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BMPH 1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What type of receptors signal using 2nd messengers?

A

G protein-coupled receptors

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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%
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3
Q

_____ block the orthosteric drug binding site of a receptor

A

Competitive antagonists

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4
Q

Nature of drugs

A

Pharmacodynamics and pharmacokinetics

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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
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6
Q

Pharmacokinetics

A

Action of body on drug:

  • Movement of drugs in body
  • Absorption
  • Distribution
  • Elimination
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7
Q

Signaling mechanisms for drug effects

A
  1. Transmembrane diffusion
  2. Transmembrane enzyme receptors
  3. Ligand-gated transmembrane receptors
  4. Transmembrane channels
  5. G-protein coupled receptors
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8
Q

Transmembrane diffusion

A

Bind to intracellular receptor

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9
Q

Transmembrane enzyme receptors

A

Outer domain provides the receptor function while inner domain provides the effector mechanism

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10
Q

Ligand-gated transmembrane receptors

A
  1. Ligand binding
  2. activate cytoplasmic tyrosine kinase (JAKs)
  3. Phosphorylation of STAT molecules that regulate transcription
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11
Q

Transmembrane channels

A

Gated open or closed by binding of drug to receptor site

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12
Q

G protein-coupled receptors

A

Use a coupling protein to activate a separate effector molecule

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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
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14
Q

EC50

A

Dose/concentration at which effect is half-maximal (1/2 Emax)

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15
Q

Emax

A

Maximal effect of drug (peak of curve)

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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
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17
Q

Kd

A

Concentration at which 50% of receptors are bound

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18
Q

Bmax

A

Maximal number of receptors bound

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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

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20
Q

Drug potency

A

Concentration (EC50) or dose (ED50) required to procure 50% of maximal effect

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21
Q

Drug efficacy

A

Concentration required for drug to bind all receptors

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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

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23
Q

What is more important: efficacy or potency?

A

Generally, efficacy.

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24
Q

Agonist

A

Activate receptor

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25
Q

Types of agonism

A

Full or partial

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26
Q

Full vs Partial agonist: dose-response

A
  • Same EC50

- Emax - full (higher) > partial (lower)

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27
Q

Full vs Partial Agonist: Competition

A

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
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28
Q

Full vs Partial Agonist: Titration

A

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
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29
Q

Inverse agonism

A
  • Lessens receptor signal
  • Must have receptor with BASAL ACTIVITY
  • Will reduce basal activity (sigmoidal below)
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30
Q

Types of antagonists

A

Competitive, Irreversible, Non-Competitive

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31
Q

Which two antagonists compete with orthopedic (main) binding site in receptor?

A

Competitive and Irreversible

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32
Q

Competitive antagonist

A

Shift sigmoidal dose-response curve to the right

  • Emax is the same
  • EC50 increases
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33
Q

Irreversible antagonist

A

Shift peak of sigmoidal dose-response curve down

  • Emax decreases
  • EC50 is the same
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34
Q

Non-Competitive Antagonist

A

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
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35
Q

Agonist treatment

A

Leads to receptor DOWN regulation

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36
Q

Antagonist treatment

A

Leads to receptor UP regulation

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37
Q

Desensitization

A

Reduced response due to continued presence of agonist

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38
Q

Resensitization

A

If agonist causing desensitization is removed after a short time, cell recover full responsiveness to more agonist.

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39
Q

Down-regulation

A

Sometimes, repeated/prologed exposure of cells to agonist promotes down-regulation instead of desensitization

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40
Q

Therapeutic index

A

= LD50/ED50

LD50 = lethal dose

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41
Q

What form of a weak acid/base can partition across cell membranes?

A

Neutral form

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42
Q

Charged drugs are ___ readily excreted than lipid-soluble drugs

A

More because they don’t pass membrane (aka, not reabsorbed) so can be filtrated

43
Q

Can charged drugs get trapped in urine?

A

Yes, not reabsorbed into cells

44
Q

Lipid-soluble drugs are excreted ___ ____

A

More slowly

45
Q

Weak acids and bases can be removed from circulation by ___

A

Altering urine pH

46
Q

The process by which the amount of active drug in the body is reduced after administration and before entering the systemic circulation.

A

First-pass effect

47
Q

Volume of distribution (Vd)

A

a proportionality factor that relates the amount of drug in the body to the concentration of drug measured in a biological fluid

48
Q

Volume of distribution vs. location in body

A

If Vd > 42 L, drug is mostly in tissues

If Vd < 42 L, drug is mostly in circulation

49
Q

The half-life is ___ regardless of the plasma concentration

A

The same

50
Q

Zero-order elimination

A

Process that describes how plasma concentration of high doses of ethanol, phenytoin, and aspirin are reduced over time

51
Q

The distribution of a drug through the body depends on ____ and ___

A

Blood flow and drug solubility

52
Q

Weak acid

A

H2COOH –> H2COO- + H+

Neutral acid –> anion + proton

53
Q

Weak base

A

NH3+ –> NH2 + H+

Cation –> neutral base + proton

54
Q

What happens to weak acids/bases in acid?

A

Acid = low pH = high [H+]

Favors protonated/neutral acid and cation/protonated base

55
Q

What happens to weak acids/bases in base?

A

Base = high pH = low [H+]

Favors deprotonated/anion acid and deprotonate/neutral base

56
Q

What form of weak acids/bases is favored if pH>pKa?

A

pH>pKa = BASIC so deprotonated form favored:

  • anion acid
  • neutral base
57
Q

Which form of weak acid/base is more lipid soluble?

A

Neutral:

  • protonated acid
  • deprotonated base
58
Q

Under what pH level is a weak acid more lipid soluble?

A

Low pH = acidic = favors protonated weak acid = neutral form

59
Q

Under what pH level is a weak base more lipid soluble?

A

High pH = basic = favors deprotonated weak base = neutral form

60
Q

What form of weak acid/base accelerated drug excretion?

A

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
Q

Under what pH conditions are weak acids charged?

A

High pH = basic = favors deprotonated weak acid = anion

62
Q

What what pH conditions are weak bases charged?

A

Low pH = acidic = favors protonated weak base = cation

63
Q

Methods of transmembrane signaling

A
  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
Q

Desensitization

A

Response of receptor diminished over times (s or min) even in continued presence of agonist

65
Q

Can desensitization be reversed?

A

Yes, happens rapidly

66
Q

GPCR Second Messengers

A
  • Cyclic Adenosine Monophosphate (cAMP)
  • Phosphoinositides and Calcium
  • Cyclic Guanosine Monophosphate (cGMP)
67
Q

Major Routes of Drug Administration

A
  • Oral
  • IV
  • IM
  • Nasal
  • Cutaneous
68
Q

ADME

A
  • Absorption
  • Distribution
  • Metabolism
  • Elimination
69
Q

What is the chemical composition of most drugs and why?

A

Weak acids or bases

- Bc pH regulates their lipid solubility

70
Q

Henderson-Hasselback Equation

A

Log (protonated/unprotonated) = pKa - pH

71
Q

pKa

A

pH where 1/2 of drug is charged

72
Q

When are weak bases charged?

A

pH < pKa

73
Q

When are weak acids charged?

A

pH > pKa

74
Q

pH values in body for drug absorption

A
  • Stomach: 2.0
  • Intestine: 8.0
  • Blood: 7.4
  • Urine: 6.5
75
Q

Drug distribution

A

Influenced by drug binding:

- If drug binds strongly to protein in vascular compartment, will be harder for it to go to extravascular space

76
Q

Volume of Distribution (Vd)

A

= Amount of drug in body / Concentration in the blood

Units = Volume

77
Q

How does Vd change if there is greater drug binding in vascular space?

A

Decrease

78
Q

How does Vd change if there is greater drug binding in extravascular spaces?

A

Increase

79
Q

Drug Clearance

A

How drug is cleared from the body

80
Q

Clearance (CL)

A

= Rate of elimination / Plasma concentration (Cp)

Unite = Volume per unit time

81
Q

Is clearance relatively constant of a broad range of plasma concentrations?

A

Yes

82
Q

The elimination rate is rapid at first and then ___ as concentration decrease.

A

Slows

83
Q

Systemic Clearance

A

= Clearance of kidney + clearance of liver + other clearance

84
Q

Half-life

A

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
Q

Steady-State concentration

A

100% Plasma concentration of drug

86
Q

How long does it take to reach steady-state in terms of half lives?

A 
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
Q

First-Order Elimination

A

*More common
Rate of elimination (units per hours) is proportional to concentration
Time (X) vs Concentration (Y) = Negative exponential

88
Q

Zero -Order Elimination

A

The rate is constant and independent of concentration

Time (X) vs Concentration (Y) = negative linear

89
Q

First Pass Effect

A

Non IV administered drugs: part of dose is lost in feces via gut and in metabolism via liver before entering systemic circulation

90
Q

Bioavailability (F)

A

Percentage of drug in circulation

For IV administration, F = 1 or 100%

91
Q

Loading dose

A

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
Q

Dosing rate (IV)

A

= Rate of elimination = CL X TC

CL: Clearance
TC: therapeutic/target concentration

93
Q

Dosing rate (non-IV)

A

= Dosing rate/F
= (CL X Desired plasma concentration) / F

Dosing rate: rate of elimination or CL X TC
F: bioavailability

94
Q

Maintenance dose

A

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
Q

Drug metabolism

A
  • Phase 1 reactions
  • Phase 2 reactions
  • Genetic factors
  • Induction of drug metabolism
  • Inhibition of drug metabolism
96
Q

Phase 1 Drug Metabolism

A

Convert drug to a more polar metabolite by introducing or unmasking a functional group such as -OH, -NH2, -SH

97
Q

Phase 2 Drug Metabolism

A

Creates highly polar conjugates between Phase 1 function groups and endogenous substrates such as glucoronic acid, sulfuric acid, acetic acid, and amino acids

98
Q

Drug metabolism enzymes

A

Phase 1: cytochrome p450

Phase 2: processed with sulfate or gluco

99
Q

Pharmacogenomics

A

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
Q

Drug metabolism usually results in a product that is (Less/more) lipid soluble than the original drug.

A

Less

101
Q

Pharmacokinetics concepts

A
  • Volume of distribution + CL –> Half-Life
  • Clearance + Vd –> Half-Life
  • Bioavailability –> First Pass Effect
  • Dosing –> Maintenance or Loading
102
Q

Surmountable antagonism

A

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
Q

Insurmountable antagonism

A

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
Q

How do we know if there are spare receptors?

A

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.

BMPH 1 (8 decks)

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