EXAM 2 VOCAB Flashcards
1
Q
Pharmacology
A
-science of INTERACTIONS of CHEMICAL compounds with BIOLOGICAL systems
-mechanisms of drug action
2
Q
Pharmacodynamics
A
-study EFFECTS and ACTION of drugs
-correlation of their EFFECTS with their CHEMICAL STRUCTURE
-looks at drug at site of action: EFFECT and RESPONSE
3
Q
Pharmacokinetics
A
-study of ADME of xenobiotics
4
Q
Mechanisms of drug action
A
HOW and WHERE drugs act
5
Q
Action of drugs
A
Agonist or antagonist
6
Q
Nature of Drugs
A
-defined by action
-act on receptors
-endogenous drugs (hormones or NT) or xenobiotics
-includes poison/toxins
7
Q
Drug chemical bond interactions
A
-covalent
-electrostatic
-hydrophobic
8
Q
Drug shape and design
A
-for receptor specificity
-enantiomers and structural studies
9
Q
Drug receptor
A
-cornerstone of pharmacology
-INTERACTS with drug and INITIATES chain of events to produce EFFECTS
10
Q
AGONIST
A
interaction with receptor stimulates response
11
Q
PharmacoDYNAMIC DR principles
A
- 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
12
Q
PharmacoDYNAMIC principles
A
-Drug binding first step
-orthosteric or allosteric
-inhibition of metabolism/reuptake
-duration of action can be influenced by receptor and drug
13
Q
orthosteric site
A
-active site
-binds endogenous substrate
-agonists, antagonists
14
Q
Endogenous ligand of dopamine receptor
A
dopamine
15
Q
Allosteric site
A
PAM and NAM
16
Q
PAM (positive allosteric modulator)
A
-allosteric activator
17
Q
Purpose of Drug Therapy
A
-produce EFFECT of the drug
-drug must achieve enough CONCENTRATION at it’s SITES of ACTION
-achieve MAXIMUM positive effects while MINIMIZING undesired effects
18
Q
NO DRUG WILL HAVE ONLY ONE EFFECT
A
TRUE
19
Q
Drug specificity
A
-AFFINITY for receptor
-DISTRIBUTION of receptor
-MULTIPLE receptors (good and bad)
-ENANTIOMERS
-ACUTE vs CHRONIC effects (tolerance)
20
Q
Drugs ___ cellular function
A
modify
21
Q
Sites of drug action
A
in, out, on cell
-may need specifics if i no feel so good
22
Q
Receptor structure types
A
-regulatory, transport, and structural proteins
-enzymes
23
Q
Receptors determine:
A
-quantitative relationship between DOSE and EFFECTS
-SELECTIVITY of drug (size, shape, charge, and changes in chemical structure)
24
Q
Antagonists
A
-bind WITHOUT altering receptor function
-blockers
25
Data of DR interactions
-Receptor BINDING/target engagement ASSAYS
-Functional assays
26
Receptor BINDING/target engagement ASSAYS
-measure static event (receptor-drug binding) not function
27
Functional assays
-assessing signaling events associated with receptor activity
-ion flux, second messenger, etc
28
Concentration-effect curves
-responses to low concentrations of drug increase proportionally
-as dose increases, response increases
-levels off
-linear or semi log (S curve)
29
linear vs Semi log
semi log better
30
10-90 = 3 log rule
3 logs between 10% and 90%
-10% +1 log = 50% (EC50)
-50% + 1 log = 90%
31
If EC50 = 10, then 90% is
100
32
If EC50 = 10, then 10% is
1
33
10^-7
100 nanomolar
34
9.5 x 10^-7
950 nanomolar
-multiply by 100 nM
35
10^-6
micromolar
36
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
36
low KD
high affinity
tight binding
37
high KD
low affinity
loose binding
38
Effect of drug is proportional to
amount of DR complex formed (receptors bound)
D+R <--> DR --> effect
Ka(on) --->
Kd(off) <----
39
rate of association
-Ka(on)
-D+R
-binding
-increasing part on dose-response curve
40
rate of dissociation
-Kd(off)
-[DR] splitting
-decreasing part on dose-response curve
41
KD (dissociation CONSTANT)
=koff/kon
=[D][R]/[DR]
-50% of receptors are bound
42
Drugs can have same affinities
but different koff or kon
43
Fast dissociation
low koff
44
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
45
50% of Bmax
=KD
46
Radio receptor binding assay
1. receptor
2. add ligand (radio labeled) and let bind
3. filter out unbound ligand
-count remaining amount of receptors bound to drug
47
Pharmacological profiling
-competition testing several unlabeled compounds simultaneously
-IC50 and Ki
MORE
MORE
MORE
48
Ki vs KD
-KD more generally
-Ki relative
49
Bmax
total # of receptors
50
Saturation Binding analysis
-requires labeled ligand
-not good for HTS
-use of heterologous competition assays for pharmacological profiling
51
COMPETITION BINDING ASSAY
-labeled ligands binding receptors
-look at ability of drug to displace (compete) ligand
-CHeng-Crusoff
-y=%binding, x=[drug]
-IC50
-Ki
52
IC50
-concentration at which 50% binding is inhibited
53
Cheng-Prusoff equation
Ki = IC50/[1+L/KD]
-L concentration of ligand
-KD of ligand
54
D2 receptors
dopamine
-parkinsons
-schizophrenia
55
H1 receptors
-histamine
-allergies
-blockage = sleepy
56
B1 receptors
-heart rate
57
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]
58
Why cant labs compare IC50 values
-dependent on KD of ligand AND ligand CONCENTRATION
-5 kappa deltas vs 500 kappa deltas
59
selectivity ratio (MOR/DOR) (IC50 drug one/IC50 drug2)
lower number is HIGHER affinity for numerator
60
H1 blockers
eepy
61
Most antipsychotic drugs act as
receptor ANTangonists
62
D1 vs D2 binding measures
D2 shows better correlation between AFFINITY/potency and EFFECTIVENESS
63
if Bmax= 20 KD=
10
64
Antagonist and agonist binding sites are
overlapping
65
Magnitude of drug RESPONSE is influenced by
pharmacokinetics and pharmacology
66
Bmax values
-REGULATED by drug treatment as an adaptive response
-receptor running away from abusive ex (antagonist) or running to cool guy (agonist)
=total # of receptors can change
67
Propanolol
-B1 blocker
-treat hypertension
68
binding of agonist results in
induced fit that activates receptor
69
binding of antagonist results in
-induced fit that does NOT activate receptor
-can bind to more of the receptor than agonist
-broader
-blocks coactivators from binding
70
Agonist spectrum
-full inverse
-partial inverse
-silent ANTagonist
-partial agonist
-full agonist
-SUPER agonist
71
Potency
-DOSE of drug required to produce particular EFFECT
-based on doses that produce similar response
-usually EC50
72
EC50
-amount of dose needed to produce 50% response
73
Lower EC50
HIGHER potency
74
Efficacy
-measure of biological response
-%
75
Strong agonist
HIGH affinity
HIGH efficacy
76
maximal efficacy limited by
TOXICITY
77
Efficacy v potency graph
-% vs log[D]
-functional assay
78
middle log value
ex: between -7 and -6
-6.52
=300nm
79
-9, -8.52, -8, -7.52, -7, -6.52, -6 log values
1nm, 3nm, 10nm, 30nm, 100 nm, 300nm, 1um
80
Partial Agonist
-produces reduced response even at full occupancy
-may inhibit competitively the response to a full agonist
-KD might be same
81
Aripiprazole
-partial agonist
-D2 receptor
-schizophrenia and depression
82
Buprenorphine
-partial agonist
-opiate receptors
-opioid addiction treatment
83
Buspirone
-partial agonist
-serotonin
-Depression
84
Partial agonist effects Opioid example
-full agonist hits a %bound to feel euphoria but increasing further [D] = die
-partial agonist goes up to % effect of euphoria and no higher
-Antagonist blocks methadone from binding at all = withdrawal
85
Partial agonist THEORY
-normal agonist close loop c of receptor
-partial half close loop c
-antagonist cannot close loop c
-by physical shape of molecule
-partial agonist engages less of the receptor
86
As partial agonist concentration increases
-FULL agonist binding decreases
-PARTIAL agonist binding increases
-decreases total response
87
Inverse Agonist
-opposite response
-requires constitutive activity
-can be full or partial
-stabilize inactive form of receptor
-response can be altered by other agonists or antagonists
-ex: rimonobant
88
Rimonobant (Acomplia)
-Cannaboid receptors
-INVERSE agonist of THC
-reduced hunger but caused depression
89
Constitutive activity
-can only work on active conformation of receptor in absence of agonist
-reversed by inverse agonist
90
constitutive activity absent
-inverse agonist looks like silent antagonists
91
Constitutive activity present
-inverse agonist reverses constitutive activity
-lower response
92
Antagonism types
-competitive
-noncompetitive
-irreversible (non competitive)
93
Competitive Antagonism
-reversible by increasing dose of AGONIST
-binds active site
-has affinity but not efficacy
94
Agonist dose-response curve in presence of antagonist
-shifted right proportional to concentration of agonist
-reduces potency
-C'=C(1+L/KD)
-only KD and EC50 changed
*note multiplication
-Schild plot (functional)
95
Schild plot
-can be used to calculate KD of ligand to generate PA2 value
-estimate AFFINITY
-functional
96
Binding Analysis of competitive antagonists
affinity generally correlates with potency
97
Magnitude of inhibition (clinical response) depends on:
-antagonist concentration
-relative potency between antagonists
-concentration of agonist
98
Noncompetitive Antagonist
-allosteric
-cannot be reversed by increasing agonist concentration
99
increase of noncompetitive Antagonist
-increase KD
-decrease Emax
100
Irreversible (noncompetitive) antagonist
-bind active site
-less easily displaced
-covalent bond
-shifted to the right
-max response still possible bc of SPARE RECEPTORS (resembles competitive)
101
Increase [Irreversible antagonist]
-max response decreases as spare receptors are occupied
-this part resembles noncompetitive
102
Irreversible vs noncompetitve
need way more information given to figure that out
103
Duration of irreversible antagonist action is dependent on
receptor turnover
104
Competitive inhibition graph
-brachiosaurus walking (competitive bc it's a race!)
105
noncompetitive inhibition graph
-brachiosaurus eating from a short tree (noncompetitive bc he just having a lil treat!)
106
Spare receptors (receptor reserve)
-max response by agonist even when less than 100% receptors bound
-irreversible Antagonists
107
Spare receptors in heart muscle
-allows heart to respond to catecholamines at 90% occupancy of irreversible antagonist
108
Spare receptors are dependent of
-system/tissues
-effector numbers
-signaling pathway
109
Functional Antagonism
-2 drugs influence system in OPPOSITE directions
-each drug unhindered
-histamine offset by epinephrine
-system wide not receptor specific
110
Chemical Antagonism
-chemical reaction between agonist and antagonist to form inactive product
-agonist inactivated in proportion to extent of reaction with agonist
-calcium antacids and tetracycline antibiotics
-cyanide and sodium nitrate
111
Allosteric Ligands
-not active site
-PAM and NAM
-signalin texture
112
Allosteric actions
-antagonism (NAM)
-potentiation (PAM)
113
Allosteric Ligand benefits
-increased specificity for receptors with similar orthosteric binding sites
-increased safety due to ceiling effect
-provide more physiological/temporal signaling
114
Temporal signaling
-PAM in parkinsons can make more dopamine for movement
-NAM in seizures makes less NT
115
PAM increases
Emax
116
Neutral allosteric ligand
-displace/block PAM and NAMs
117
PAM safety
safer than orthosteric agonists
118
5 types of receptors
1. intracellular
2. cytokine
3. tyrosine kinase
4. ion channel
5. Gprotein coupled
119
Intracellular receptors
-lipid-soluble ligand crosses membrane to work on receptor
-steroids, vitamin D
-work on gene expression
120
Intracelular receptor
-DR binds to specific DNA sequences near gene
-stimulate transcription of genes
-target gene regulated
-response
121
Intracellular receptor therapeutic significance
-lag period
-effects persist after drug gone bc of slow turnover of proteins
-high affinity
-no correlation between plasma level of hormone and effect
122
Other intracellular receptors
-effector enzymes
-adenyylyl cyclase, phospholipase, kinases, phosphatases, ubiquitinases
-any intracellular protein with downstream activity
123
Effector enzymes
-regulate cellular function
-intracellular nonreceptor receptor
-translation, transcription, membtane potential
124
Cytokine receptor pathway (JAK-STAT pathway)
-cytokine binds extracellular domain
-conformational change
-Janus kinase recruited
-kinase phosphorylates receptor
-recruit STAT protein
-dimerization of stat
-gene regulation by STAT in nucleus
125
cytokine receptor ex
IL, IFN, Growth hormone, prolactin
126
cytokine receptors
-similar to protein tyrosine kinases
-JAK-STAT
-COVID-19 storm
127
Protein Tyrosine kinases
-extracellular hormone binding domain and cytoplasmic enzyme domain with protein tyrosine kinase activity
-inactive kinase
-ligand binds
-dimerization
-phosphorylation
=affinity to bind Grb2
-invoke activation of Ras pathway
=gene transcription
128
tyrosine kinase action
-limited by down regulation
-upon ligand binding, endocytosis of receptor is stimulated
129
ion channels
-voltage activated
-ligand activated
130
voltage activate ion channels
-regulated by membrane potential
-positive ions = more likely to fire
-allosteric site
-local anesthetics
131
voltage-gated ion channels are regulated by
-phosphorylation
-G proteins
132
ligand-gated ion channels
-mimicked by many drugs
-acetylcholine, GABA, glutamate
133
ligand-gated ion channels mechanism
-ligand binds
-signal transmitted across membrane by increasing transmembrane conduction of ion
-alters electrical potential
-FAST --important for synapses
134
steroid receptors
-HOURS
135
G protein-coupled receptors (GPCRs)
-7 transmembrane receptor
-B receptor
-800 which is alot
-involved in like EVERYTHING
-target of 40% of all drugs
-Gproteins, effectors, 2nd messenger
136
Bonus question
1971: Earl Sutherland Jr
137
1971: Earl Sutherland Jr
CYCLIC AMP
138
GPCR classes
A, B, C
-C is venus flytrap glutamate
139
GPCR 2nd messengers
-cyclic AMP and GMP
-Ca2+
-phosphoinositides
140
GPCR signaling components
R-G-E
141
GPCR signaling
-ligand detected by cell surface receptor (R)
-receptor activates G-protein
-Ga or GBy changes activity of an effector
-effector changes concentration of 2nd messenger = effect
142
G protein cycle
-detect ligand
-Ga-GDP inactive
-Ga-GTP or GBy disassociate and activate enzyme
-enzyme releases second messengers
143
G protein subunits
-Gas
-Gai
-Gaq/11
-Ga12/13
-GBy
-all regulate adenylyl cyclases and ion channels
-but also lots of others
144
Gas (stimulatory)
-INCREASE adenyl cylcases
-Gas and Gaolf
145
Gai (inhibitory)
-DECREASE adenylyl cyclases
-Gi1-3, Gao,z,t,g
146
Gaq/11
-INCREASE phospholipase C 1B
-Gq
147
Ga12/13
Rho guanine exchange factors (recruit)
148
GBY
-DECREASE adenylyl cyclases
-open Ca, K ion channels
149
second messengers
-cAMP
-Gs-AC-cAMP
-cGMP
-Calcium and phosphoinosotides
-diverse and complex
150
cAMP
-stimulates cAMP-dependent protein kinases (PKA)
-specificity depends on substrates of kinases expressed in different cells and through cellular compartmentalization of signaling complexes
-B1 receptor for asthma
151
cAMP effector enzyme
-adenylyl cyclase
-converts ATP to cAMP
152
measuring cAMP
-nonradioactive approaches
-EPAC (protein based)
-HTRF (fluorecent)
153
Calcium and phosphoinosotides
-effector enzyme: Phospholipase C (PLC)
= release of phosphotides and diacylglycerol
154
phosphoinositides
-from PLC
=release of calcium
155
diacylglycerol
-from PLC
-can activate protein kinase C
-M3 muscarinic receptors in alzheimers
156
cGMP
-effector: guanyl cyclase
-cGMP activates kinase (PKG)
-regulated by nitric oxide
-more specific
157
cGMP/NO
-breaks down byPDE5
158
viagra
-blocks PDE5
-prolongs cGMP/NO
159
more drugs target
kinases than phosphatases
160
receptor-induced adaptations
-homologous desensitization
-heterologous
161
Homologous desensitization
-rapid desensitization
-receptor uncoupling-arrestin binding
-sequestration and fate =
-recycling (dephosphorylation) and
-lysosomal degradation
-ACTIVATED RECEPTOR DESENSITIZES SELF
162
B arrestins
-adaptor protein that links GPCRs to MAP kinase pathway
163
Recycling
-dephosphorylation
164
