
drugs can be ___ specific than endogenous ligands
more
carrier proteins
transporters; bind to NTs to transport them back to presynaptic neurons
2 drugs that block carrier proteins
SSRIs (block 5HT)
cocaine (blocks DA and NE)
net effect of transporter blockage
increase amount of NT available in synaptic cleft
two gradients affecting ion flow
- voltage gradient
2. concentration gradient
degradative enzymes
function to break down NTs
___ are used as pesticides and nerve gases
irreversible acetylcholine esterase inhibitors
___ are used as cognitive enhancers in alzheimer’s disease and to increase muscle contractions in myasthenia gravis
reversible AChE inhibitors
monoamine oxidase inhibitors inhibit ___ breakdown of ___ and ___
presynaptic
NE & DA
optical isomers
molecular optical images, like left and right hand
+ or D isomer rotates ___, and - or L isomer rotates ___
clockwise
counterclockwise
50/50 combination of D and L is called a ___
racemic mixture
___ can occur if ligand activation is chronically blocked. example of drug type that causes this?
- up regulation/supersensitivity
2. antipsychotics that block DA receptors
dose response curves (37); what are the two x axes used?
- percentage of subjects responding
2. intensity of response
4 variables DRCs give info about
- potency
- slope
- efficacy
- variability
potency
concentration at which drug produces desired effect; usually attach more tightly than less potent drugs. high affinity does not equal high potency
what is the difference between potency and affinity?
potency is a function of both efficacy and affinity; for a drug to be potent, it must both bind strongly and initiate a strong response. an antagonist can have high affinity but no potency
slope
linear central part of curve which indicates how sharply effect changes with each change in dose
if a small change in dose produces a large change in effective, slope is ___
steep
if a large change in dose produces small changes in effect, the slope is ___
shallow
efficacy
the maximum effect obtainable with higher doses producing no additional effect
what is the difference between potency and efficacy?
some drugs may be potent, but might never be able to produce a peak response no matter how much is given
a drug that is more efficacious produces a ___ peak than a less efficacious drug
higher/greater maximum
spare receptors
maximum effect obtainable with a drug can occur when not all of the receptors have been bound by ligand
variability
individ difference in drug response can include potency, max effect, or slope
4 types of DRCs
- full agonistic
- partial agonistic
- antagonistic
- inverse agonistic
a partial agonist has a similar action to a full agonist, but is less ___
efficacious
antagonist
blocks or limits action of ligand, but has no effect of its own (no potency)
inverse agonist
binding to receptor site produces effect opposite to that of the endogenous ligand
allosteric modulators
affect receptor response by binding to site that is diff from site to which endogenous ligand binds
positive allosteric modulators ___ response to endogenous ligand
increase
negative allosteric modulators ___ effect of endogenous ligand
diminish
ED50
drug dose that produces desired effect in 50% of subjects
LD50
lethal dose for 50% of test subjects
TI
therapeutic index; ratio of LD50 to ED50
TR
therapeutic ratio; dose that causes adverse fx in 50% of pop to dose that causes therapeutic effect in 50%
the greater the TI, the ____ the drug
safer
TI =
LD50/ED50
The lower the ED50, the ___ the potency. the lower the TI, the ____ the safety
potency
safety
double-blind tests with placebo run-in period
every patient given a placebo for a week; those who respond positively removed
nocebo effect
negative expectation of phenom causes it to have more negative effect
polypharmacy
combining meds to improve outcome
pharmacodynamic redundancy
two drugs have same or overlapping mechanisms of action
pharmacodynamic interaction
two drugs may oppose each other. e.g. antipsychotic blocks DA type 2 receptors, while ADHD stimulant increases DA levels
pharmacokinetic interactions
one drug may affect another drug’s ADME
axes of a graph of PK
axes of a graph of PD
combination graph?
- concentration vs. time
- effect vs. conc(log)
- PK/PD - effect vs. time
