EXAM 2 VOCAB Flashcards
Pharmacology
-science of INTERACTIONS of CHEMICAL compounds with BIOLOGICAL systems
-mechanisms of drug action
Pharmacodynamics
-study EFFECTS and ACTION of drugs
-correlation of their EFFECTS with their CHEMICAL STRUCTURE
-looks at drug at site of action: EFFECT and RESPONSE
Pharmacokinetics
-study of ADME of xenobiotics
Mechanisms of drug action
HOW and WHERE drugs act
Action of drugs
Agonist or antagonist
Nature of Drugs
-defined by action
-act on receptors
-endogenous drugs (hormones or NT) or xenobiotics
-includes poison/toxins
Drug chemical bond interactions
-covalent
-electrostatic
-hydrophobic
Drug shape and design
-for receptor specificity
-enantiomers and structural studies
Drug receptor
-cornerstone of pharmacology
-INTERACTS with drug and INITIATES chain of events to produce EFFECTS
AGONIST
interaction with receptor stimulates response
PharmacoDYNAMIC DR principles
- D + R –> DR for all
-DR –> effector molecule
-DR –> coupling molecule –> effector molecule
-DR –> inhibition of metabolism of ligand –> effector molecule
-all end in effect
PharmacoDYNAMIC principles
-Drug binding first step
-orthosteric or allosteric
-inhibition of metabolism/reuptake
-duration of action can be influenced by receptor and drug
orthosteric site
-active site
-binds endogenous substrate
-agonists, antagonists
Endogenous ligand of dopamine receptor
dopamine
Allosteric site
PAM and NAM
PAM (positive allosteric modulator)
-allosteric activator
Purpose of Drug Therapy
-produce EFFECT of the drug
-drug must achieve enough CONCENTRATION at it’s SITES of ACTION
-achieve MAXIMUM positive effects while MINIMIZING undesired effects
NO DRUG WILL HAVE ONLY ONE EFFECT
TRUE
Drug specificity
-AFFINITY for receptor
-DISTRIBUTION of receptor
-MULTIPLE receptors (good and bad)
-ENANTIOMERS
-ACUTE vs CHRONIC effects (tolerance)
Drugs ___ cellular function
modify
Sites of drug action
in, out, on cell
-may need specifics if i no feel so good
Receptor structure types
-regulatory, transport, and structural proteins
-enzymes
Receptors determine:
-quantitative relationship between DOSE and EFFECTS
-SELECTIVITY of drug (size, shape, charge, and changes in chemical structure)
Antagonists
-bind WITHOUT altering receptor function
-blockers
Data of DR interactions
-Receptor BINDING/target engagement ASSAYS
-Functional assays
Receptor BINDING/target engagement ASSAYS
-measure static event (receptor-drug binding) not function
Functional assays
-assessing signaling events associated with receptor activity
-ion flux, second messenger, etc
Concentration-effect curves
-responses to low concentrations of drug increase proportionally
-as dose increases, response increases
-levels off
-linear or semi log (S curve)
linear vs Semi log
semi log better
10-90 = 3 log rule
3 logs between 10% and 90%
-10% +1 log = 50% (EC50)
-50% + 1 log = 90%
If EC50 = 10, then 90% is
100
If EC50 = 10, then 10% is
1
10^-7
100 nanomolar
9.5 x 10^-7
950 nanomolar
-multiply by 100 nM
10^-6
micromolar
Affinity
-ability of drug to interact with receptor
-KD
-determinant of POTENCY
-one drug can have many for diff receptors
-differ from receptor to receptor
low KD
high affinity
tight binding
high KD
low affinity
loose binding
Effect of drug is proportional to
amount of DR complex formed (receptors bound)
D+R <–> DR –> effect
Ka(on) —>
Kd(off) <—-
rate of association
-Ka(on)
-D+R
-binding
-increasing part on dose-response curve
rate of dissociation
-Kd(off)
-[DR] splitting
-decreasing part on dose-response curve
KD (dissociation CONSTANT)
=koff/kon
=[D][R]/[DR]
-50% of receptors are bound
Drugs can have same affinities
but different koff or kon
Fast dissociation
low koff
Law of mass action
D+R –> DR —> effect
when [D][R] = [DR], KD is concentration where 50% receptors are bound
-50% Bmax=KD
*assumptions made
50% of Bmax
=KD
Radio receptor binding assay
- receptor
- add ligand (radio labeled) and let bind
- filter out unbound ligand
-count remaining amount of receptors bound to drug
Pharmacological profiling
-competition testing several unlabeled compounds simultaneously
-IC50 and Ki
MORE
MORE
MORE
Ki vs KD
-KD more generally
-Ki relative
Bmax
total # of receptors
Saturation Binding analysis
-requires labeled ligand
-not good for HTS
-use of heterologous competition assays for pharmacological profiling
COMPETITION BINDING ASSAY
-labeled ligands binding receptors
-look at ability of drug to displace (compete) ligand
-CHeng-Crusoff
-y=%binding, x=[drug]
-IC50
-Ki
IC50
-concentration at which 50% binding is inhibited
Cheng-Prusoff equation
Ki = IC50/[1+L/KD]
-L concentration of ligand
-KD of ligand
D2 receptors
dopamine
-parkinsons
-schizophrenia
H1 receptors
-histamine
-allergies
-blockage = sleepy
B1 receptors
-heart rate
What parameter is NOT required to calculate Ki from Competitive binding assay data?
Kd of radioligand
Bmax value
IC50 of test compound
Concentration of radio ligand [L]
Bmax
all we need : Ki= IC50/[1+L/Kd]
Why cant labs compare IC50 values
-dependent on KD of ligand AND ligand CONCENTRATION
-5 kappa deltas vs 500 kappa deltas
selectivity ratio (MOR/DOR) (IC50 drug one/IC50 drug2)
lower number is HIGHER affinity for numerator
H1 blockers
eepy
Most antipsychotic drugs act as
receptor ANTangonists
D1 vs D2 binding measures
D2 shows better correlation between AFFINITY/potency and EFFECTIVENESS
if Bmax= 20 KD=
10
Antagonist and agonist binding sites are
overlapping
Magnitude of drug RESPONSE is influenced by
pharmacokinetics and pharmacology
