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R&B Pharmacology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What is clinical pharmacokinetics (PK) concerned with?

A

Clinical pharmacokinetics (PK) is concerned with studying how the body affects a drug, particularly in terms of absorption and distribution.

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2
Q

What is generally measured as a representation of drug concentrations in target tissues during clinical PK?

A

Plasma concentrations are generally measured as a representation of drug concentrations in target tissues during clinical PK.

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3
Q

What are the factors that contribute to the variability in drug doses for therapeutic effect between individuals?

A

Variability in drug doses for therapeutic effect between individuals can be attributed to bioavailability, an animal’s body size and fluid composition, variability in drug distribution, and variability in metabolism and excretion.

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4
Q

How is bioavailability related to drug absorption and distribution?

A

Bioavailability is related to drug absorption and distribution, and it is determined by comparing the AUC of concentration vs time for the extravascular formulation of a drug to that of the IV formulation.

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5
Q

What are 2 types of compartment models in PK?

A

open and closed models.

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6
Q

Describe the central compartment and its significance in drug elimination.

A

The central compartment is the vascular space highly perfused tissues that equilibrate quickly with the drug. Elimination occurs mainly from the central compartment, which contains the liver and kidneys.

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7
Q

Explain the concept of open and closed models in pharmacokinetics.

A

Open models describe drugs that are eliminated from the body, while closed models describe drugs that are recirculated within the body (e.g., drugs that undergo enterohepatic circulation).

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8
Q

What is the central compartment mainly composed of, and from where does elimination occur?

A

The central compartment is mainly composed of highly perfused tissues, and elimination occurs mainly from this compartment.

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9
Q

How is a peripheral compartment different from a central compartment?

A

A peripheral compartment is less perfused tissues (e.g., skeletal muscle and connective tissues), and drugs in clinical use are usually described by a one or two-compartment model.

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10
Q

Provide examples of drugs that undergo zero order elimination.

A

PBZ

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11
Q

What is a first-order reaction, and why are most drugs absorbed and eliminated by first-order processes?

A

A first-order reaction is where the amount of drug changes at a rate proportional to the amount of drug remaining. Most drugs are absorbed and eliminated by first-order processes. Glomerular filtration is a first-order process.

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12
Q

Describe the clinical applications of a one-compartment open model with IV injection.

A

A one-compartment open model with IV injection describes the movement of a drug into and out of the central compartment using rate constants K0 and K10.

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13
Q

What are the characteristics of a two-compartment open model with IV injection?

A

A two-compartment open model with IV injection has two compartments: central (blood/highly vascularized) and peripheral (less vascularized), with elimination considered to only occur from the central compartment.

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14
Q

What is the volume of distribution (Vd), and how does it relate to drug distribution in the body?

A

The volume of distribution (Vd) describes the apparent volume of the body in which the drug is dissolved, indicating drug distribution.

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15
Q

What factors affect the volume of distribution (Vd) of a drug?

A

Factors affecting the volume of distribution (Vd) include ionization, lipid solubility, molecular size, and degree of protein binding.

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16
Q

Define bioavailability and its significance in pharmacokinetics.

A

Bioavailability (F) is a measure of the systemic availability of a drug administered by any route other than IV.

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17
Q

How is bioavailability measured in clinical settings?

A

Bioavailability is measured by comparing the AUC of concentration vs time for the extravascular formulation of a drug to that of the IV formulation.

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18
Q

Why is the variation in bioavailability within a population more clinically significant than the mean?

A

The variation in bioavailability within a population is more clinically significant than the mean, and drugs should be dosed according to the lowest F, not the mean.

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19
Q

What does lipid solubility determine in the context of drug pharmacokinetics?

A

Lipid solubility determines how readily a drug crosses biologic membranes in drug pharmacokinetics.

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20
Q

How does the ionization of drugs influence their lipophilicity?

A

unionised drugs only cross biologic membranes. Strongly ionised cannot

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21
Q

In which pHs are weak acids and weak bases ionised?

A

Weak acids are non-ionized in acidic environments, and weak bases are non-ionized in basic environments.

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22
Q

What is the significance of pKa and pH in drug ionization?

A

pKa and pH play a crucial role in drug ionization. When pH equals pKa, 50% of the drug is ionized (log1=0).

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23
Q

Describe the pH-partition hypothesis in drug pharmacokinetics.

A

The pH-partition hypothesis states that drugs tend to be non-ionized in environments where they are non-ionized in body fluids.

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24
Q

How do weak bases behave in acidic environments according to the pH-partition hypothesis?

A

Weak bases are ionised in acidic environments. They are highly non-ionized in plasma and readily cross lipid membranes, becoming ionized and ‘ion trapped’ in tissues.

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25
Q

What is the effect of weak acids on tissue penetration based on the pH-partition hypothesis?

A

Weak acids are ionised in plasma and have poor penetration into tissues.

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26
Q

What are amphoteric drugs, and how do they differ from weak acids and weak bases?

A

Amphoteric drugs, such as fluoroquinolones and tetracyclines, have both acidic and basic groups and a pH range where they are maximally non-ionized.

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27
Q

Why do aminoglycosides, despite being weak bases, have poor penetration into certain tissues?

A

Despite being weak bases, aminoglycosides have poor penetration into certain tissues due to their large size and high pKa values.

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28
Q

In drug protein binding, what happens to drugs bound to plasma proteins?

A

In drug protein binding, drugs bound to plasma proteins become too large to pass through membranes, and only free drug is available for tissues.

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29
Q

Which plasma protein do acidic drugs primarily bind to?

A

Acidic drugs primarily bind to albumin in drug protein binding.

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30
Q

What is the role of α-1 acid glycoprotein in binding basic drugs?

A

Basic drugs primarily bind to α-1 acid glycoprotein (APP) in drug protein binding.

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31
Q

Describe the equilibrium between free and bound drug in drug protein binding.

A

There is an equilibrium between free and bound drug in drug protein binding.

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32
Q

How does drug protein binding affect duration of action?

A

Highly bound drugs act as drug depots, allowing for increased duration of action.

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33
Q

What happens when drug interactions alter protein binding?

A

Changes in protein binding caused by drug interactions are assumed to instantaneously change free drug concentrations, affecting drug distribution and elimination.

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34
Q

Explain the concept of adjustments in dosing regimes due to hypoproteinaemia or concurrent administration of highly bound drugs.

A

Adjustments in dosing regimes due to changes in protein binding are generally unnecessary, except in the rare case of a drug with a high hepatic extraction ratio and narrow therapeutic index given parenterally.

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35
Q

Provide an example of a drug interaction related to protein binding and its correction.

A

An example of a drug interaction related to protein binding is the concurrent administration of phenylbutazone and warfarin. However, the increase in free drug is transient.

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36
Q

Why is it generally unnecessary to adjust dosing regimes due to changes in protein binding?

A

Adjustments in dosing regimes due to hypoproteinaemia or concurrent administration of highly bound drugs are generally transient and not necessary.

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37
Q

What is the role of albumin in drug protein binding?

A

Albumin is a key plasma protein in drug protein binding.

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38
Q

How can hepatic disease, PLN, and PLE affect drug protein binding?

A

Hepatic disease, PLN, and PLE can affect drug protein binding by decreasing albumin levels.

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39
Q

What are the key factors affecting drug bioavailability?

A

Factors affecting drug bioavailability include volume contraction conditions, dehydration, changes in acid-base balance, and neonates.

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40
Q

How is the volume of distribution (Vd) calculated by the area method in clinical applications?

A

The volume of distribution (Vd) calculated by the area method is used to predict the amount of drug remaining in the body.

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41
Q
A

Complete

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42
Q

complete

A
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43
Q

complete

A
44
Q

complete

A
45
Q

complete

A
46
Q

Give 2 methods of drug elimination

A

excretion
biotransformation

47
Q

Define drug elimination

A

removal of intact drug

48
Q

Define drug biotransformation

A

conversion of a drug into a metabolite that is more readily excreted, usually by adding a chemical group to make it more soluble.

49
Q

Define Elimination rate constant (K)

A

sum of drug elimination by excretion and metabolism

50
Q

Define a drugs’ half life (t1/2)

A

Time for drug concentration to decrease by 1/2

51
Q

What does this describe:

A

half life for first order reactions

52
Q

What is the mean residence time?

A

equivalent of T½ when pharmacokinetics is calculated using statistical moment theory/ An estimate of the average time a drug molecule spends in the body

53
Q

Is t1/2 or MRT used to calculate the drug dosage interval?

A

t1/2

54
Q

How many t/12 to decrease plasma concentration by 99.9%?

A

10

55
Q

What effect does doubling the dose have on drug withdrawl time?

A

adds one t1/2 to the time it takes to reach an acceptable concentration.

56
Q

What is Ka?

A

absorption rate constant (=K (elimination) for long acting preparations)

57
Q

How do you ID flip-flop elimination kinetics?

A

compare the plasma concentration over time curve for the extravascular route of admin to the curve for IV. If the elimination phases of the curves are not parallel, delayed absorption is prolonging elimination and the flip-flop phenomenon has occurred.

58
Q

Why might a bioavailability be >100%?

A

flip flop elimination kinetics

Flip-flop kinetics refers to when the rate of absorption of a compound is significantly slower than its rate of elimination from the body. Therefore, the compound’s persistence in the body becomes dependent on absorption rather than elimination processes. This sometimes occurs when the route of exposure is dermal.

59
Q

What is clearance?

A

A measure of drug elimination from the body without reference to the mechanism of elimination= sum of all elimination mechanisms.

60
Q

Why is the clearance the most important PK parameter?

A

It is the only parameter that controls overall drug exposure and is used to calculate the dosage to maintain an average steady state concentration.

61
Q

How is clearance measured?

A

administer a single IV dose of a drug and then measure plasma concentrations over time.
○ Cl = Dose/AUC
○ where AUC is the area under the plasma concentration time

62
Q

How is the extraction ratio related to clearance?

A

CI= CO x E

63
Q

If E=1 (100% removal on the first pass), how does CI compare to CO

A

Approximately 50%: Liver/ kidneys receieve around 50% of the CO

64
Q

Why is t/12 a poor indicator of physiologic/pathologic changes affecting drug disposition?

A

It is derived from a rate constant and does not have a physiologic basis.

65
Q

Give 3 mehanisms of renal drug clearance.

A

Glomerular filtration
Active tubular secretion
Tubular reabsorption

66
Q

What equation defines renal clearance?

A

ClR= ClF + Cls -FR
where ClR is total renal clearance, ClF is clearance attributed to glomerular filtration, ClS is clearance attributed to active tubular secretion, and FR is the fraction of drug reabsorbed from the tubule back to circulation

67
Q

What is a requirement for glomerular filtration of a drug?

A

small and unbound

68
Q

Where in the tubules does active tubular secretion occur?

A

Proximal

69
Q

Why does tubular secretion require energy?

A

Moves drug against concentration gradient.

70
Q

What would indicate tubula reabsorption of a drug is occuring?

A

CIR< GFR

71
Q

Is tubular reabsorption active or passive?

A

active process for
endogenous compounds (e.g., vitamins, electrolytes, glucose).
It is a passive process for the majority of drugs

72
Q

Where does tubular reabsorption primiarily occur?

A

Distal tubule

73
Q

Are acidic or alkaline drugs most easily reabsorbed?

A

Equine urine is alkaline -> bases non-ionised-> more lipid solube -> more easily reabsorbed

74
Q

5 factors that influence drug reabsorption in the distal tubule.

A

pKa
urine pH
urine flow
drug lipid solubility
drug size

75
Q

What equation governs hepatic drug clearance? (ClH)

A

ClH= QH x ERH
QH= hepatic blood floe
ERH= extraction ratio: intrinsic ability of the liver to extract the drug

76
Q

If a drug has a high degree of first pass metabolism, ERH is…

A

high (approaching 1)

77
Q

T/F, drugs with a high ERH are highly influenced by changes in hepatic blood flow

A

T

78
Q

What affects clearance of drugs with an ERH< 0.2

A

hepatic microsomal system activity, protein binding

79
Q

5 factors influencing biotransformation of a drug:

A

Chemical composition of the liver
activity of major drug metabolism enzymes
hepatic volume (perfusion rate)
drug accessibility to and extraction by hepatic metabolic sites
Physicochemical properties of the drug.

80
Q

Phase 1 reactions typically

A

add functional groups to the drug molecule necessary for phase 2 reactions

81
Q

Phase 2 reactions typically

A

conjugate the molecule and increase the water solubility of the drug.

82
Q

T/F: cP450 system is primarily reductive

A

F: oxidative

83
Q

T/F: cP450 system catalyses hydroxylation of poorly lipophilic drugs

A

F: highly lipophilic

84
Q

3 examples of drugs causing hepatic enzyme induction

A

Rifampin, azoles, phenobarbital

85
Q

Examples of drugs causing hepatic enzyme inhibition:

A

Erythromycin and enrofloxacin are known
inhibitors of the metabolism of theophylline; concurrent administration can cause central nervous system toxicity and seizures

86
Q

2 drugs obeying zero order kinetics

A

PBZ, phenytoin

87
Q

Most drug metabolism obeys … order kinetics

A

first

88
Q
A
89
Q

What is the principle of superposition in drug administration?

A

The principle of superposition assumes that successive doses of a drug do not affect the pharmacokinetics of subsequent doses. Most drugs, with equal doses at constant intervals, reach a steady-state with plateaued plasma concentration-time curves.

90
Q

How is steady-state defined, and what influences the values of Cmax and Cmin at steady-state?

A

Steady-state is when Cmax (peak) and Cmin (trough) remain constant from dose to dose. The time to steady-state depends on the elimination half-life (approximately 5 to 6 half-lives to reach 99% steady-state levels). The drug dose and dosage frequency influence the values of Cmax and Cmin at steady-state.

91
Q

What are the clinical consequences of dosage intervals less than the half-life, and which drugs are mentioned in this context?

A

Dosage intervals less than the half-life can lead to drug accumulation, especially with drugs like phenobarbital, potassium bromide, phenylbutazone, and digoxin. Predicted Accumulation Ratio (RA) can be calculated using the formula RA = 1/(1 - e^(-λz * τ)), where λz is the elimination phase slope, and τ is the dosage interval.

92
Q

For drugs with dosage intervals greater than the half-life, what is the potential consequence and which drugs fall into this category?

A

Drugs with dosage intervals greater than 10 times the half-life may experience minimal drug accumulation. Marked fluctuation between Cmax and Cmin occurs, and missing a dose can greatly affect concentrations. Drugs like IV penicillin and cephalosporins are mentioned.

93
Q

What factors influence drug concentrations in dosage regimen design, and why is dosage regimen design crucial for drug therapy?

A

Factors influencing drug concentrations include dose, route of administration, release, absorption, distribution, and elimination. Dosage regimen design is crucial for the success of drug therapy. Antimicrobials with broad safety ranges may not need precise individualization, while drugs with narrow therapeutic margins (e.g., digoxin, aminoglycosides) require careful individualization.

94
Q

What physiological changes occur in geriatric horses that impact drug pharmacokinetics?

A

In geriatric horses, changes in body composition, reduced cardiac output, altered blood flow, and other factors impact drug absorption, distribution, and elimination. These changes can increase the risk of drug toxicity, especially in the brain and heart.

95
Q

How does drug disposition vary in neonates, and what challenges are associated with drug administration in foals?

A

Neonates have greater blood flow to the heart and brain, making them more susceptible to drug-induced cardiotoxicity and neurotoxicity. Challenges include decreased GI absorption, variable gastric pH, changes in absorption from IM and SC sites, and differences in body composition leading to altered drug distribution.

96
Q

What are the general considerations for drug use in horses with renal failure, and what dosage adjustment methods are mentioned?

A

General considerations include avoiding unnecessary drugs, using hepatically metabolized and biliary excreted drugs, and monitoring for signs of efficacy and toxicity. Dosage adjustment methods include the dose-reduction method (adjusting the drug dose while maintaining the dosing interval) and the interval-extension method (maintaining the drug dose but extending the dosing interval).

97
Q

How does the interval-extension method in dosage adjustment affect drug concentrations, and why is it preferred for certain drugs?

A

The interval-extension method produces Cmax and Cmin values similar to those in healthy patients but results in substantial periods of time with subtherapeutic drug concentrations. It is preferred for drugs like aminoglycosides, which have a long postantibiotic effect, and a low trough concentration is desirable to reduce the risk of nephrotoxicity.

98
Q

In the dose-reduction method, what is the potential consequence regarding drug accumulation, and why is it preferred for certain antibiotics?

A

The dose-reduction method may lead to significant drug accumulation depending on the elimination half-life to the dosage interval relationship. However, at steady-state, there are no periods of subtherapeutic concentrations. This method is preferred for penicillin and cephalosporin antibiotics, as maintaining plasma concentration above the pathogen’s minimum inhibitory concentration (MIC) correlates with efficacy, and these drugs are relatively nontoxic even if accumulation occurs.

99
Q

When designing drug dosage regimens, what factors determine whether precise individualization is necessary?

A

Precise individualization is necessary for drugs with narrow therapeutic margins (e.g., digoxin, aminoglycosides, theophylline). Factors such as the dose required to keep the plasma concentration above the minimum inhibitory concentration (MIC) play a role in determining the need for individualization.

100
Q

How is the loading dose followed by maintenance dose regimen utilized, and for which type of drugs is it recommended?

A

The loading dose followed by maintenance dose regimen is used for drugs with long elimination half-lives (e.g., phenobarbital). A loading dose is administered initially to rapidly achieve therapeutic drug concentrations, followed by a reduced maintenance dose to maintain steady-state concentrations.

101
Q

What is the objective of therapeutic drug monitoring (TDM), and when is it particularly valuable?

A

The objective of TDM is to monitor and adjust drug therapy by measuring plasma drug concentrations. TDM is particularly valuable when there is a relationship between plasma drug concentration and clinical effects or adverse effects. It is also useful in horses with systemic diseases affecting pharmacokinetics and when multiple drugs are administered simultaneously.

102
Q

Which drugs are commonly subjected to therapeutic drug monitoring (TDM), and what characteristics make a drug suitable for TDM?

A

Drugs commonly subjected to TDM include those with serious toxicity, a steep dose-response curve, marked pharmacokinetic variability, easily saturable elimination mechanisms, or when the cost justifies confirming plasma drug concentration. Examples include digoxin, phenobarbital, aminoglycosides, theophylline, and cyclosporine.

103
Q

When should samples for TDM be taken, and what is the significance of loading doses in this context?

A

Samples for TDM should be taken after about 5-6 elimination half-lives, ensuring a steady state in the patient. Loading doses may be administered to rapidly achieve therapeutic drug concentrations, and TDM helps determine the proper maintenance dose after loading.

104
Q

Why is monitoring for drug elimination time significant, and when is it essential to collect samples for this purpose?

A

Monitoring for drug elimination time is significant to identify whether the horse has a shorter- or longer-than-normal elimination time for the drug. It is essential to collect samples when the response to therapy is unexpected, helping adjust the dosage regimen promptly.

105
Q

In dosage adjustment for renal failure, how does the dose-reduction method differ from the interval-extension method, and under what circumstances are they preferred?

A

The dose-reduction method adjusts the drug dose while maintaining the dosing interval, while the interval-extension method maintains the drug dose but extends the dosing interval. The choice depends on the drug’s relationship between efficacy and toxicity. The interval-extension method is more convenient for clients and may be preferred for drugs available in fixed dosage forms.

106
Q

What are the general considerations for drug use in horses with renal failure, and why is therapeutic drug monitoring impractical for many drugs?

A

General considerations include avoiding unnecessary drugs, using hepatically metabolized and biliary excreted drugs, and monitoring for signs of efficacy and toxicity. Therapeutic drug monitoring is impractical for many drugs due to cost and practicality, leading to the need for alternative methods, such as dosage adjustments based on available renal function tests.

R&B Pharmacology (4 decks)

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