Pharmacology Flashcards
(104 cards)
1
Q
What type of receptors signal using 2nd messengers?
A
G protein-coupled receptors
2
Q
In a system with no spare receptors, what fraction of receptors would be estimated to be occupied at a drug concentration 10-fold lower than the EC50 value?
A
9.1%
B=(Bmax x C)/ (C+Kc)
B/Bmax = C/(C+Kc)
Kc=1/2 max
C=1/10 Kc
B/Bmax = (1/10 Kc)/ (1/10 Kc + Kc) B/Bmax = (1/10)/(11/10) = 1/11 = 0.0909 B/Bmax = 9.1%
3
Q
_____ block the orthosteric drug binding site of a receptor
A
Competitive antagonists
4
Q
Nature of drugs
A
Pharmacodynamics and pharmacokinetics
5
Q
Pharmacodynamics
A
Action of drug on body:
- Receptors, effectors
- Dose-response curves, spare receptors
- Agonists, partial agonists, biased agonists, antagonists, inverse agonists
- Signaling mechanisms
- Receptor regulation
6
Q
Pharmacokinetics
A
Action of body on drug:
- Movement of drugs in body
- Absorption
- Distribution
- Elimination
7
Q
Signaling mechanisms for drug effects
A
- Transmembrane diffusion
- Transmembrane enzyme receptors
- Ligand-gated transmembrane receptors
- Transmembrane channels
- G-protein coupled receptors
8
Q
Transmembrane diffusion
A
Bind to intracellular receptor
9
Q
Transmembrane enzyme receptors
A
Outer domain provides the receptor function while inner domain provides the effector mechanism
10
Q
Ligand-gated transmembrane receptors
A
- Ligand binding
- activate cytoplasmic tyrosine kinase (JAKs)
- Phosphorylation of STAT molecules that regulate transcription
11
Q
Transmembrane channels
A
Gated open or closed by binding of drug to receptor site
12
Q
G protein-coupled receptors
A
Use a coupling protein to activate a separate effector molecule
13
Q
Dose-response curves
A
Relation b/t drug dose/concentration (x) and drug effect (Y)
- If dose = linear, curve = hyperbolic
- If dose = log, curve = sigmoidal
14
Q
EC50
A
Dose/concentration at which effect is half-maximal (1/2 Emax)
15
Q
Emax
A
Maximal effect of drug (peak of curve)
16
Q
Dose-binding curves
A
Relation b/t drug/concentration (X) and % receptors bound
- If dose = linear, curve = hyperbolic
- If dose = log, curve = sigmoidal
17
Q
Kd
A
Concentration at which 50% of receptors are bound
18
Q
Bmax
A
Maximal number of receptors bound
19
Q
Spare receptors
A
If system has spare receptors, EC50 is lower than Kd –> to achieve 50% of maximal effect, less than 50% of receptors must be activated.
Clinical: need less drug for response in system
Graph: Effect < binding
20
Q
Drug potency
A
Concentration (EC50) or dose (ED50) required to procure 50% of maximal effect
21
Q
Drug efficacy
A
Concentration required for drug to bind all receptors
22
Q
Potency vs Efficacy (Graphically)
A
More potency to the left: less concentration required to reach EC50
More efficacy to the top: highest peaks = highest number of receptors bound
23
Q
What is more important: efficacy or potency?
A
Generally, efficacy.
24
Q
Agonist
A
Activate receptor
25
Types of agonism
Full or partial
26
Full vs Partial agonist: dose-response
- Same EC50
| - Emax - full (higher) > partial (lower)
27
Full vs Partial Agonist: Competition
Maximal binding curves
- full will bind more than partial at lower concentrations
- as concentrations of both inc, full binding dec while partial binding inc
- Curves cross
- at highest concentrations, partial binds more than full
28
Full vs Partial Agonist: Titration
Dose-response curves
1. Constant dose of full agonist starting at Emax concentration
2. Titrate in the partial starting low and inc
3. Partial competes will full in binding
4. Full dec while partial inc
5. Partial only increases to partial Emax
29
Inverse agonism
- Lessens receptor signal
- Must have receptor with BASAL ACTIVITY
- Will reduce basal activity (sigmoidal below)
30
Types of antagonists
Competitive, Irreversible, Non-Competitive
31
Which two antagonists compete with orthopedic (main) binding site in receptor?
Competitive and Irreversible
32
Competitive antagonist
Shift sigmoidal dose-response curve to the right
- Emax is the same
- EC50 increases
33
Irreversible antagonist
Shift peak of sigmoidal dose-response curve down
- Emax decreases
- EC50 is the same
34
Non-Competitive Antagonist
Binds to allosteric site to lower the efficacy of agonist that binds to orthosteric receptor site.
Shift peak of sigmoidal dose-response curve down
- Emax decreases
- EC50 is the same
35
Agonist treatment
Leads to receptor DOWN regulation
36
Antagonist treatment
Leads to receptor UP regulation
37
Desensitization
Reduced response due to continued presence of agonist
38
Resensitization
If agonist causing desensitization is removed after a short time, cell recover full responsiveness to more agonist.
39
Down-regulation
Sometimes, repeated/prologed exposure of cells to agonist promotes down-regulation instead of desensitization
40
Therapeutic index
= LD50/ED50
LD50 = lethal dose
41
What form of a weak acid/base can partition across cell membranes?
Neutral form
42
Charged drugs are ___ readily excreted than lipid-soluble drugs
More because they don't pass membrane (aka, not reabsorbed) so can be filtrated
43
Can charged drugs get trapped in urine?
Yes, not reabsorbed into cells
44
Lipid-soluble drugs are excreted ___ ____
More slowly
45
Weak acids and bases can be removed from circulation by ___
Altering urine pH
46
The process by which the amount of active drug in the body is reduced after administration and before entering the systemic circulation.
First-pass effect
47
Volume of distribution (Vd)
a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid
48
Volume of distribution vs. location in body
If Vd > 42 L, drug is mostly in tissues
| If Vd < 42 L, drug is mostly in circulation
49
The half-life is ___ regardless of the plasma concentration
The same
50
Zero-order elimination
Process that describes how plasma concentration of high doses of ethanol, phenytoin, and aspirin are reduced over time
51
The distribution of a drug through the body depends on ____ and ___
Blood flow and drug solubility
52
Weak acid
H2COOH --> H2COO- + H+
| Neutral acid --> anion + proton
53
Weak base
NH3+ --> NH2 + H+
| Cation --> neutral base + proton
54
What happens to weak acids/bases in acid?
Acid = low pH = high [H+]
| Favors protonated/neutral acid and cation/protonated base
55
What happens to weak acids/bases in base?
Base = high pH = low [H+]
| Favors deprotonated/anion acid and deprotonate/neutral base
56
What form of weak acids/bases is favored if pH>pKa?
pH>pKa = BASIC so deprotonated form favored:
- anion acid
- neutral base
57
Which form of weak acid/base is more lipid soluble?
Neutral:
- protonated acid
- deprotonated base
58
Under what pH level is a weak acid more lipid soluble?
Low pH = acidic = favors protonated weak acid = neutral form
59
Under what pH level is a weak base more lipid soluble?
High pH = basic = favors deprotonated weak base = neutral form
60
What form of weak acid/base accelerated drug excretion?
To accelerate, need to be less lipid soluble so drug stays in circulation (aka, not cross lipid membrane) --> to avoid absorption in cells, need to be charged
61
Under what pH conditions are weak acids charged?
High pH = basic = favors deprotonated weak acid = anion
62
What what pH conditions are weak bases charged?
Low pH = acidic = favors protonated weak base = cation
63
Methods of transmembrane signaling
1. Lipid-soluble ligand crosses membrane to act on intracellular enzymatic activity
2. Ligand binds extracellularly to transmembrane receptor protein with intracellular enzymatic activity
3. Transmembrane receptor binds and stimulates intracellular tyrosine kinase
4. Ligand-gated transmembrane ion channel
5. Transmembrane receptor protein stimulated G protein that modulates intracellular 2nd messenger production
64
Desensitization
Response of receptor diminished over times (s or min) even in continued presence of agonist
65
Can desensitization be reversed?
Yes, happens rapidly
66
GPCR Second Messengers
- Cyclic Adenosine Monophosphate (cAMP)
- Phosphoinositides and Calcium
- Cyclic Guanosine Monophosphate (cGMP)
67
Major Routes of Drug Administration
- Oral
- IV
- IM
- Nasal
- Cutaneous
68
ADME
- Absorption
- Distribution
- Metabolism
- Elimination
69
What is the chemical composition of most drugs and why?
Weak acids or bases
| - Bc pH regulates their lipid solubility
70
Henderson-Hasselback Equation
Log (protonated/unprotonated) = pKa - pH
71
pKa
pH where 1/2 of drug is charged
72
When are weak bases charged?
pH < pKa
73
When are weak acids charged?
pH > pKa
74
pH values in body for drug absorption
- Stomach: 2.0
- Intestine: 8.0
- Blood: 7.4
- Urine: 6.5
75
Drug distribution
Influenced by drug binding:
| - If drug binds strongly to protein in vascular compartment, will be harder for it to go to extravascular space
76
Volume of Distribution (Vd)
= Amount of drug in body / Concentration in the blood
Units = Volume
77
How does Vd change if there is greater drug binding in vascular space?
Decrease
78
How does Vd change if there is greater drug binding in extravascular spaces?
Increase
79
Drug Clearance
How drug is cleared from the body
80
Clearance (CL)
= Rate of elimination / Plasma concentration (Cp)
Unite = Volume per unit time
81
Is clearance relatively constant of a broad range of plasma concentrations?
Yes
82
The elimination rate is rapid at first and then ___ as concentration decrease.
Slows
83
Systemic Clearance
= Clearance of kidney + clearance of liver + other clearance
84
Half-life
Time required for half of the drug to be eliminated
= (0.693 X Vd) / CL
Units = Time
*Note: need to have Vd and CL provided --> these are not calculated!*
85
Steady-State concentration
100% Plasma concentration of drug
86
How long does it take to reach steady-state in terms of half lives?
```
In Half-Lives:
1 = 50%
2 = 75%
3 = 87.5%
4 = 93.75%
5 = 96.875%*******
```
A drug is said to have reached the steady-state plateau after 5 half-lives (actually 97% of plateau)
87
First-Order Elimination
*More common
Rate of elimination (units per hours) is proportional to concentration
Time (X) vs Concentration (Y) = Negative exponential
88
Zero -Order Elimination
The rate is constant and independent of concentration
| Time (X) vs Concentration (Y) = negative linear
89
First Pass Effect
Non IV administered drugs: part of dose is lost in feces via gut and in metabolism via liver before entering systemic circulation
90
Bioavailability (F)
Percentage of drug in circulation
For IV administration, F = 1 or 100%
91
Loading dose
Dose needed to achieve therapeutic steady state immediately --> amount in the body immediately following the loading dose
= V X TC
V: Volume of distribution
TC: therapeutic/target concentration
92
Dosing rate (IV)
= Rate of elimination = CL X TC
CL: Clearance
TC: therapeutic/target concentration
93
Dosing rate (non-IV)
= Dosing rate/F
= (CL X Desired plasma concentration) / F
Dosing rate: rate of elimination or CL X TC
F: bioavailability
94
Maintenance dose
Dose over internal of time to maintain drug plasma concentration at therapeutic/target steady-state
= Dosing rate X Dosing interval
= ((CL X Desired plasma concentration)/F) X Dosing Interval
95
Drug metabolism
- Phase 1 reactions
- Phase 2 reactions
- Genetic factors
- Induction of drug metabolism
- Inhibition of drug metabolism
96
Phase 1 Drug Metabolism
Convert drug to a more polar metabolite by introducing or unmasking a functional group such as -OH, -NH2, -SH
97
Phase 2 Drug Metabolism
Creates highly polar conjugates between Phase 1 function groups and endogenous substrates such as glucoronic acid, sulfuric acid, acetic acid, and amino acids
98
Drug metabolism enzymes
Phase 1: cytochrome p450
| Phase 2: processed with sulfate or gluco
99
Pharmacogenomics
Most people metabolize drugs normally, but some:
1. Metabolize too fast --> less drug in blood --> inc dose
2. Metabolize slower --> more in blood --> dec dose
100
Drug metabolism usually results in a product that is (Less/more) lipid soluble than the original drug.
Less
101
Pharmacokinetics concepts
- Volume of distribution + CL --> Half-Life
- Clearance + Vd --> Half-Life
- Bioavailability --> First Pass Effect
- Dosing --> Maintenance or Loading
102
Surmountable antagonism
Competitive bc more agonist could push out and decrease effect of antagonist.
As concentration of antagonist increases, EC50 inc but Emax stays the same. At higher and higher concentrations of antagonist, EC50 will continue to increase and Emax will also start to decrease bc antagonist is overwhelming agonist.
103
Insurmountable antagonism
Non-competitive bc no matter go much agonist is added, it cannot overcome effect of the agonist.
As antagonist increases, Emax will decrease while EC50 stays the same bc antagonist does not bind at orthosteric site.
104
How do we know if there are spare receptors?
Using an irreversible antagonist, as more of it is added, Emax will stay the same while EC50 increases because not a lot of agonist is needed to reach Emax, so there are spare receptors. But, as antagonist continues to be added, there is a point where EC50 stops decreasing and Emax decreases instead bc the antagonist is not blocking the spare receptors.
