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VETM 443 Pharmacology > Pharmacokinetics and Pharmacodynamics > Flashcards

Pharmacokinetics and Pharmacodynamics Flashcards

1
Q

Define pharmacodynamics

A

How the drug affects the body

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2
Q

Define pharmacokinetics

A

How the body affects/processes the drug. It includes time to the clinical effect, the magnitude of the effect and the duration of action.

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3
Q

What are the 8 Principles of pharmacodynamics

A
  • Drugs act via molecular targets
  • Receptor type determines the response
  • Can turn receptors off and on
  • Many mechanisms can result in antagonism
  • Efficacy doesn’t equate to potency
  • Receptors are not static, they can be up or down regulated or desensitized
  • Selectivity is very important
  • Body tries to maintain homeostasis
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4
Q

How do alpha 1 agonists impact the body

A

no cardiovascular impacts

result in vasoconstriction

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5
Q

How do alpha 2 agonists impact the body

A

no cardiovascular impacts

Result in presynaptic vasoconstriction and then vasodilation

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6
Q

How do beta 1 agonists impact the body

A

increase cardiovascular output

no respiratory impacts

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7
Q

How do beta 2 agonists impact the body

A

no cardiovascular impacts

causes vasodilation of cardiac and skeletal muscle, along with bronchodilation

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8
Q

What would an alpha 1 antagonist do to the body

A

It would cause vasodilation because the agonist effect is vasoconstriction.

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9
Q

What would a beta 1 antagonist do to the body

A

It would reduce cardiac output because the agonist effect is increasing cardia output.

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10
Q

What would a beta 2 antagonist do to the body

A

It would result in vasoconstriction in cardiac and skeletal muscle and bronchoconstriction. These are the opposite to the agonist effects

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11
Q

What would an alpha 2 antagonist do to the body

A

It would oppose the agonist effect and cause pre synaptic vasodilation followed by vasoconstriction

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12
Q

What features of drug targets can impact pharmacokinetics?

A

The physiology of the drug targets can impact the interaction with the drug. For example, the affinity (strength) of binding is impacted by the type of interaction with drug targets. Van der Walls are the weakest interaction, then hydrogen bonding, then ionic, and the strongest is covalent bonding. It is important to note that affinity doesn’t equate to efficacy.

Additionally, there are multiple targets that a drug can act on to create the same result.

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13
Q

What are the types of receptors that drugs can bind? What are the features and purposes of the drug receptors? Provide examples of receptors of each type?

A

Cell receptors are either on the surface or intracellularly. They all have an endogenous ligand and act to transduce and amplify the signal.

ligand-gated ion channel: cholinergic nicotinic receptor

G protein-coupled receptor: more amplification due to signal cascade, alpha/beta adrenergic

enzyme-linked receptor: form dimers, insulin receptor

intracellular receptor: changes gene transcription, steroid receptors

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14
Q

Rank the speed of reaction of different drug receptor types

A

fastest
- ligand-gated ion channel
- g-protein couple receptor
- enzyme-linked receptor
- intracellular receptor
slowest

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15
Q

Define antagonist and agonist action

A

Antagonists prevent the action of the receptor by binding

Agonists increase the action of the receptor

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16
Q

What are the 2 mechanisms antagonists use to prevent receptor action? How does that impact the effect of the drug?

A

There ar 2 mechanisms; competitive and non-competitive binding

Competitive binding will bind at the endogenous ligand binding site. This will block endogenous ligand binding. This outcompete the ligand and thus the effect of the drug will be dependent on endogenous ligand concentration. If you increase ligand you can conversely outcompete the drug.

Non-competitive binding is when the drug binds to an alternate site on the receptor. This means the effect of the drug is independent to the concentration of the endogenous ligand because they are not competing for the same binding site.

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17
Q

Define; inverse agonist

A

A drug that will reduce the effect of the receptor below baseline levels

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18
Q

What are physiological antagonists?

A

Agents that produce opposite effects

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19
Q

What are chemical antagonists?

A

Drugs that have incompatible interactions, or binding by the body

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20
Q

What are pharmacokinetic antagonists

A

Drugs that change other drugs

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21
Q

What are two types of agonists?

A

Full and partial agonists. They differ as full agonist increases the effect to the maximum. Partial agonists increase the effect but not to the max.

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22
Q

Why is dose selectivity important? How is dose related?

A

It informs off target and adverse effects. Higher doses are more likely to result in adverse effects

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23
Q

Describe a dose response curve? What are the important features displayed on these curves?

A

A does response curve measures the effect (y axis) and the log dose (x axis)

From this curve you can identify the EC5 (the dose at which you will see half the maximal effect) and Emax (the maximum effect) and C max (the concentration at which you will see the max effect)

From this you can assess potency an efficacy.
- Potency is determined based on how much drug (dose) is needed to achieve an effect. The smaller the does needed, the more potent the drug - observe the placement on the curve on the x axis (EC50)
- Efficacy can be determined by observing the Emax. The higher the Emax, the more effective the drug. Observe the height of the graph on the y axis.

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24
Q

Compare potency and efficacy

A

Potency evaluates the dose required to achieve an effect. It can be displayed as the EC50

Efficacy is evaluating how effective the drug is at generating a response. Observe the Emax. In clinics this is measured as clinical response. Pharmacologically this is based on in vitro receptor function.

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25
Q

Compare reversible and irreversible binding of receptors and their impact on outcome?

A

Irreversible binding results in a permanent impact on the receptor. The receptors must be replaced to regain normal function. This results in an increase of antagonism over time.

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26
Q

Define Cmax. What can impact the Cmax?

A

It is the highest blood concentration of the drug in plasma. It can be affected by bioavailability of the drug, the first pass effect, and the rate of absorption and elimination

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27
Q

Define Tmax

A

The time when the drug reaches Cmax

28
Q

What is T1/2?

A

The half life of the drug: when the concentration of the drug is reduced by half. It is usually referred to ass elimination half life because it considers the absorption, distribution

29
Q

How does t1/2 impact the dosing schedule of a drug?

A

It informs the duration of action of drug. With this information the steady state concentration can be determined. This is because the steady state concentration occurs after 5 half lives of the drug.

30
Q

How does the half life change if you double the dose of a drug

A

The half life will be extended by 1 T1/2

31
Q

What occurs after 5 half lives of a drug?

A

Steady state is reached

32
Q

What does the area under a concentration-time curve tell you?

A

Gives you an animal’s total drug exposure

33
Q

Define Css. What factors can impact it?

A

Steady state

It can be impacted by bioavailability, clearance, dose, and dose interval

34
Q

How does dose impact the steady state?

A

Steady state can be maintained at a higher concentration if a higher dose is given at the same time interval

35
Q

How does dosing interval impact steady state of a drug (same t1/2)

A

Increasing the dosing interval will reduce the steady-state concentration because you are waiting longer between doses and thus allowing more time for metabolism and elimination

Reducing the dosing interval will have thee opposite effect and increase the steady state concentration

36
Q

How do you reduce fluctuations of steady-state concentration?

A

No change to steady state will occur if the frequency of the dose is increased, as long as the total dose in a single time interval is kept the same. This would reduce the fluctuation of the drug in the system. This may be useful if the drug being used has a small therapeutic window/range.

A CRI would be the method that achieves the least fluctuation in steady state concentration

37
Q

What are the upper and lower bounds of the dose range?

A

Upper: maximum safe concentration
Lower: minimum therapeutic dose

You want to achieve the therapeutic dose

38
Q

How is the dose interval determined

A

It is determined by the clearance and half life times. If over 5 half lives pass the drug will be fully cleared.

39
Q

Define clearance. Why is it important?

A

It is the volume of plasma that would need to be removed to remove drug. Basically assessing how fast the drug leaves the body.

It is important because it informs the steady state dossing. The CRI dose would be equivalent to clearance.

40
Q

How does half life inform withdrawl time

A

5 half lives result in 95% clearance of the drug

10 half lives result in 99% clearance of the drug
- typical to have withdrawal times set to 10 half lives (validation is required because the half lives in tissue and blood can vary)

41
Q

Define loading dose. Why is it important?

A

It is when you give a larger initial dose to reduce the time to clinical effect. This is important for drugs with a longer half life (days to weeks)

Do not give a loading dose of drug at each dosing interval as it can exceed therapeutic levels

42
Q

What does ADME stand for

A

absorption
distribution
metabolism
excretion

43
Q

How does absorption vary depending on the route of drug administration

A

IV administration does not have an absorption stage because it is injected directly into the bloodstream.

SC/IM has slower absorption

Oral has varied absorption because it depends on individual characteristics, the type of GI system, whether the animal is fe dor fasted, and the GI transit time. Not available for all meds as some are broken down by stomach acid.

44
Q

How does the method of administration impact the Cmax of the drug?

A

IV administration would result in Cmax being equal to given dose

SC/IM administration will have a reduced Cmax because the Tmax is higher (slower). IM is much faster than SC.

45
Q

What features of the drugs impact absorption

A

Their ability to pass through cell membranes impacts the absorption. There are many mechanisms to cross cell membranes including diffusion, transporters, and receptors.

Molecules that have better absorption are hydrophobic/non-ionic

46
Q

What is the relative risk of drugs administered via different routes

A

higher risk
IV
SC/IM
PO
low risk

47
Q

What is the first pass effect

A

It is the loss of drug before entering systemic circulation. Drug can be lost via metabolism upon absorption in liver. It may be excreted in the bile.

48
Q

Define bioavailability. What can impact bioavailability?

A

It is the amount of drug that arrives at the target.

Bioavailability is reduced if there is a higher first pass effect.

There is 100% bioavailability when drugs are administered IV

highest IV > IM > PO

49
Q

Define pKa

A

It is the pH at which half the compound is in its ionized form

This indicates the acidity of the drug

50
Q

What drug (ionized or unionized) can better cross cell membranes

A

unionized (hydrophobic)

51
Q

What determines if a drug is in its ionized or unionized form

A

The pKa of the drug and the pH of the environment interaction. For every pH unit difference between environmental pH and pKa result in a 10x difference between ionized and unionized form.

52
Q

What pH/pKa relationship results in more deprotonated drug

A

if pH > pKa

53
Q

What is ion trapping?

A

It is when drugs preferentially accumulate in certain body compartments. This is due to ionization state.

Like is ionized in like: for example an acidic drug is ionized in an acidic environment. Therefore in acidic environments, acidic drugs will be less able to cross membranes and are ‘trapped’ in that compartment

54
Q

What are 2 factors that impact the distribution of a drug in the body

A

It depends on blood flow and thee rate of diffusion across membranes

55
Q

Define volume of distribution. What does this value indicate?

A

It is the theoretical volume of blood that is needed to contain the total administration of a drug. SQ, IM, and orally administered drugs will have a Vd that equates to Cmax. Drugs administered IV will have a Vd of Co.

A lower Vd indicates that more of the drug remains in the blood vs leaves to the tissue. A higher Vd will have a higher proportion of the drug leave the blood

56
Q

How does plasma protein binding impact drug distribution?

A

Protein binds to drugs via electrostatic attraction. If a drug is protein bound, >90% will be bound. Only the free floating drug will interact with the receptors. This causes a slow release effect for the drug which can make the drug longer acting. Also these drug can compete for binding sites. It is important to note that hypoproteinemia can impact drug effect.

For example convenia is 99% protein bound. It slowly dissociates and also is actively resorbed in kidneys resulting in a longer acting drug.

57
Q

What are the 4 metabolites types that may be created from metabolism of drugs

A
  1. inactive
  2. active with a similar action of drug
  3. prodrugs that are only active after metabolism
  4. toxic
58
Q

What factors can impact drug metabolism

A

Many factors including age (for example, neonates without functioning enzymes). Health of the animal. For example, if you had liver disease that would impact protein production and drug metabolism. Also species differences can heavily impact metabolism. It is difficult to impossible to extrapolate between species. You cant just use doses for other species

59
Q

What are the phases of metabolism

A

There are 2 phases of metabolism.

Phase 1 is the redox phase. t heavily relies on the enzyme cytochrome P450 which is found on the intracellular oganelles of the liver. They can be up or down regulated.

Phase 2 is conjugation of the drug to endogenous substrates to increase solubilty. It uses process like acetylation, glucuronidation, and sulfate conjugation.

60
Q

How is cytochrome p450 named?

A

CYP (cytochrome P450)
2 (family)
C (subfamily)
21 (enzyme ID)

= CYP2C21

There are different CYP in different species. CYP1A1 is found in all species.

61
Q

What species differences exist in phase 2 of drug metabolism

A

Cats are not good at glucuronidation and drugs metabolized this way will have a long excretion time.

Dogs are poor at acetylation.

62
Q

How do transporters impact metabolism? What is an example of an important transporter?

A

They help uptake and/or efflux of drug into and/or out of the cell.

P-glycoprotein is an efflux transporter. The effects depend on the location of the transporter. If found on the BBB it helps remove drug from the brain. In small intestine it will remove drug and prevent absorption. In the kidney, it will help prevent excretion.

Animals deficient in P glycoprotein may be at higher risk for CNS effects from drugs.

63
Q

What impacts the rate of excretion

A

filtration + secretion - re-absorption

64
Q

Where are drugs excreted?

A

Main sites of excretion are kidney and liver. The kidney is the most important site of excretion

Excretion in the kidney is mainly for small molecules via urine. Drugs that are protein bound will not be filtered out. Some drugs are actively excreted in the proximal tubule. Additionally, local metabolism can occur and create various metabolites (could be toxic).

Excretion in the liver is primarily for larger molecules. They can undergo enterohepatic recirculation.

65
Q

What is enterohepatic recirculation

A

It is when the drug is excreted in the liver and secreted in bile. It is then reabsorbed in the small intestine. this increases thee exposure of the drug in the body.

VETM 443 Pharmacology (11 decks)

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