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Therapeutic Drug Monitoring Flashcards

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1
Q

What is Therapeutic Drug Monitoring (TDM)?

A

TDM is the measurement of drug concentrations in body fluids, usually plasma or whole blood, and sometimes serum or urine, to ensure optimal therapeutic levels.

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2
Q

What is the purpose of Therapeutic Drug Monitoring (TDM)?

A

The purpose of TDM is to quantify drug concentration in body fluids and interpret the findings to optimize drug therapy, ensuring efficacy while minimizing toxicity.

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3
Q

Which body fluids are commonly used for Therapeutic Drug Monitoring (TDM)?

A

Common fluids for TDM include plasma, whole blood, and sometimes serum or urine.

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4
Q

How is drug concentration measured in TDM?

A

Drug concentration is measured by analyzing body fluids (e.g., plasma, serum, whole blood) using various laboratory techniques to quantify the amount of drug present.

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5
Q

How are TDM results interpreted?

A

TDM results are interpreted by comparing drug concentrations to therapeutic ranges, assessing if levels are within the desired range for efficacy and safety, and making dose adjustments as needed.

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6
Q

Why is Therapeutic Drug Monitoring (TDM) important?

A

TDM is important to ensure that drug levels are within the therapeutic range, to avoid toxicity or suboptimal therapeutic effects, and to tailor drug therapy to individual patient needs.

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7
Q

What factors can influence the results of Therapeutic Drug Monitoring (TDM)?

A

Factors influencing TDM results include individual patient metabolism, adherence to medication, drug interactions, and timing of sample collection.

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8
Q

How is TDM used in clinical practice?

A

TDM is used in clinical practice to monitor drug levels in patients on medications with narrow therapeutic ranges, adjust dosages based on individual responses, and prevent adverse drug reactions.

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9
Q

What does Pharmacokinetics (PK) refer to?

A

PK refers to what the body does to the drug, including the processes of absorption, distribution, metabolism, and excretion.

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10
Q

How is Pharmacokinetics (PK) represented in relation to Therapeutic Drug Monitoring (TDM)?

A

The PK triangle represents how the drug concentration in plasma (Cp) is influenced by the dose administered, assuming equilibrium between plasma and tissue concentrations.

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11
Q

What does Pharmacodynamics (PD) refer to?

A

PD refers to what the drug does to the body, including the biological and physiological effects of the drug and its mechanisms of action.

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12
Q

How is Pharmacodynamics (PD) represented in the context of Therapeutic Drug Monitoring (TDM)?

A

The PD triangle represents how the drug concentration in plasma (Cp) correlates with the therapeutic effect or response.

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13
Q

What is the role of plasma concentration (Cp) in connecting PK and PD?

A

Plasma concentration (Cp) is the central point linking PK and PD, as it is crucial in both the body’s handling of the drug (PK) and the drug’s effects on the body (PD).

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14
Q

How does the dose to effect relationship work in the context of Therapeutic Drug Monitoring (TDM)?

A

The dose to effect relationship illustrates how the initial dose (input) affects the plasma concentration (intermediate), which then determines the drug’s effect (output).

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15
Q

Why is the relationship between Pharmacokinetics (PK) and Pharmacodynamics (PD) important in Therapeutic Drug Monitoring (TDM)?

A

This relationship is fundamental in TDM as it helps to optimize drug therapy by maintaining drug concentrations within a therapeutic range that maximizes efficacy while minimizing toxicity

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16
Q

What is the aims of TDM

A
  1. Toxicity- avoid toxicity
  2. Dosing- optimise dose
  3. Efficacy- improve efficacy
  4. Diagnosis- assist in diagnosis
  5. Adherence- assess adherence
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17
Q

How does Therapeutic Drug Monitoring (TDM) assist in cases of failure of therapy?

A

TDM helps distinguish between genuine drug resistance, issues with adherence, and adverse effects that may mimic the disease state. By measuring drug levels, it can identify whether therapy failure is due to insufficient drug levels, poor adherence, or an adverse effect.

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18
Q

How can Therapeutic Drug Monitoring (TDM) aid in diagnosing overdose?

A

TDM can measure plasma drug levels to differentiate between drug-induced symptoms and organic disease. For example, it helps distinguish between coma caused by a sedative overdose and other causes. This can influence management strategies, such as the use of N-acetylcysteine in paracetamol overdose.

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19
Q

How is Therapeutic Drug Monitoring (TDM) used in cases of drug abuse?

A

TDM can confirm abstinence from drugs, which is useful in settings like narcotic treatment programs and athletic screening. It provides evidence of compliance with treatment or the absence of prohibited substances.

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20
Q

How does Therapeutic Drug Monitoring (TDM) relate to medication adherence?

A

While TDM is not specifically performed to assess adherence, it can indirectly reveal whether a patient is adhering to their medication regimen. If drug levels are consistently below the therapeutic range, it may suggest issues with adherence.

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21
Q

What are some individual indications for Therapeutic Drug Monitoring (TDM)?

A

TDM is indicated for:

  • Lack of clinical response: To ensure the drug level is within the therapeutic range.
  • Suspected toxicity: To identify if the drug level is too high and causing adverse effects.
  • Adherence: To assess whether the patient is taking their medication as prescribed.
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22
Q

How do co-morbidities influence the need for Therapeutic Drug Monitoring (TDM)?

A

TDM is important in the presence of co-morbidities such as:

  • Drug-drug interactions: To monitor for interactions that could affect drug levels and efficacy.
  • Renal/hepatic impairment: To adjust drug dosages and avoid toxicity due to altered drug metabolism or excretion.
  • Malabsorption: To ensure adequate drug levels despite potential absorption issues.
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23
Q

Why is Therapeutic Drug Monitoring (TDM) especially important in special populations?

A

Pregnancy
Paediatrics
Elderly
Obesity
Genetics

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24
Q

Why is Therapeutic Drug Monitoring (TDM) necessary for drugs with high inter-patient variability in plasma concentrations?

A

TDM is essential for drugs with high inter-patient variability to ensure that each patient maintains drug levels within the therapeutic range. This variability can lead to significant differences in drug efficacy and safety between individuals.

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25
How does a narrow therapeutic window influence the need for Therapeutic Drug Monitoring (TDM)?
Drugs with a narrow therapeutic window have a small margin between therapeutic and toxic levels. TDM helps in maintaining drug concentrations within this narrow range to maximize efficacy and minimize toxicity.
26
Why is TDM important for drugs with a good correlation between plasma concentrations and clinical effects?
For drugs where plasma concentrations closely correlate with clinical effects, TDM ensures that drug levels are optimized to achieve the desired therapeutic effect while avoiding adverse effects.
27
How does the availability of cost-effective, accurate drug assays impact the use of Therapeutic Drug Monitoring (TDM)?
The availability of cost-effective and accurate drug assays with rapid turnaround and small blood volume requirements makes TDM more feasible and practical, facilitating routine monitoring and adjustments of drug therapy.
28
Why is TDM crucial for drugs whose pharmacological effect persists and is dependent on plasma concentration?
For drugs where the pharmacological effect is dependent on maintaining specific plasma concentrations, TDM is crucial to ensure that these levels are achieved and sustained for optimal therapeutic outcomes.
29
What constitutes the central compartment in pharmacokinetics?
The central compartment includes the intravascular compartment (blood) and highly perfused lean organs such as the heart, brain, liver, lungs, and kidneys. These are often clustered together as a single central compartment.
30
What is the peripheral compartment in pharmacokinetics?
The peripheral compartment consists of more slowly perfused tissues that do not metabolize the drug significantly, such as muscle, skin, fat, and bone.
31
What does the first-order elimination rate constant (Ke) represent, and how is it calculated?
Ke represents the rate of irreversible drug elimination from the body per unit time. For example, if 25% of the drug is eliminated per hour, the Ke is 0.25/hr. It is calculated as Ke = -0.693 / t1/2, where t1/2 is the half-life of the drug.
32
What are K12 and K21 in the context of drug distribution?
K12 and K21 represent the reversible distribution of the drug between the central compartment (blood and highly perfused organs) and the peripheral compartment (non-metabolizing tissues). K12 is the rate constant for drug transfer from the central to the peripheral compartment, while K21 is the rate constant for transfer from the peripheral to the central compartment.
33
Why is the pharmacological effect of some drugs dependent on plasma concentration?
For drugs whose pharmacological effects are dependent on maintaining specific plasma concentrations, the effect persists as long as the drug concentration remains within the therapeutic range. Monitoring plasma concentrations helps ensure that drug levels are maintained for optimal efficacy and safety.
34
Examples of drugs that require TDM
- Aminoglycosides - Vancomycin - Anticonvulsants - Digoxin - Theophylline
35
Aminoglycosides (gentamicin/amikacin)
Toxicity relates to trough concentrations Efficacy relates to peak concentrations
36
Vancomycin
Efficacy dependent on total drug exposure, efficacy and toxicity relates to trough concentration
37
Anticonvulsants (phenytoin/ carbamazepine)
Large interpatient variability
38
Digoxin
Narrow therapeutic window, toxicity is main concern
39
Theophylline
Narrow therapeutic window, toxicity is main concern
40
TDM in disease states
Renal impairment Liver impairment
41
TDM in Transplant
Immunosuppressants
42
TDM in psychiatry
Lithium Tricyclic antidepressants
43
TDM in Cardiology
Digoxin
44
TDM in infectious diseases
Vancomycin Amikacin Gentamicin Rifampicin
45
TDM in neurology
Phenytoin Valproic acid Carbamazepine
46
How is the Therapeutic Index (TI) defined and calculated?
The Therapeutic Index (TI) is defined by the ratio of the TD50 (dose that elicits toxicity in 50% of subjects) to the ED50 (dose that elicits a therapeutic effect in 50% of subjects). It is calculated as TI = TD50 / ED50. A higher TI indicates a wider therapeutic window and a safer drug.
47
How is a dose-response curve represented on a semilog scale, and what do the axes represent?
On a semilog scale, the dose-response curve plots drug doses on a logarithmic scale on the X-axis and the population percentage (0%, 50%, 100%) on the Y-axis. The ED50 is the dose at which 50% of the population shows the desired therapeutic effect, while the TD50 is the dose at which 50% of the population experiences toxicity
48
What does ED50 represent in a dose-response curve?
ED50, or the median effective dose, is the dose of a medication at which 50% of the population achieves the specific therapeutic effect. It indicates the dose required for half of the population to experience the desired effect.
49
What does TD50 represent in a dose-response curve?
TD50, or the median toxic dose, is the dose of a drug at which toxicity occurs in 50% of the cases. It reflects the dose at which half of the population experiences adverse effects.
50
What does the therapeutic window refer to, and how is it measured using the Therapeutic Index (TI)?
The therapeutic window refers to the range of drug doses that are effective without causing unacceptable toxicity. It is measured using the Therapeutic Index (TI), which is the ratio of TD50 to ED50. A larger TI indicates a wider therapeutic window, meaning there is a larger margin between effective and toxic doses.
51
How can the dose-response curve indicate whether a drug has a narrow or wide therapeutic window?
On a semilog scale, a dose-response curve with a steep slope between the ED50 and TD50 indicates a narrow therapeutic window, meaning the difference between effective and toxic doses is small. Conversely, a curve with a more gradual slope indicates a wide therapeutic window, where there is a larger margin between effective and toxic doses.
52
How does the Therapeutic Index (TI) relate to the safety profile of a drug?
The higher the Therapeutic Index (TI), the better the safety profile of the drug. A high TI indicates a larger margin between the dose that produces a therapeutic effect and the dose that causes toxicity, meaning the drug is safer because there is a lower risk of reaching toxic levels at therapeutic doses.
53
What are the key features of phenytoin's pharmacokinetics?
1. Inter-individual Variability: Phenytoin exhibits significant variability in drug levels among individuals. 2. Saturable Metabolism: Phenytoin follows zero-order kinetics at higher doses, meaning the rate of elimination is constant and independent of concentration. Small dose increases can lead to disproportionate rises in blood levels and toxicity. 3. Zero-Order Kinetics: At higher doses, the elimination process becomes zero-order, where a constant amount of drug is eliminated per unit time, irrespective of the drug concentration. 4. First-Order Kinetics: At lower doses, phenytoin metabolism follows first-order kinetics, where the rate of elimination is proportional to the drug concentration. 5. Nonlinear Relationship: The relationship between phenytoin dosage and plasma concentration is nonlinear due to saturable metabolism. As dosage increases, the liver's capacity to metabolize phenytoin becomes saturated, leading to large increases in plasma levels and potential toxicity. 6. Half-Life: The drug's half-life increases significantly when blood levels are high due to the saturation of metabolic pathways.
54
Practical considerations
1. Laboratory able to measure drug? 2. What biological sample should be used? 3. What is the optimum time to take the sample with respect to the last dose taken? 4. Is there an accepted ‘therapeutic range’ - MEC - threshold concentration above which efficacy is expected in most patients with the disorder - MTC - upper concentration above which the rate and severity of adverse effects become unacceptable
55
When should you sample a drug concentration if the goal is dose adjustment?
Sample before the next planned dose when the concentration is at its minimum (trough).
56
When should you sample a drug concentration to determine if efficacious concentrations are being achieved?
Sample shortly after the dose, during peak or mid-peak time.
57
When should you sample a drug concentration to determine if low clearance is leading to toxicity?
Sample just before the next planned dose to reveal potential drug accumulation.
58
Why is it crucial to monitor drug concentrations for Aminoglycosides?
Aminoglycosides have a narrow therapeutic index, and small changes in drug concentration can lead to severe adverse events, such as nephrotoxicity and ototoxicity.
59
What is the importance of monitoring Vancomycin levels?
Vancomycin, a first-generation glycopeptide antibiotic, has a narrow therapeutic index. Monitoring is essential to avoid toxicity and ensure effective treatment of MRSA and Enterococcal infections.
60
Why should Digoxin levels be carefully monitored?
Digoxin has a narrow therapeutic index. Small fluctuations in its concentration can lead to significant adverse effects, including cardiac toxicity.
61
What are the symptoms associated with different levels of Lithium concentration?
>1.2mmol/L – 1.5mmol/L: Fatigue, nausea, and tremor. >1.5mmol/L – 3mmol/L: Confusion, agitation, and slurred speech. >3mmol/L: Coma or death.
62
Why is it important to differentiate between acute episode and maintenance dose targets for Lithium?
Different targets are necessary because the therapeutic range for acute episodes and maintenance doses of Lithium varies to prevent toxicity while managing the condition effectively.
63
Interpretation of results
- Time of sample collection - Time of last dose - Dosage regimen - Indication for drug monitoring
64
What could be the reasons for a low drug concentration in a patient?
- Dose too low - Poor adherence - Rapid elimination - Timing of sample
65
What are possible causes of a high drug concentration?
- Dose too high - Taking incorrectly - Slow elimination - Timing of sample
66
What could explain a therapeutic drug concentration that is in range but shows no clinical response?
Altered receptor sensitivity (tolerance) Pharmacodynamic action not resulting in clinical effect (requires switch/new mechanism of action)
67
What should be considered to determine if there is therapeutic failure or clinical toxicity?
Evaluate if the patient is experiencing symptoms of therapeutic failure (lack of desired effect) or clinical toxicity (adverse effects).
68
Should the drug concentration be sampled at steady-state, and if so, should it be a trough or peak sample?
Yes, sampling should be at steady-state. Determine whether a trough (just before the next dose) or peak (shortly after the dose) sample is appropriate based on the drug’s pharmacokinetics and the clinical question.
69
How do you determine the appropriate sampling time for therapeutic drug monitoring?
The appropriate sampling time should be based on the drug’s pharmacokinetics, the dosing schedule, and the clinical question (e.g., peak, trough, or mid-interval sample).
70
How should the concentration be interpreted relative to the target range?
Compare the measured concentration to the established therapeutic target range to determine if it is within, above, or below the desired range.
71
Should the dose be modified based on the drug concentration, and how should this be done?
Yes, modify the dose if necessary. Increase the dose if the concentration is below the target range, decrease the dose if it is above the target range, and adjust the dosing interval if needed, considering the drug’s pharmacokinetics and patient-specific factors
72
How are most drugs bound in the serum, and how is this measured
Most drugs are electrochemically bound to proteins in the serum, measured as a percentage from 0-100%.
73
To which protein do acidic drugs primarily bind?
Acidic drugs bind largely to albumin.
74
To which proteins do basic drugs primarily bind?
Basic drugs bind mainly to α-1-acid glycoprotein, albumin, and β-lipoproteins.
75
What happens when drugs are displaced from protein-binding sites?
Displacement from protein-binding sites has little effect on pharmacodynamics (PD) but may affect pharmacokinetics (PK) and interpretation of TDM.
76
Which component of a drug is pharmacologically active?
The free drug is pharmacologically active.
77
Is dosage alteration usually required in states of altered protein binding?
Except for rare occasions, no alteration in dosage is required in states of altered protein binding.
78
Why is the concentration of free drug important?
The concentration of free drug, not total drug, is important in terms of desired effects and side effects.
79
What do drug assays in clinical TDM usually measure?
Drug assays usually measure total drug concentration (protein-bound drug + free drug).
80
What is the effect of higher free drug concentrations?
Higher free drug concentrations can enhance drug delivery to the tissues.
81
What can affect the concentration of free drug in the plasma?
Conditions that affect plasma protein concentration can alter the concentration of free drug.
82
What would happen to the concentration of the free drug if there were no drug elimination and a protein-binding displacer was introduced?
The introduction of a protein-binding displacer would increase the concentration of the free drug.
83
What actually happens to the drug concentration in the body considering drug elimination?
In reality, drug elimination does occur.
84
What happens to the free drug concentration after displacement when drug elimination is considered and the dose administered remains the same?
Provided that the dose administered remains the same and there are no effects on free drug clearance, the free drug concentration returns to its predisplacement level.
85
What happens to the total drug concentration after displacement when drug elimination is considered?
The total drug concentration is now lower than it was prior to the displacement.
86
When are changes in protein binding clinically relevant?
Changes in protein binding are clinically relevant when concentrations are close to efficacy or toxicity levels.
87
What is an example of a highly protein-bound drug where changes in protein binding can lead to adverse clinical effects?
Examples include phenytoin and ceftriaxone.
88
What type of high clearance drugs are influenced by changes in protein binding?
High clearance drugs that are predominantly eliminated by glomerular filtration or have saturable metabolism.
89
Why are drugs where dosing is not titrated to effect problematic when protein binding changes?
Because changes in protein binding can lead to concentrations that are too high or too low, leading to inefficacy or toxicity.
90
What are three features that influence whether changes in protein binding can lead to adverse clinical effects?
1. Highly protein-bound drugs (e.g., phenytoin, ceftriaxone). 2. High clearance drugs predominantly by glomerular filtration or with saturable metabolism. 3. Drugs where dosing is not titrated to effect (e.g., antibiotics).
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