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E'Pharmacology Test 1 Fall '24 > 8/26 Pharm lecture 2 > Flashcards

8/26 Pharm lecture 2 Flashcards

1
Q

What dictates the duration of drug action?

A
  1. only as long as the drug binds to the receptor (bind and release)
  2. long term downstream effects last until downstream effectors go away (when downstream is used up)
  3. desensitized or degraded receptor. (think g protein) (if covalent bonds stick for too long)
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2
Q

Good receptor properties:

A
  1. selective- drug binds to a single receptor or receptor type (if not many other drugs affect it)
  2. alteration- a drug binds to receptor, changes to create a downstream effect (interacting with something in the cell)
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3
Q

Bad receptor properties:

A

They bind to the drug with not detectable changes. No effects on the body.
Inert binding sites—–Drug carriers like Albumin

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4
Q

When drug is not bound to a carrier, is said to be in it’s

A

free form (cant cross barriers if bound to protein)

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5
Q

What is the most important drug carrier? how many binding sites does it have?

A

albumin (has 2 binding sites)

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6
Q

Why decrease levels of medication in malnourished pts and liver damage pts?

A

Low albumin…
Not much albumin for drugs to bind to in higher doses. This leads to toxicity faster. (phenytoin is usually 90% bound to albumin- thus we usually give higher does)

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7
Q

What can happen when drugs are given together in regards to carrier proteins?
Examples?

A

They can kick each other off of it. e.g. Phenytoin and Carbamazepine.

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8
Q

When a plasma protein is bound to a drug, that drug (can or cannot) cross ______.
Why?

A

cannot cross barriers/membranes
the protein is too large

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9
Q

When can a drug cross barriers?

A

when it is in it’s free form

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10
Q

What will affect how much of a drug we have to give? (proteins)

A

plasma protein binding.
The more bound to protein the less that’s usable to bind to receptors.

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11
Q

Giving phenytoin to a malnourished patient will have what kind of effect?

A

A higher effect. Because they don’t have as much albumin for the drug to bind to.

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12
Q

What are the 3 types of carrier receptors?

A

Albumin
alpha 1 acid glycoprotein
lipoproteins

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13
Q

What type of drug does albumin bind to?

A

acidic drugs (2 binding sites)

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14
Q

What type of drugs does alpha 1 acid glycoproteins bind to?

A

basic drugs

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15
Q

what type of drugs to lipoproteins bind to?

A

neutral drugs

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16
Q

Define potency

A

concentration or dose of a drug required to produce 50% of that drugs maximal effect.

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17
Q

A drug is potent when _________

A

A small amt is given and max effect is seen.

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18
Q

what is the maximal efficacy? Must also take into account of ?

A

Greatest possible response a dose can deliver (better than potency); toxicity

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19
Q

The clinical effectiveness of a drug depends on _________ and not on ________

A

Maximal efficacy; potency

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20
Q

Describe the Potency of drug A, B, C, and D.

A

Drug B is very potent because it’s 50% response only takes a small drug dose.
Drug A, C, and D each have less and less potency, because it takes more and more the drug to reach it’s 50% response. ACD are more efficacious (A>C>D)

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21
Q

Which 2 drugs are an example of potency and efficacy

A

Tylenol vs fentanyl.
Tylenol is more potent one but Fentanyl is the more efficacious.
Tylenol is not given for amputation.

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22
Q

The larger the therapeutic index, the ______

A

safer the drug

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23
Q

What is the therapeutic index?

A

Difference between maximal dose effect and seeing toxic effects.

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24
Q

What is the therapeutic index ratio?

A
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25
Q

What type of drugs have a wide therapeutic index?

A

OTC drugs

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26
Q

What is the ED50?

A

Dose that produces a specific therapeutic response in 50% of the population taking the dose.

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27
Q

What is the TD 50?

A

dose at which toxicity is seen in 50% of the population.

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28
Q

What is an idiosyncratic response?

A

A unusual drug response (we don’t know the reason behind it)

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29
Q

What causes idiosyncratic responses?

A

Genetic factors (Hyporeactive and Hyperreactive).

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30
Q

What is tolerance?

A

When a person changes their response to a drug over time.
Need more and more morphine

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31
Q

What is tachyphylaxis?

A

quick tolerance

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32
Q

WHat are 2 other variations in drug responsiveness and what they entail? (antagonism)

A

Chemical antagonism (other drugs)
Physiologic antagonism (something in the body itself)

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33
Q

What are the 4 causes of variation in drug responsiveness?

A
  1. Alteration in concentration of drug that actually reaches the receptor.
    (i.e. age, weight, sex, disease state (liver failure) Rate of absorption, distribution.
  2. variation in concentration of endogenous receptor ligand (ligand may bind into receptor and block meds)
  3. alteration in number or function of receptors
  4. Changes in components of response distal to receptor. (the downstream effect) Post receptor process,,, Largest and most important cause of variation.
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34
Q

What is the largest and most important cause of variation in drug response?

A

Changes in components of response distal to receptor. (downstream effect)

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35
Q

Can a drug cause desired and toxic effects at the same receptor?

A

yes. i.e. racemic mixtures

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36
Q

Toxicity can stem from extension of ______________-

A

Therapeutic effects (e.g. sedatives and hypnotics)

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37
Q

In order to cross barriers effectively, drugs should be_______

A

uncharged

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38
Q

What effects the charge of a drug?

A

The disassociation constant and the pH of the environment that it is in.
It tells us at which pH you’re going to have equal amouts of both the charged and the uncharged form.

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39
Q

Acids ________ H+ into solutions, and Bases _______ H+ from solution

A

Releases; absorb

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40
Q

if pH < pKa——- protonated or unprotonated

A

favors protonated form.

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41
Q

How can you predict if a drug is going to be charged?

A

If pH<pKa; favors the protonated form

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42
Q

What is the protonated form?

A

When the Hydrogen ion is attached

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43
Q

What is the unprotonated form?

A

when the hydrogen ion is not attached

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44
Q

How can you predict if a drug is going to be uncharged?

A

if the pH>pKa; favors the unprotonated form and vise versa

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45
Q

Are weak bases charged or uncharged when it’s protonated?

A

charged

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46
Q

Are weak acids charged or uncharged when it’s protonated?

A

uncharged

47
Q

Aspirin (weak acid); pKa=3.5
in stomach pH=1.5
protonated/unprotonated?
charged/uncharged?

A

protonated
uncharged

48
Q

morphine (weak base) pKa= 7.9
in stomach pH=1.5
protonated/unprotonated?
charged/uncharged?

A

protonated
charged

49
Q

Aspirin (weak acid); pKa=3.5
in intestine pH=6.5
protonated/unprotonated?
charged/uncharged?

A

Unprotonated
charged

50
Q

morphine (weak base) pKa= 7.9
in blood pH=7.4
protonated/unprotonated?
charged/uncharged?

A

technically protonated & charged
near equilibrium because there is a minor difference in 7.4 and 7.9

51
Q

What are biologic drugs?

A

created by living organisms or extracted from living systems (abx, blood, microbiota, transplant) or modified in the lab. Monoclonal antibodies— more and more seen in practice now.

52
Q

Monoclonal Antibodies are created from ________

A

A single parent cell

53
Q

We can make it only bind to a receptor by:

A

Isolate the receptor and produce monoclonal antibodies based on that receptor. (even if there is no other drug to bind to that one)

54
Q

what is recombinant DNA technology? What are some examples?

A

take a protein that’s normally produced in a human,
put it in an animal (living thing, can be bacteria)
animal produces protein for us
E.g Insulin, growth hormones, interferons

55
Q

Normal functions of antibodies in body (not meds)

A

Recognize and bind antigen; induce immune response after binding

56
Q

what are fusion proteins?

A

monoclonal antibodies that are produced from recombinant DNA

57
Q

Chimeric

A

Mouse variable region attached to human.

58
Q

What is a monoclonal antibody?

A

an antibody produced from a single clone of a plasma cell that produces antibodies.

59
Q

Why do monoclonal antibody dugs have less adverse effects?

A

They have an area called the antigen binding site which only binds to a particular antigen. Very specific.

60
Q

-mab tells us the drug is a

A

monoclonal antibody

61
Q

Describe how a monoclonal antibody is made.

A

Target an antigen in the body e.g. cancer cell
inject the antigen into a mouse
mouse makes antibodies (titer drawn to check this)
kill mouse
use spleen cells (ELISA) (where antibodies are made)
merge it with myeloma cell to make it immortal (single clone of cell to make billions) (if not merged it will die)

-isolate culture ( that single clone of that single cell)
-propagate (grow in culture)
-harvest (in billions)

62
Q

What is an antigen?

A

a substance that causes the immune response to make antibodies against it

63
Q

In order for a drug to be on the market approved by the FDA, the drug has to be both

A

safe and effective

64
Q

How many drugs do FDA approve in a year

A

50-60

65
Q

FDA also grants approval for__________,(basically what you can say or not)

A

Marketing

66
Q

Safety is not equals to efficacy (in respect to prescriptions)…. explain this in terms of a medication mentioned

A

Omeprazole works better than any other prescribed drug and its an OTC. Basically not all prescribed drugs are more effective.

67
Q

Are all OTC drugs safe?

A

NO. OTC Doesn’t necessarily equate to safety.

68
Q

pure botanicals like Multivitamins/supplements, to be approved by the FDA, have to be

A

safe, but not necessarily effective

69
Q

Who was instrumental in blocking Thalidomide from being approved in this country?

What was Thalidomide used for? Why was it banned?

A

Dr. Frances Kathleen Oldham-Kelsey.

Morning sickness; teratogen (pregnancy test 1st).

70
Q

Why FDA refused approval for Thalodomide?

A

safety testing is not thorough enough

71
Q

Thalidomide is currently used to treat ____________

A

multiple Myeloma

72
Q

Describe the process from discovering a drug till it gets on the market.

A

A. In vitro studies-done on the cell to find a lead compound
B. apply for a patent
C. animal testing
D. investigational new drug has to be approved (can we test in Humans)
E. clinical testing in 3 phases
1. is it safe, pharmacokinetics? (healthy people- juniors -100 people)
2. does it work in humans? (sick patients (200 people))
3. does it work on pts. with the disease (1000 people)?
F. Marketing (after NDA application is accepted by FDA
4. post marketing surveillance

73
Q

Better pic for FDA testing phases…
NDA meaning

A

New Drug Application (can we market it?)

74
Q

receptors are what type of molecule?

A

protein

75
Q

relationship between where drug is given and site of action

A

Drug wont work where you give it. Must travel to site. At best-give brain drug in spinal fluid.

76
Q

Distribution means_______

A

where the drug goes:
aqueous compartments (blood, interstitial cells, cytosol, etc)
hydrophobic compartments (cell wall - cholesterol)
Bones
fatty tissue
muscles etc

77
Q

Permeation can be

A

Aqueous diffusion (cells just let drugs in usually if water soluble) molecules can be large (30K MW)
lipid difusion (steroids — if lipid soluble and has to be unsoluble)
special carriers (bind, internalize, spit on other side)
endocytosis and exocytosis (engulfs–brings in–and spits out in cell)

78
Q

Goal of rational dosing?

A

to achieve desired beneficial effect with minimal adverse effects

79
Q

Does permeation in pharmacokinetics refer to the cell wall?

A

No. Refers to the cells in the gut or so. Cross here and get to the blood stream.

80
Q

In order to get pharmacologic effects we want, we have to take into account all

A

Pharmacokinetic variables. ADME.

81
Q

Receptor __________ determines dose

A

Affinity ( Kd)

82
Q

Receptor ____________ varies per drug

A

Selectivity

83
Q

Receptors can be __________ (agonist) or ___________ (antagonist)

A

activated; blocked

84
Q

What is an orphan receptor?

A

a receptor that has no known native ligand. We dont know what they bind to

85
Q

Regulatory Proteins

A

Affect transcription, mitosis, regulate some processes.

86
Q

what is the most common and important category of receptors called?

A

seven-transmembrane (7TM) receptors
GPCR 2/3 of non antibiotic drugs bind here.

87
Q

What are the5 steps of cell signaling

A

Signaling molecules
Receptor
Signal transduction proteins
second messengers (not proteins)
effectors (where the money is) - affects change

88
Q

An effector protein is the thing that will _________

A

produce a change in the cell. e.g Change in metabolism, move, may increase transcription of gene.

messaged relayed to them by signal transduction proteins.

89
Q

What is the first step in cell signaling?

A

a ligand binds to a receptor

90
Q

what are second messengers?

A

compounds within the cell that have an effect on the cell

91
Q

What are effector proteins?

A

proteins that effect the cell in some way and make it change. (the downstream response)

92
Q

What is a lag period?

A

Time it takes to see an effect from a drug. e.g transcription/translation of a drug (30mins in bacteria and hrs in humans)

93
Q

What is persistence?

A

When a drug is given once and its’ effects remain for hours or days.
d/t delayed protein pathway degradation (it may take a while for the downstream effect to finally stop)

94
Q

After coupling (binding to receptor), the receptor undergoes a _________ change and then we see a _____________ cellular response

A

conformational change (receptor changes in some form); and then we see a downstream cellular response

95
Q

Dose responses can be a related to the _________ of receptors bound (linear) or the _________ of the signal transduction cascade (multiple responses)

A

Number (linear) - more receptors give more responses;
Strength (1 to 2 to 4 to 8 and so on)

96
Q

What is a kinase?

A

an enzyme that attaches to a phosphate group to another protein

97
Q

What attaches to the phosphate group and makes a protein active in a signal transduction cascade?

A

a kinase

98
Q

The Seven trans-membrane spanning domain has what 2 ends?

A

An amino terminal end (outside) and a carboxyl group end (inside cell) (interacts with G-protein here.
Each 7 strings of amino acid cross the membrane.

99
Q

G-proteins are [guanine nucleotides that are] Trimeric proteins. This means that they have ______ to help it function
What do they do?

A

Alpha, beta and gamma subunits
Beta and gamma help binding to the receptor itself, alpha (important) will bind to the GDP or GTP(active form) .

100
Q

End result of phosphorylation cascade:

A

activate some effector

101
Q

Are there intracellular receptors?

A

Yes. These have to be uncharged as they go through membranes and bind intracellularly

102
Q

What is a catalytic receptor?

A

A receptor that activates an enzyme on the inside

103
Q

What are the two types of catalytic receptors?

A
  1. the receptor itself becomes an enzyme and activates
  2. the receptor activates a protein which activates a number of additional enzymes
104
Q

What is a G protein coupling receptor?
GPCR

A

a receptor that has a g protein attached to it. When activated, the g protein is released and finds an enzyme to activate.

105
Q

How many orphan GPCRs are there in the body

A
  1. also 500 identified.
106
Q

Which does the alpha subunit (part of G-Protein) bind to?

A

guanine diphosphate (inactive form)
or guanine triphosphate (active form)

107
Q

Describe GPCRs

A
  1. drug binds to the receptor and activates a G-protein
  2. G protein with (GDP already attached) gets rid of GDP and binds GTP (alpha portion attaches to GTP)
  3. G-Protein (now activated) leaves and goes to effector protein and activates it.
    4.Effector protein (adenylyl cyclase) then sets up second messenger cascade by activating cAMP from ATP (most common 2nd messenger- this might set up a phosphorylation cascade)
  4. After activating cAMP, GTP goes back to GDP (inactive), binds to receptor and can be activated again.
108
Q

Can a drug bind more than once to a single receptor (gpcr)

A

It is possible, when the alpha subunit leaves, the drug also leaves. The drug can then rebind, or another ligand can bind to that receptor. (bind and release theory)

109
Q

If a GDP is bound to a receptor, is the protein active or inactive?

A

Inactive. It takes 3 phosphates for the protein to become active.

110
Q

GPCRs can also affect other effectors other than adenylyl cyclase like …

A

Phospholipase C

111
Q

What are examples of secondary messengers?

A

cAMP
IP3
DAG
Calcium

112
Q

Secondary messengers are activated by _______

A

the effector protein (adenylyl cyclase)

113
Q
A

E'Pharmacology Test 1 Fall '24 (5 decks)

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