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PHAR 300 > L3: Pharmacodynamics 2 > Flashcards

L3: Pharmacodynamics 2 Flashcards

1
Q

What is biological variation and how does it apply to drugs?

A

Biological variation is the fact that everybody is different due to their genetics and environmental factors that influence them. Therefore, drugs will effect everyone differently in terms of side effects and/or responses. This is why trials are done with large groups of people.

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2
Q

What is a normal distribution? Define the axes.

A

Y: # of people responding
X: drug dosage
Shape: Gaussian = normal distribution
This is because, since there is such a large sample size, some people respond at very low drug levels and some at very high, but most people are in the middle.

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3
Q

Define the possible axes of a dose response curve.

A

Y: Cumulative % of people responding
X: Dosage
OR
Y: Response to the drug in % of a maximum
X: Concentration of drug in blood (in a log scale for linear curve)
Looks like an S

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4
Q

What is ED50?

A

“Effective dose”

The dose of the drug (x axis) required to produce an effect on 50% of the population (y axis).

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5
Q

What is a dose response curve used for?

A
  1. Comparing drugs

2. Studying the magnitude of a drug effect

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6
Q

What does it mean to say drug is more potent than another? What does this look like on a dose response curve?

A
  1. It requires less of the drug to get the same % response. (Has lowest EC50: effective concentration of drug that gives 50% response)
  2. The drug whose curve is furthest to the left is most potent. IF THEY ALL HAVE THE SAME % RESPONSE
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7
Q

What is the “threshold” of a dose response curve?

A

The point where you start to see an effect of the drug. Smallest dose to get a response.

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8
Q

What is the “ceiling dose” of a dose response curve?

A

The point at which the effect of the drug levels off, and you don’t see anymore effects even if you increase the dose. (saturation)

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9
Q

What is potency?

A

Amount of drug you need to give in order to have a response.

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10
Q

Do all available receptors need to be bound by an agonist in order to achieve 100% response? Why?

A

No, we have a lot of spare receptors as a fail safe mechanism.

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11
Q

How does a drugs association or dissociation constant (affinity) relate to drug potency? What does this look like on the dose response curve.

A

A drug that has a higher affinity (higher association constant and lower dissociation constant) has a higher potency because it needs less drug concentration to get the same effect than a drug with a lower affinity.
A drug with higher affinity will be further to the left on the dose response curve than a drug with lower affinity. (same as potency).

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12
Q

What is efficacy?

A

The proportion of receptors that are forced into their active conformation when occupied by a particular drug and that give the desired response.

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13
Q

What is more important for determining a drug’s usefulness in a clinical setting? Potency or efficacy? Why?

A

Efficacy is more important because a drug can be more potent but not reach the desired max response (not efficient).

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14
Q

What is a full agonist?

A

A full agonist binds its receptor and leads to a large response (high efficacy).

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15
Q

What is a partial agonist?

A

A partial agonist binds the receptor but only leads to a small response in the cell (low efficacy).

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16
Q

What is the benefit of a partial agonist?

A

You can block the effect of a full agonist by administering a partial agonist because the partial agonist binds to the same site that the full agonist binds to.
- Good to prevent overdose.

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17
Q

What is the difference between a partial agonist and an antagonist?

A

An antagonist totally eliminates the effect of the drug whereas a partial agonist only decreases the effect of the drug.

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18
Q

What happens to the dose response of an agonist as you increase the concentration of its partial agonist?

A

The maximal response decreases as the concentration of the partial agonist increases until the curve reaches the maximal response of the partial agonist. This is when the receptors are saturated with the partial agonist.

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19
Q

What are the types of antagonists?

A

Competitive/noncompetitive

Reversible/irreversible

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20
Q

What is a competitive antagonist?

A

Binds to the same site as the agonist. You will get some effect of the agonist if there is a larger concentration of the agonist than of the antagonist because they will be competing for the same binding site.

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21
Q

Can you still get a maximum response in the presence of a competitive antagonist? Explain. What will the dose response curve look like?

A

Yes. If you have a high concentration of agonist or a low concentration of antagonist, then the agonist can overcome the receptor blockade caused by the competitive antagonist and give 100% response. This is due to the available spare receptors.
The dose response curve will be shifted to the right because you need a higher concentration of agonist to overcome the antagonist.

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22
Q

What happens at VERY large doses of competitive antagonists?

A

Eventually, the antagonist will block so many receptors that you start to see a decrease in the maximal response to the agonist.

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23
Q

What is a non-competitive antagonist?

A

Antagonist that binds to a different site than the agonist (Allosteric site or somewhere inside cell) and changes the conformation of the endogenous site, blocking the agonist from binding.

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24
Q

Can the increased dose of an agonist overcome the effect of the non-competitive antagonist? Why?

A

No. Because it does not bind to the same site as the agonist, therefore there is no competition to overcome. The noncompetitive antagonist lowers the peak of the dose response curve. The maximum response of the agonist wont be obtained if the non competitive antagonist is present. The larger the dose of noncompetitive antagonist, the lower the response peak.

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25
Q

What is an irreversible antagonist?

A

Binds to the receptor irreversibly (longer effect) and decreases the number of available receptors. Therefore, body must synthesize more receptors and increase receptor turnover.

26
Q

What is a reversible antagonist?

A

Binds to the receptor reversibly.

27
Q

What happens to the dose response curve if a molecule binds to an allosteric site and potentiates it?

A

Dose response curve shifts to the left.

28
Q

What is TD50?

A

Dose of the drug required to produce a toxic effect if 50% of the population. Toxic effects are non-lethal side effects ex: headaches, nausea, headaches, diarrhea.

29
Q

What is LD50?

A

The dose of the drug needed to produce a lethal effect in 50% of the population.

30
Q

What is the therapeutic index (TI)?

A

TI= LD50/ED50
OR
TI= TD50/ED50
The larger the TI, the safer it is.

31
Q

What is the therapeutic window?

A

The dose range within which most people get therapeutic effects without getting side effects.

32
Q

What is the ideal therapeutic window?

A

Getting 100% of people to respond to the drug before any toxic effects start.

33
Q

What is the safety factor?

A

TD1/ED99
The larger the safety factor, the safer the drug.
TD1: Toxic dose for 1% of people
ED99: effective dose for 99% of people

34
Q

What is the problem with only using the therapeutic index to determine drug safety?

A

The TI only depends on the ED50 and TD50 (or LD50). It does not take the slope of the dose response curve into consideration.
The TI can be the same for two different drugs, but the therapeutic windows can be different (due to having different slopes).

35
Q

What is a benefit outlier?

A

People that respond to the drug at lower doses while getting a good therapeutic effect.
OR
People that need a higher concentration of the drug to get the therapeutic effect.

36
Q

What is a toxicity outlier?

A

People that have a toxic response at a low dose of the drug (when you are supposed to be getting therapeutic benefit). THESE PEOPLE SHOULD NOT TAKE THE DRUG.
OR
Individuals very resistant to the drug and have little-to-no adverse effects at high concentrations of the drug.

37
Q

What is a toxic threshold?

A

Where you start to see toxic effects of substances. Some drugs have no threshold (you see toxicity right away).

38
Q

What is absorption?

A

Transfer of a drug from site of administration to blood stream (need to pass plasma membrane).

39
Q

How do drugs pass through plasma membranes?

A
  1. Aqueous pores: small molecules, water soluble molecules, and ions
  2. Passive diffusion: lipid soluble molecules, gases, small polar molecules
  3. Transporters (active transport): Large molecules (glucose), charged particles (amino acids, ions)
40
Q

Where is the first place a drug goes after it is swallowed? Describe the environment.

A

Stomach: acidic, low pH because of HCl, little absorption happens in stomach (it is a reservoir).

41
Q

Where does the drug go after passing through stomach? Describe the environment.

A

The small intestine: neutral to basic pH (6-8). Large absorptive surface area. Most absorption happens here.

42
Q

Where does the drug go after being absorbed by the small intestine?

A

The liver for the first pass effect before entering the systemic circulation.

43
Q

Describe how a weak acid drug would be absorbed in basic or acidic mediums?

A

When weak acids are in an acidic environment (low pH) they are un-ionized (no charge) and lipid soluble. This allows them to absorbed through membranes of the cells.
Ex: Weak acids in the stomach.

When weak acids are in a basic environment (high pH) they are ionized (charges) and not lipid soluble. This inhibits them from passing through membranes of the cells passively. They need other transport mechanisms in order to be absorbed.
Ex: Weak acids in the intestine.
Weak Bases = opposite

44
Q

What is the binding effect in the stomach?

A

When a drug can interact with and bind to something in the stomach (another drug, food, etc.) that can prevent it from being absorbed. Lower amount gets into circulation.

45
Q

Is it feasible to drastically increase drug concentration of a drug so that it overcomes the first pass effect? why?

A

No. Even if the first pass effect knocks out most of the drug, the metabolites of the drug can be toxic and you can start to see adverse effects. Find another method of administration.

46
Q

What administration methods bypass the first pass effect?

A 
Sublingual
Parenteral
Inhalation
Transdermal
Rectal (variable)
47
Q

What is bioavailability?

A

The fraction of the drug administered reaching the systemic circulation. If the first pass effect is large, then you have a lower bioavailability.

48
Q

What is distribution in Pharmacokinetics?

A

Distribution of drug to all cells of the body once in the systemic circulation where it can bind to various proteins at various tissue sites, to blood cells, or can travel to its specific site of drug action. Only the free drugs can move through the plasma membrane, bound drugs cannot.

49
Q

What affects where the drug goes, with respect to time, once it is in the circulation?

A

The rate of blood flow. It varies with respect to different organs Ex: very intense to brain and heart.

50
Q

What is the one compartment model? Is it accurate?

A

The drug evenly distributes in all of the organs. Not accurate.

51
Q

What is the two compartment model? Is it accurate? What are the compartments?

A

First, drug is concentrated in organs with more blood flow. Eventually, it is distributed evenly throughout body after a long time.
Central compartment: blood and tissues with extensive blood flow
Peripheral compartment: Rest of body
More accurate than 1 compartment model, less accurate than 3 compartment model. Inaccurate because it doesn’t get evenly distributed.

52
Q

What is the three compartment model? Is it accurate?

A

Drug goes to brain first (blood and tissues with extensive blood flow), then to muscles (medium blood flow), then to the fat (slow blood flow, more slowly). The drug is distributed unequally.
Most accurate.

53
Q

What does P Glycoprotein do and where is it?

A

It’s a powerful component in the cell membrane that transports drugs back out. It makes it difficult to get a good concentration of drugs in the cells.

54
Q

What can drugs bind to in the blood?

A

Albumin (impaired in liver disease) and glycoproteins (increased in inflammation).

55
Q

What can alter drug distribution?

A

Diseases. Ex: Cancer tumour

The rate of blood flow to different organs.

56
Q

Define the therapeutic window in terms of MEC (minimum effective concentration).

A

Therapeutic window = “MEC desired” to “MEC adverse”
You want the “MEC adverse” to be considerably above the peak effect of the drug and the “MEC desired” to be considerably lower than the “MEC adverse”.

57
Q

What is the blood brain barrier?

A

Membrane of tight junctions (between capillaries) that exists to protect your brain from substances in your circulation.

58
Q

What are the mechanisms that protect your brain from circulating substances?

A
  1. Blood brain barrier
  2. Protein bound drug (cant exit circulation)
  3. Non lipid soluble free drugs need to be actively transported to get through BBB
59
Q

What is the purpose of tight junctions in the blood brain barrier?

A

Water soluble molecules can no longer pass through the spaces in between the endothelial cells. Anything that wants to get into the brain needs to be able to passively diffuse through the membrane or be brought in by active transport mechanisms (glucose and amino acids).

60
Q

When is the blood brain barrier defective?

A
  1. In underdeveloped new borns (administer drugs with care)
  2. People with infections
  3. There is no barrier between the CSF and the brain, so if something gets into the CSF it is transported all the way around the brain.
61
Q

How is a drug removed from the brain?

A

Through the CSF which is drained back into the venous system. Not much of the drug us metabolized in the brain.

62
Q

Is the placenta an effective barrier to drugs? Why? What does this implicate?

A

No. Lipid soluble drugs rapidly diffuse through placenta, water soluble drugs get through slowly. This implies that some drugs can concentrate in the fetus.

PHAR 300 (20 decks)

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