Lecture 1 - Drug-receptor interaction Flashcards
1
Q
What is a drug?
A
- A substance used as a medicine to treat, prevent, or diagnose a disease
- A substance used with intent of producing a change within the body
2
Q
What are pharmacokinetic processes?
A
- Absorption, distribution, metabolism, and elimination
- The actions of the body on the drug
3
Q
What are pharmacodynamic processes?
A
- Receptor and signal transduction
- The actions of the drug on the body
4
Q
What is a receptor?
A
A protein molecule in a cell that interacts with drugs and initiates a chain of events causing some form of cellular response
5
Q
Where are receptors located?
A
- Cell membrane
- Cytoplasm
- Nucleus
6
Q
What is the structure of receptors made from?
A
Proteins
7
Q
What is the function of receptors?
A
Bind to ligands to activate or inhibit post-receptor signaling, which triggers a biological response
8
Q
What is the main significance of receptors?
A
They transduce signals from outside a cell to inside a cell
9
Q
What are the 4 receptor families?
A
1) G protein-coupled receptors
2) Ligand-gated ion channels
3) Enzyme-linked receptors
4) Intracellular receptors
10
Q
What is the biggest family of receptors?
A
G-protein coupled receptors
11
Q
Which receptors are the most common site of drug action?
A
GPCRs
12
Q
What are the 2 subunits of a G protein?
A
1 alpha-subunit and 1 beta gamma-subunit
13
Q
What does the alpha subunit of a G protein do?
A
Binds GTP and GDP
14
Q
What does the beta gamma subunit of a G protein do?
A
Inhibits the alpha subunit
15
Q
What are some second messengers?
A
- cAMP
- Ca2+
- IP3
- DAG
16
Q
What happens when GPCRs are activated?
A
They either increase or decrease production of second messengers, depending on which G protein is activated
17
Q
What are 5 examples of GPCRs?
A
1) Muscarinic receptors
2) Adrenergic receptors
3) Dopamine receptors
4) Serotonin (5-HT) receptors
5) Opioid receptors
18
Q
What are drug examples of muscarinic receptors?
A
- Acetylcholine
- Drugs for parasympathetic NS
19
Q
What are drug examples of adrenergic receptors?
A
- Alpha, beta receptors
- Norepinephrine, epinephrine
- Drugs for sympathetic NS
20
Q
What are drug examples of dopamine receptors?
A
- Dopamine
- Antipsychotics
21
Q
What are drug examples of serotonin (5-HT) receptors?
A
- Serotonin
- Antipsychotics
22
Q
What are drug examples of opioid receptors?
A
- Endorphins
- Morphine and other analgesics
23
Q
Which ions are more abundant on the INSIDE of a cell?
A
- K+
- H+ (equal on both sides)
- A- protein
24
Q
Which ions are more abundant on the OUTSIDE of a cell?
A
- Na+
- Ca2+
- Cl-
- H+ (equal on both sides)
25
What does ligand binding trigger?
A conformational change in the receptor
26
What determines the direction of movement through an ion channel?
The electrochemical gradient
27
What are examples of ligand-gated ion channels?
- Nicotinic acetylcholine receptor
- Glutamate N-methyl-D-aspartate receptor
- Gamma-aminobutyric acid receptor
28
Which ion does the nicotinic acetylcholine receptor transfer?
Na+
29
Which ion does the glutamate N-methyl-D-aspartate receptor transfer?
Ca2+
30
Which ion does the gamma-aminobutyric acid receptor transfer?
Cl-
31
What is a drug example of a nicotinic acetylcholine receptor?
Succinylcholine
32
What is the function of a nicotinic acetylcholine receptor?
Muscle contraction
33
What is the function of a glutamate N-methyl-D-aspartate receptor?
Long-term potentiation
34
What are drug examples of a glutamate N-methyl-D-aspartate receptor?
- Memantine
| - Ketamine
35
What is the function of a gamma-aminobutyric acid receptor?
CNS depression
36
What is a drug example of a gamma-aminobutyric acid receptor?
Benzodiazepines
37
What occurs in ion pumps?
Ions move across a membrane against their concentration gradient, using ATP
38
What occurs in ion channels?
Ions move down their concentration gradients
39
What is another name for cell membrane enzyme-linked receptors?
Tyrosine kinase receptors
40
Which receptors can form dimers?
Enzyme-linked receptors
41
What are functions of enzyme-linked receptors?
- Induce tyrosine phosphorylation
- Convert kinases from inactive to active form
- Metabolism, growth, and differentiation
42
What are drug examples of tyrosine kinase receptors and what do they treat?
- Imatinib (gleevec) - chronic myeloid leukemia
| - Interleukin-2 (proleukin) - cancers
43
What is the most common intracellular enzyme-linked receptor?
Soluble guanylyl cyclase
44
Where is guanylyl cyclase located?
Cytoplasm
45
What is the structure of guanylyl cyclase?
- Forms a heterodimer composed of an alpha and a beta-subunit
- Contains a regulatory domain, a coiled-coil domain, and a cyclase domain
46
What activates guanylyl cyclase?
Nitric oxide
47
How are guanylyl cyclase and adenylyl cyclase different?
Adenylyl cyclase is activated by a G-protein; guanylyl cyclase is activated by nitric oxide
48
What are 2 drug examples of guanylyl cyclase and what do they treat?
- Nitroglycerin (glyceryl trinitrate) - angina
| - Sildenafil (viagra) - hypertension and erectile dysfunction
49
Describe the structure of intracellular receptors
Ligand binding domain and DNA binding domain
50
Where are intracellular receptors generally located?
Nucleus
51
Receptor ligands for intracellular receptors are ____ soluble
Lipid
52
How are intracellular receptors regulated?
The ligand must diffuse into the cell to interact with nuclear receptor
53
What is the function of intracellular receptors?
Regulate gene expression
54
What are 2 examples of intracellular receptors?
- Steroid receptors
| - Non-steroid nuclear receptors
55
What are drug examples of steroid receptors?
- Cortisone
- Estrogen
- Progesterone
- Testosterone
56
What are drug examples of non-steroid nuclear receptors?
- Retinoic acid
- Vitamin D
- Thyroid hormone
57
List the 4 families of receptors from shortest to longest duration of action
1) Ion channels (milliseconds)
2) GPCRs (seconds to minutes)
3) Enzyme-linked receptors (seconds to minutes, or minutes to hours)
4) Intracellular nuclear receptors (hours to days)
58
What are the 3 isoforms of the alpha subunit of a G protein and what does each do?
- G alpha s -> stimulatory -> adenylyl cyclase -> cAMP
- G alpha i -> inhibitory -> inhibits adenylyl cyclase -> inhibits cAMP
- Gq -> activates phospholipid-regulated signaling -> phospholipase C -> second messengers
59
Which ion has the greatest difference between intracellular and extracellular levels?
Ca2+
60
Where are ion channels abundant?
On excitable cells
61
What is Bmax?
The maximal specific binding of a ligand to a receptor
62
What does Bmax indicate?
The total concentration of receptor sites
63
What is Kd?
The equilibrium dissociation constant between ligand and receptor
64
What does Kd represent?
The concentration of drug at which half-maximal binding is observed
65
What is affinity?
The ability of a drug to bind to a receptor
66
What does affinity describe?
The strength of binding between a ligand and its receptor (how attractive a receptor is to its drug)
67
How are Kd and affinity related?
- Kd determines the affinity of a drug for its receptor
| - Lower Kd means higher affinity
68
What is selectivity?
The degree to which a drug acts on a given site relative to other sites
69
What does selectivity describe?
Preference for one receptor over another
70
What is Emax?
The maximal effect induced by a drug (full agonist)
71
What is EC50?
The concentration of drug producing an effect that is 50% of the maximum
72
What is potency?
A measure of the amount of drug required to produce an effect of given magnitude
73
What is the relationship between EC50 and potency?
- EC50 determines potency
| - Higher EC50 means a lower potency
74
What is efficacy?
A measure of the ability of a drug to elicit a biological response by agonist
75
What is the relationship between efficacy and Emax?
- Emax determines efficacy
| - Higher Emax means higher efficacy
76
When selecting a drug, is efficacy or potency more important?
Efficacy (usually)
77
What are agonists?
Agents that can bind to a receptor and elicit a biologic response
78
What is a full agonist?
A drug binds to a receptor and produces a maximal biologic response that mimics the response of the endogenous ligand
79
Do full agonists have good or bad efficacy?
Good
80
What are some characteristics of partial agonists?
- Have affinity for the receptor but have low efficacy
| - Binding site is the same as full agonist
81
What occurs when a partial agonist is administered alone?
It activates the receptor
82
What occurs when a partial agonist is administered in the presence of a full agonist?
The partial agonist reduces the effects of the full agonist
83
What are some characteristics of inverse agonists?
- Have affinity for the receptor but have negative effect
| - Reverse the constitutive activity of receptors
84
What are some characteristics of antagonists?
- Drug has affinity for the receptor, but has no efficacy
- Can bind to a receptor but fails to produce a response
- Can decrease actions of agonist or endogenous ligands
85
What happens when an antagonist is used alone?
No biological effect is produced
86
What happens when a partial agonist is used alone?
Produces less of a biological effect
87
What happens when an antagonist is used with a full agonist?
Antagonist will reduce biological effect
88
What happens when a partial agonist is used with a full agonist?
Biological effect will be reduced
89
What happens when an antagonist is used with a partial agonist?
Antagonist will block partial agonist
90
What is the mechanism of competitive antagonists?
Bind to the same site on the receptor with the agonist
91
What is the function of a competitive antagonist?
Prevent an agonist from binding to its receptor
92
How can competitive antagonists be overcome?
By increasing the concentration of the agonist to the receptor
93
What happens to the dose-response curve of the agonist when a competitive antagonist is added?
The curve shifts to the right
94
What happens to the EC50 of the agonist when a competitive antagonist is added?
Increases
95
What is the mechanism of irreversible antagonists?
- Bind covalently or with very high affinity to the active site of the receptor
- Bind to an allosteric site
96
What happens to Emax of the agonist when an irreversible antagonist is added?
Decreases
97
What happens to the potency of the agonist when a competitive antagonist is added?
Decreases
98
What is an adverse effect?
An undesired harmful effect resulting from a medication
99
What are 4 examples of adverse effects?
1) Too much therapeutic effect
2) Poor tissue selectivity
3) Poor receptor selectivity
4) Drug interactions
100
What is TD50?
The drug dose that produces a toxic effect or adverse effect in 50% of patients taking the drug
101
What is ED50?
The drug dose that produces a therapeutic response in 50% of patients taking the drug
102
How can you determine therapeutic index (TI)?
TD50/ED50
103
What does a high TI mean?
A wide therapeutic window and a high safety
104
What will the therapeutic index be of a drug that has a high affinity and high selectivity?
High TI
105
What is hyporeactive?
Lower response to a drug than is usual
106
What is hyperreactive?
Higher response to a drug than usual
107
What is idiosyncratic?
Individuals exhibit an unusual drug response
108
What is tachyphylaxis?
An acute rapid loss of response to a drug
109
What is tolerance?
A decreased response to a drug when the drug is taken repeatedly
110
What is receptor desensitization?
A mechanism that reduces the receptor response to an agonist
111
What occurs in phase 1 of clinical trials?
- Screening for safety
| - Find the maximum tolerated dose
112
What occurs in phase 2 of clinical trials?
Identify the therapeutic dose and study the efficacy
113
What occurs in phase 3 of clinical trials?
Further establish and confirm safety and efficacy
114
What occurs in phase 4 of clinical trials?
Monitor the safety of the new drug under actual conditions of use
