Introduction to pharmacodynamics Flashcards
Difference between pharmacokinetics and pharmacodynamics
kinetics–effects of body on drugs
dynamics effects of drugs on body
covalent bonds
irreversible
drug removal/receptor re-activation requires resynthesis of the receptor or enzymatic removal of the drug
non-covalent bonds
reversible
most drugs bind to receptors via non-covalent bonds
non covalent bonds strongest to weakest
ionic bonds (bw positive and negative charged ions) hydrogen bonds (electrostatic bond bw net positive charge of H and net negative charge of electronegative atom hydrophobic interactions (bw hydrophobic regions of the drug and receptor) van der waals forces (weak electrostatic interactions involving dipole moments within functional groups)
dose-response curve presented 2 ways. What are the two ways and what are the differences between the two?
- Arithmetically–drug dose vs. drug effect=hyperbolic curve
- Logarithm of drug dose vs. effect=sigmoidal curve
What is the drug response curve?
relationship bw drug dose and its effects
drug dose on x axis
drug effect on y axis
dose response cruve 2 phases
linear phase
plateau phase
hyperbolic curve or sigmoidal curve
dose-response curve is more commonly presented how?
logarithm of drug dose vs. response
sigmoidal curve
still have linear phase and plateau phase
What is EMax?
maximal effect that can be produced by the drug
wHAT IS ED50?
Effective Dose 50
dose of drug that produces 50% of maximal effect
3 parameters describing the interaction of a drug with a receptor
affinity
selectivity
intrinsic activity
what is affinity?
how readily/tightly a drug binds to its rec
high affinity=good drug-rec interaction; LESS drug needed to produce a response
Low affinity=poor drug-receptor interaction; MORE drug needed to produce a response
What describes the affinity?
Kd (equilibrium dissociation constant)–molar concentration is the unit
drug conc at which 50% of the drug rec binding sites are occupied by the drug
lower Kd=higher affinity of drug for rec
higher Kd=lower affinity
What is selectivity?
- property of a drug determined by its affinities at various binding sites
- measured by comparing affinities of a drug to different receptors
- MORE selective drug affects FEWER targets
What is intrinsic activity?
ability of a drug to change a receptor function and produce a physiologic response upon its binding to the rec
What do agonists do?
bind to rec and stabalize it in a particular conformation (usually the active conformation), producing a physiologc response
-have intrinsic activity
What do antagonists do?
bind to rec but dont change its function
prevent action of the receptor in presence of agonist
do NOT have intrinsic activity
What do full agonists do?
fully activate receptors
produce a maximal pharmacological effect when all receptors are occupied
MAXIMAL intrinsic activity
What do partial agonists do?
partially activate receptors
produce a sub-maximal pharmacological effect when all receptors are occupied
intrinsic efficacy varies depending on drug but is ALWAYS SUBMAXIMAL
What do inverse agonists do?
decrease receptor signaling
decrease response at receptors with a level of constitutive receptor activity
intrinsic activity is present–inhibits receptor function
What do antagonists do?
do not change function of receptor upon binding
no pharmacological effect in absence of agonists
no intrinsic efficacy
Difference in Emax between full agonists and partial agonists
Emax is lower in partial agonists than in full agonists
Pharmacologic (R) antagonism
action at the same Rec as endogenous ligands or agonist drugs
What is chemical antagonism?
When chemical antagonist make the other drug unavailable
What is physiologic antagonism?
Occurs bw endogenous pathways regulated by different receptors
Types of pharmacologic antagonism
competitive and non competitive
what do competitive antagonists do?
compete with endogenous chemicals or agonist drugs for binding of receptors
can be displaced from the receptor by other drugs
What do non-competitive antagonists do and what are the two types?
Receptor inactivation not possible
two types: irreversible and allosteric
How do irreversible antagonists work?
irreversibly bind to and occlude the agonist site on the rec by forming covalent bonds
How do allosteric antagonists work?
bind to a site other than the agonist site to prevent or reduce agonist binding or activation of receptor
competitive antagonism graph
agonist EC50 increases
Emax does not change
Non-competive antagonism graph
agonist Emax decreases and EC50 does not change
Beneficial effects of a drug–full agonists
mimic the actions of endogenous chemicals at receptors
Example: action of mu opiod receptors by opiod analgesics–pain killers)
Beneficial effects of a drug–antagonists, partial and inverse agonists
blocks the endogenous ligands at receptors
example–blocking alpha adrenoceptors by antihypertensive drugs
beneficial and adverse effects are mediated by the same receptors/signal transduction pathway on the same cell types…how to manage?
a tight dowse control–can become toxic with too much drug
example: insulin
beneficial and adverse effects are mediated by the same receptors/signal transduction pathway on different cell types–how to manage?
avoid systemic administration
example: B2 agonist relaxes bronchial smooth muscle; increases breakdown of glycogen in liver
beneficial and adverse effects are mediated by different types of receptors
highly selective drugs–have less side effects
lower selectivity leads to increased incidence of side effects
What is potency?
amount of drug required to produce a specific phamacological effect
drugs with higher affinities for a recepter (lower Kd)=more potent
What is efficacy?
maximal pharmacological effect that a drug can produce
related to total number of receptors available to bind a drug (Bmax)
higher Bmax=higher efficacy
what is potency represented by?
amount of drug required to produce a specific effect
ED50
lower ED50=more potent drug
What is efficacy represented by?
maximal effect that a drug can produce
represented by Emax
greater Emax=more efficacious
What is a graded response and what does it answer?
answers “how much?”
response varies
mean value within a population or single subject
what does quantal response answer?
does the response occur or not?
in how many?
pre-defined response
frequency of a response within large population
graded-dose response curve
relates dose to the magnitude of a drug’s effect on a continuous scale (how much)
What does a quantal dose response curve do?
relates dose to frequency of a response within general population (in how many)
what is a non-cumulative quantal dose response curve?
number or % of individuals responding at a dose of a drug and only at that dose
cumulative quantal dose response curve
number or % of individuals responding at a dose of a drug AND at all doses lower than that dose
TI (therapeutic index)
TI=TD50/ED50
higher the TI=safer the drug
ED50=median effective dose
TD50=median toxic dose
therapeutic window
range of doses of a drug or of its concentration in a bodily system that provides safe and effective therapy
