Week 3 - Pharmacodynamics Flashcards
1
Q
Pharmacodynamics describes the relationship between drug _________ and _____ of action at the ______ level.
A
concentration, intensity, receptor
2
Q
Most drugs act via an ________ with certain proteins either of the ____ or of the ______
A
interaction, host, pathogen
3
Q
**Four types of protein are targeted by drugs:
A
- Enzymes
- Carriers (transporters)
- Ion channels
- Receptors
4
Q
The term receptor is only used when the interaction triggers a _____ of events for _____ ______.
A
cascade, signal transmission
5
Q
Binding site
First, the drug molecule and its _____ must interact.
The selective interaction must result in a response = ?
A
target, Lock and Key
6
Q
Drug responses more commonly reflect the interaction of the drug, acting as a _____, with receptor
A
ligand
7
Q
Drug is a molecule that interacts with _____ molecular components of an organism to produce ______ and _____ changes/effects.
A
specific, biochemical, physiological
8
Q
Drugs may be viewed as ________ ____.
A
exogenous ligands
9
Q
Inhibitors →
A
Normal reaction inhibited.
10
Q
False substrate →
A
Abnormal metabolite produced
11
Q
Prodrug
A
12
Q
Make cards for remaining
A
13
Q
Cyclooxygenases are the target site for ______ and their inhibition leads to the ______ of ________ _______.
A
NSAIDs, suppression, proinflammatory prostaglandins
14
Q
Acetylcholinesterase (metabolizes _______), is a target site for ________ inhibitors e.g., ?
A
acetylcholine, cholinesterase, neostigmine and physostigmine
15
Q
Antibiotics may act by _____ enzymes involved in cell ____ biosynthesis, _____ ____ metabolism and ____, or ______ synthesis.
A
inhibiting, wall, nucleic acid, repair, protein
16
Q
Enzyme as a Target: Cyclooxygenase-1 and 2
A
Do not need to memorize these mechanisms
17
Q
Non-steroidal antiinflammatory drugs (NSAIDs) block the ________-_ and __ and stop thereby the synthesis of _________.
A
cyclooxygenase-1, 2, prostaglandins
18
Q
Enzyme as a Target: Acetylcholinesterase (AChE)
A
19
Q
AChE is a ________ enzyme primarily found at
________ neuromuscular junctions, especially in ______ and _____.
A
cholinergic, postsynaptic , muscles, nerves
20
Q
_______ breaks down acetylcholine (ACh) into _____ ____ and choline. The primary role is to ________ neuronal transmission and signaling between _____ to prevent ACh dispersal and ______ of nearby receptors
A
AChE, acetic acid, terminate, synapses, activation
21
Q
Carriers, also termed ______ _____ proteins, are _____ sites for many drugs.
A
membrane transport, target
22
Q
The Na+/K+/2Cl- symport in the nephron is the site of action of _______ and other _____ such as torasemide. The biophase (effect site) for all diuretics is the _____, not _____ to develop their diuretic action.
A
furosemide, diuretics, urine, plasma
23
Q
Sodium pump Na+/K+ ATPase, ATP-powered ion pumps, are the target sites for __________ _______.
A
cardioactive digitalis
24
Q
The ______ pump in the gastric parietal cells is the target site for proton pump ______ such as ______.
A
K+/H+, inhibitors, omeprazole
25
Carrier as a Target: The Na+/K+ ATPase
26
The molecular target of cardiac glycosides is the \_\_\_\_\_\_\_\_\_\_\_, which maintains sodium and potassium gradients across the plasma membrane.
Na+/K+ ATPase,
27
Those gradients are required for the regulation of ___ \_\_\_\_\_, ____ transport of molecules or the creation and propagation of the ____ or ___ potential of electrically excitable cells such as _____ cells.
cell volume, active, action, resting, cardiac
28
Carrier as a Target: NKCC Carrier
29
The diuretics furosemide and bumetanide block the ____ carrier (?) causing a decrease in ____ reabsorption and a concomitant increase in water _______ by the kidneys.
NKCC, sodium, potassium, 2 chloride
carrier aka BSC = bumetanide-sensitive carrier, NaCl, elimination
this carrier was discovered with this drug
30
Carrier as a Target: H+/K+ ATPase (Proton pump)
Omeprazole interacts with this transporter
31
Omeprazole blocks the activity of the _____ \_\_\_\_\_\_ in the ____ cells of the \_\_\_\_\_
reducing the secretion of ____ and the formation of _______ \_\_\_\_ (\_\_\_)
H+/K+ ATPase, parietal, stomach, protons, hydrochloric acid, HCl
32
Some drugs can produce their effects by interacting with ___ \_\_\_\_\_.
ion channels
33
Voltage-dependent gated ____ channels are the main target of the most calcium-channel \_\_\_\_\_\_, such as the _________ drugs \_\_\_\_\_.
calcium, blockers, antiarrhythmic, verapamil
34
Ion Channels as a Target: Na+ and K+ Channels
Receptor 0, 1, 3
35
Several antiarrhythmic drugs ____ ion channels located on the membrane of ____ cells, thereby altering the cardiac _____ \_\_\_\_\_ or its generation or propagation. This results in changes of the spread of _____ or the pattern of \_\_\_\_\_\_. Thereby, these drugs suppress ________ \_\_\_\_\_\_.
block, cardiac, action potential, activation, repolarization, cardiac arrhythmia
36
Receptors is a term reserved only for _______ proteins that play a role in _____ \_\_\_\_\_\_\_.
regulatory, cell communication
37
\*\*Note, \_\_\_\_\_\_, ____ \_\_\_\_\_\_\_, and ______ are not classified as receptors
enzymes, ion channels, carriers
38
Some important properties of receptors are illustrated by the action of _______ (?) on the heart.
adrenaline, epinephrine
39
The β1 adrenoceptor serves as a recognition site for _______ and other \_\_\_\_\_\_. When ______ binds to this receptor, a train of reactions is initiated, leading to an ______ in force and ____ of the _____ \_\_\_\_.
adrenaline, catecholamines, adrenaline, increase, rate, heart beat
40
Adrenoceptor = ?
Adrenergic receptor
41
What is the largest family of receptors?
G-protein-coupled receptors (GPCR; metabotropic receptors)
42
50% of all commercial drugs act in a _____ \_\_\_\_\_\_ or \_\_\_\_\_\_. Many new drugs will probably be target \_\_\_\_.
GPCR, directly, indirectly, GPCRs
43
\_\_\_\_\_\_ are involved in almost all physiological processes
GPCRs
44
Examples of GPCRs
o Neurotransmitters (adrenalin, acetylcholine, dopamine, etc)
o Hormones (angiotensin, calcitonin, gastrin, etc)
o Olfactory stimuli
o Opioids
“Oh No Harry, Opioids!"
45
Cell Signaling via G-Protein coupled Receptors (GPCRs)
GPCR receptor
Once a ligand binds to receptor, works in function with GTP protein. Once this reaction occurs, this protein can stimulate three different pathways (red, green, blue).
46
GPCRs as Targets: Beta 2 adrenergic receptor
Receptor once activated works with protein G.
47
Describe the function of the bronchodilatory albulterol.
The bronchodilator albuterol produces its effect through interaction with β2- adrenergic receptors (β2AR) located in the plasma membrane of airway smooth muscle cells.
The β2AR is linked to a stimulatory guanine-nucleotide–binding protein (Gs).
Albuterol binding to the β2AR changes the conformation of Gs, leading to the activation of adenylate cyclase (AC), which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP).
cAMP activates the protein kinase A (PKA) which leads to smooth muscle cell relaxation in the airways (bronchodilation)
48
Receptor is a ______ or a ______ structure on the ______ of/or _____ a cell.
molecule, polymeric, surface, inside
49
Receptors possess an _____ system called signal-transduction pathways.
effector,
50
A receptor recognizes and binds an _______ compound, also termed \_\_\_\_\_.
endogenous, ligands
51
Endogenous neurotransmitters, such as hormones, are __________ \_\_\_\_\_.
endogenous ligands
52
Drugs may be viewed as ?
exogenous ligands
53
After attachment to a receptor site, a drug may produce ?
a cascade of biochemical events that result in drug action.
54
Drugs ______ or ______ the actions of endogenous ligands
mimic, prevent
55
The distinction between agonists and antagonists only exists for ________ receptors. We cannot usefully speak of agonists for the other classes of drug target.
pharmacological
56
Types of protein targeted by drugs
1. Enzymes
2. Carriers (transporters)
3. Ion channels
4. Receptors
57
Agonist and Antagonist Ligands
Agonist interacts with receptor -→ induces?
Antagonist?
58
Drug receptor theories consist of a collection of _______ models that permit ______ and _____ description of the relationship between drug ______ and their \_\_\_\_.
evolving, qualitative, quantitative, concentration, effect
59
\_\_\_\_\_\_ _____ was the first model proposed by Clark in 1923
Occupancy theory
60
The receptor-ligand interaction was described as a ________ interaction and the \_\_\_\_\_-\_\_\_\_\_\_\_ complex was considered responsible for the generation of an effect.
biomolecular, receptor, ligand
61
The occupancy theory model assumes that drug response is a ______ function of drug occupancy at the _____ level.
linear, receptor
This model postulated that when there is more receptor occupied by agonist → greater reaction.
62
The drug has to occupy ____ \_\_\_\_\_\_ to achieve a _____ effect (Emax) and the response is terminated when the drug ______ from the receptor.
all receptor, maximal, dissociates
Reaction is only possible with agonist or anatagnoist is bound to receptor. Once dissocaited, no reaction anymore.
63
Response is proportional to the number of ______ \_\_\_\_\_. The more receptors occupied by a drug the ______ the response.
activated, receptors, greater
64
In which Effect is the ______ effect; Emax is the _______ possible effect; kd is the _________ constant of _______ (a parameter measuring \_\_\_\_\_) and Drug is the drug \_\_\_\_\_\_\_
observed, maximal, equilibrium, dissociation, affinity, concentration
65
Agonist activates these receptors → very high Emax response.
Antagonist does not activate receptor.
66
In the Occupancy Theory (Graded Activation Model)
• The unliganded receptor is _____ (no ____ activity)
• The level of response is explained by the concept of \_\_\_\_\_
• The more receptors occupied by a drug the _____ the response
• An antagonist is a drug with a ___ (molecular) efficacy but that blocks ______ to the _____ of other ligands.
silent, basal, efficacy, greater, null, access, receptor
67
The physiological response produced by a ligand is _____ directly ________ to occupancy and it was evident that some drugs acting at the same receptor could elicit ______ maximal effects at maximal receptor occupancy leading to the notion of _____ agonist versus ____ agonist.
not, proportional, different, partial, full
68
Today, the \_\_\_\_-\_\_\_\_ model of drug action is consistent with the most observations of agonists and antagonists.
two-state
69
The two-state model of receptors assumes that the __________ \_\_\_\_\_\_\_ exists in two extreme conformations with the _____ and _____ forms in dynamic equilibrium. This equilibrium may be shifted by the binding of _____ to the \_\_\_\_\_. It is the _______ change of the receptors from an _____ to ____ state that initiates
the pharmacological response.
receptor molecule, active, inactive, ligands, receptor, conformational, inactive, active
70
Two-state model of receptors
Drug binding to R may shift the equilibrium in either direction
71
Two-state model of receptors
R1 reacts with LRa, etc.
72
An agonist is a drug with a _____ affinity for Ra than for __ will drive the equilibrium to Ra and thereby _____ the receptor.
higher, Ri, activate
73
A full agonist is a drug is selective enough regarding ___ to drive all the receptor in its ____ state and get a _____ response
Ra, active, maximal
74
A partial agonist is a drug that has only a ______ greater affinity for Ra than for Ri, its effect will be ____ than for a full agonist.
moderately, lower
75
An inverse agonist is a drug with a _____ affinity for Ri than for Ra will shift the equilibrium towards ___ and will produce an effect ______ to that of an agonist.
higher, Ri, opposite
76
A neutral agonist is a drug that binds Ra and Ri with ____ affinity will ___ alter the equilibrium between Ra and Ri, will have ___ \_\_\_\_ effect of its own, and will act as ______ antagonist.
equal, not, no, net, competitive
Antagonist is viewed as a neutral agonist in two-state model.
77
Difference between classical receptor versus two-state model.
78
In the frame of the two-state model, any drug is viewed as an agonist, and an antagonist is a _____ agonist producing no response. According to this model, efficacy is genuinely explained by the relative affinity of the
drug for ____ of the states of the receptor (activated or resting state)
neutral, one
79
Example of two-state model of receptors
GABA-benzodiazepine receptor exists in two conformations:
• An active open channel conformation with high affinity for GABA and an inactive closed conformation with low affinity for GABA (the two forms are in equilibrium).
• Diazepam (an agonist) shows high affinity for the active conformation stabilizing the binding of GABA to the activated conformation.
• The inactive conformation would be favored in the presence of an inverse agonists
80
A drug is said to be an agonist when it binds and activates receptors to _____ stimulatory effects of _______ ligands. It produces a measurable _______ or _______ response (characteristic of the receptor (e.g., ?)
mimic, endogenous, physiological, pharmacological, contraction, relaxation, secretion, enzyme activation
81
Primary agonist: ?
A drug binds to the same site as the endogenous ligands
82
Allosteric agonist: ?
A drug binds to a different region of the receptor
83
Most anesthetic drugs
\_\_\_\_\_\_\_\_ ______ \_\_\_\_\_ and disrupt corresponding physiological circuits.
allosterically modulate GABAR
84
Full (pure) agonist: produces a _____ effect
maximal
85
\_\_\_\_\_\_\_ and _______ are full agonist of opioid (\_\_\_) receptors and able to initiate strong
analgesia.
Morphine, fentanyl, mu
86
Partial agonist: produces only a _______ effect regardless of the ______ of drug applied
submaximal, amount
87
\_\_\_\_\_\_\_\_\_ is a partial agonist. Even if it is unable to achieve a same level of analgesia provided by a full agonist, it may be preferred for _______ analgesia because it causes _____ adverse effects.
Buprenorphine, postsurgical, fewer
88
Inverse agonist: produces an effect ______ to that of an agonist
opposite
89
\_\_\_\_\_\_\_ and _______ are inverse agonists of H2 receptors
Cimetidine, ranitidine
90
After attachment to the receptor site, some drugs may be _______ \_\_ ______ any action on their own.
unable to trigger
91
Antagonist are viewed as _____ \_\_\_\_\_\_ (drugs)
silent ligands
92
Most drugs used in therapeutics are ________ \_\_\_\_\_\_ and prevent the action of natural agonists such as _______ and \_\_\_\_\_\_\_\_.
receptor antagonists, neurotrasmitters, hormones
93
Butorphanol, a central-acting opioid analgesic, is mainly an ______ at the mu receptor but is an _____ at the kappa receptor
antagonist, agonist
94
Affinity is determined by the ?
chemical structure of the drug
95
Affinity determines the ?
concentration of drug required to form the drug-receptor
complexes that are responsible for drug action (biological response)
96
Define the constant of affinity (Ka)
The numerical representation of affinity for both agonist and an antagonist is the
97
98
Efficacy is the drug‘s ability, once \_\_\_\_\_\_, to initiate _____ that lead to the production of \_\_\_\_
bound, changes, responses
99
Efficacy is used to characterize the level of _______ \_\_\_\_\_ (\_\_\_) induced by an \_\_\_\_\_
maximal response, Emax, agonist
100
In contrast, a pure antagonist has ______ \_\_\_\_\_\_ _____ because it does not initiate a change in ____ \_\_\_\_\_.
no intrinsic efficacy, cell functions
101
The efficacy term is not to be confused with the drug‘s _____ \_\_\_\_\_ whereby an antagonist may be fully efficacious
clinical efficacy
102
Potency: ?
Concentration of drug required to achieve a given effect
103
Potency is expressed by ?
EC50
104
EC50 (ED50) Is defined as..
Concentration of an agonist which produces 50% of the maximum possible response for
that agonist.
105
Potency can be used to ?
compare drugs with similar effects
106
Potencies of drugs vary ______ with the numerical value of their EC50.
inversely
107
The most potent drug is the ?
one with the lowest EC50
108
Which drug is more potent?
A b/c EC50 is not high here.
The higher the potency, the lower the EC50
109
A ___ \_\_\_\_\_ is only a disadvantage when the effective dose is too ___ to be convenient.
low potency, large
110
The volume to be administered must be small and only
relative potent drugs can be administered this way
111
The potency of an antagonist (the effect is an inhibition) is determined by ?
its IC50.
112
IC50 is defined as?
the concentration of an antagonist that reduces the response of an agonist by 50%
113
Drug C is a more potent antagonist than drug B
114
Competitive antagonism: Antagonists act on the _____ receptor as the \_\_\_\_
same, agonist
115
It is _______ \_\_\_\_\_\_ ______ when it can be surmounted by increasing the concentration of agonist
reversible competitive antagonism
116
Agents acting by competitive antagonism
Atropine (an antimuscarinic agent)
• Propranolol (a beta blocker)
117
In irreversible competitive antagonism, a _______ of the antagonist from its binding site cannot be achieved by ______ the
agonist concentration. There are few drugs of this type.
displacement, increasing
118
119
Irreversible competitive antagonism are used as experimental probes for investigating
\_\_\_\_\_\_\_ \_\_\_\_\_\_.
receptor function
120
In the presence of a competitive antagonist the dose-response curve for an agonist is shifted to the _____ without a change in ____ or ______ \_\_\_\_.
What happens to potency?
What happens to Efficacy?
right, slope, maximum effect
Decreases
No change
121
The ED50 of an agonist will _______ in the presence of increasing dose of competitive antagonist (its potency \_\_\_\_\_\_\_\_). Thus, it will take more _______ to achieve the same effect that occurred in the _______ of antagonist.
increase, decreases, agonist, absence
122
Noncompetitive antagonism: ?
A drug blocks the cascade of events. The noncompetitive agonist acts like a “wedge” that prevents the normal chain of events from occurring. No amount of Agonist binding to the receptor will allow for the chain of events to occur. This is why the agonist's Emax is reduced b/c the agonist's normal maximal effect can not be reached.
This occurs with Ca2+ channel blockers, such as nifedipine, which prevent the influx of calcium ions through the cell membrane and nonspecifically block any agonist action requiring calcium mobilization
123
In the presence of a noncompetitive antagonist, the maximal response (efficacy, Emax ) of the
agonist is \_\_\_\_\_\_\_\_
reduced
124
125
The drug receptor interaction is responsible for ?
the specificity of drug action
126
A drug may be specific at a _____ concentration if it activates only ___ type of \_\_\_\_
| (enzyme, receptor, etc)
low, one, target
127
If the drug concentration is \_\_\_\_\_\_, ____ targets may be involved simultaneously
increased, several
128
Most drugs can display activity towards ?
a variety of receptors. Specificity is unusual
129
What are the clinical implications of the dose-response curve?
* Increasing the dose of a drug when the response is sub-maximal will ______ the therapeutic effect
* Increasing the dose of a drug when the response is maximal will ____ \_\_\_\_\_ the therapeutic effect but may elicit ____ effects
enhance, not improve, toxic
130
131
Efficacy is the parameter of interest for a ______ but potency may be a _____ factor if the drug has to be administered in a ____ volume
clinician, limiting, small
132
Efficacy (Emax) gives information on the ?
maximum reachable effect of a drug
133
Potency is an expression of the activity of a drug in terms of the _______ of the drug required to produce a _______ effect. It does not reflect how ______ a drug is.
concentration, desired, effective
134
Each drug has its own ?
Emax and EC50
135
136
Partial agonist versus full agonist
137
Partial agonist may be more or less potent than ___ agonists
full
138
Buprenorphine
1. Is most often used as an analgesic for ___ to ____ pain.
2. Is not as effective as an analgesic as ___ agonist (\_\_\_\_\_).
3 Has a ____ agonist activity at the mu-receptor
and is considered __ times more potent than
morphine.
4 Shows a high affinity for \_\_\_-receptors in the CNS
mild, moderate, full, morphine, partial, 30, mu
139
Efficacy of morphine vs buprenorphine vs naloxone?
Morphine \> buprenorphine \> naloxone
140
Affinity of morphine vs buprenorphine vs naloxone?
Buprenorphine = naloxone \> \> morphine
141
Affinity = capacity of the drug to bind to receptor.
Bupe has a higher affinity but the efficacy is not as high as morphine
142
Clinical efficacy refers to the _________ \_\_\_\_\_\_\_ of the drug in patients. It is the ________ \_\_\_\_\_ effect that can be produced by a drug.
therapeutic effectiveness, maximal therapeutic
antagonist is to occupy the receptor binding site normally occupied by an agonist.
143
Intrinsic efficacy describes ?
the capacity of agonists to activate a receptor
144
Many useful therapeutics agents are ?
antagonists. Whereas these molecules exhibit NO intrinsic efficacy but they exhibit remarkable clinical efficacy
145
Drugs A and B have similar intrinsic efficacies and can produce the same amount of cAMP accumulation.
Do these drugs necessarily have the same clinical efficacy to reduce blood pressure? No
146
cAMP generation leads to ?
vascular smooth muscle cell relaxation which can lower blood pressure
147
Drug B produces receptor coupling to machinery that increases cAMP throuhout the cell. Greater
effect on VSMC relaxation.
Drug A produces receptor coupling to machinery that increases cAMP only in certain regions of
the cell. Less effect on VSMC relaxation
148
Despite drugs A and B each having the capacity to induce similar levels of cAMP production (similar intrinsic efficacies), therapeutically, drugs A and B have different abilities to reduce blood pressure (different clinical efficacies).
149
Quantal responses are known as the relationship between the _____ of the drug and the ________ of a population of patients that _______ to it.
dose, proportion, responds
150
Quantal dose-response curves are useful for ?
determining doses to which most of the population responds
151
Parameters determined from quantal dose-response curves
ED50
TD50
LD50
152
ED50
• Median ________ dose
• Dose at which **% of subjects exhibit a** ______ response to a drug
• in a graded dose-response curve ED50 = the dose of a drug that produces **% of the** _____ effect
effective, 50, therapeutic, 50, maximal
153
TD50
• Median _____ dose
• Dose at which \_\_\_\_% of subjects experience a ______ effect
toxic, 50, toxic
154
LD50
• Median ______ dose
• Dose at which \_\_\_% of subjects \_\_\_\_
lethal, 50, die
155
What is the therapeutic index formula?
TI = TD50/ED5
156
```
The therapeutic index (IT) of a drug is the ratio of the dose that produces _______ in \_\_\_
the population (TD50) to the dose that produces a ______ \_\_\_\_\_\_\_ or _______ response
(ED50) in ____ the population.
```
toxicity, half, clinically, desired, effective, half
157
The TI is a measure of a drug‘s \_\_\_\_\_\_\_, because a ______ value indicates a wide margin
between doses that are ______ and doses that are \_\_\_\_\_\_.
safety, larger, effective, toxic
158
```
ED50 = median therapeutic (or effective) dose
TD50 = median toxic dose
Therapeutic Index (TI) = TD50/ED50
```
In the example, TI = 300/100 = 3
159
A CSF \> 1 indicates that a dose effective in 99% of the population is _____ than that which would be _____ (?) in 1% of the population
less, lethal, toxic
160
The therapeutic window is the range of drug doses that provides ______ efficacy with minimal _______ AKA the range between _______ and the _______ of the _____ curve.
therapeutic, toxicity, ED50, start, curve.
161
162
Penicillin has a ______ therapeutic index.
Large
163
Label the chart accordingly
