Lecture 4 Flashcards

Question

What is therapeutic index? How is it calculated? What is margin of safety?

Answer 1

Therapeutic Index- Measure of the safety of a drug Calculation: LD50/ED50 Margin of Safety: Margin between the therapeutic and lethal doses of a drug Margin of Safety: • The difference between the effective dose (ED50) and the toxic dose (TD50) of a drug. It provides additional insight into drug safety. The **Margin of Safety** does refer to the "margin" or gap between the therapeutic and lethal doses of a drug, but it's more accurately described as a **ratio** rather than a simple numerical difference. Here’s a clearer explanation: ### Margin of Safety: - The **Margin of Safety** is a measure of how safe a drug is by comparing doses that produce therapeutic effects to those that produce lethal effects. It provides a more conservative safety measure compared to the **Therapeutic Index (TI)**. - **Definition**: It is the ratio of the dose that causes a lethal effect in a small percentage of the population (e.g., **LD1**) to the dose that is therapeutically effective in nearly all of the population (e.g., **ED99**). \[ \text{Margin of Safety} = \frac{\text{LD1}}{\text{ED99}} \] ### Understanding the Concept: - **LD1 (Lethal Dose for 1% of the Population)**: The dose at which 1% of the population would experience lethal effects. - **ED99 (Effective Dose for 99% of the Population)**: The dose at which 99% of the population experiences the desired therapeutic effect. - The Margin of Safety shows how much higher the lethal dose is compared to the effective dose for nearly all patients. A **larger Margin of Safety** indicates a safer drug because there is a wider gap between the effective and potentially lethal doses. ### Difference vs. Ratio: - When we say "margin" in this context, it can be misunderstood as a simple **difference** (subtraction) between lethal and therapeutic doses. However, in pharmacology, the "margin" is typically expressed as a **ratio** to quantify the safety of a drug more meaningfully. ### Example: - If a drug has an **LD1** of 100 mg and an **ED99** of 10 mg: \[ \text{Margin of Safety} = \frac{100 \, \text{mg}}{10 \, \text{mg}} = 10 \] - This means the lethal dose for 1% of the population is 10 times higher than the effective dose for 99% of the population, indicating a relatively safe drug. ### Summary: The **Margin of Safety** is indeed the "margin between the therapeutic and lethal doses of a drug," but it is typically expressed as a **ratio** rather than a simple difference to provide a clearer understanding of drug safety. The term Margin of Safety can indeed be described as the difference between the effective dose and the toxic dose, though it’s more commonly expressed as a ratio in pharmacological contexts. Here’s a detailed breakdown: Margin of Safety: • Definition: The Margin of Safety represents the difference between the dose that causes a therapeutic effect and the dose that causes toxic effects. It helps to gauge how much higher the toxic dose is compared to the effective dose. \text{Margin of Safety} = \text{TD50} - \text{ED50} where: • TD50 is the dose at which 50% of the population experiences toxic effects. • ED50 is the dose at which 50% of the population experiences the desired therapeutic effect

Answer 2

Drug induced responses are not an “all or none” phenomenon. Many drug effects are not strictly all-or-none but rather follow a dose-response curve where a minimal dose is needed to achieve a noticeable effect. effects can vary incrementally with dose. Increase in dose may: -Increase therapeutic response -Increase risk of toxicity

Answer 3

-Select appropriate drug for clinical indication -Select appropriate dose Consider pathophysiologic processes in patient such as hepatic or renal dysfunction Consider developmental and maturational changes in organ systems and the subsequent effect on PK and PD -Select appropriate formulation and route of administration -Determine anticipated length of therapy -Monitor for efficacy and toxicity -Pharmacogenetics Will play a larger role in the future For a critically ill child or infant, consider the fact that they won’t have matured livers,kidneys,etc and won’t have enzymes in optimum proportions for metabolism of drugs so you must becareful about the dosage and dosing interval of drugs

Answer 4

Other factors -Drug-drug interaction: cause the drugs they are taking and the drugs you want to give with their interactions can cause the following: Altered absorption Inhibition of metabolism Enhanced metabolism Protein binding competition Altered excretion Other factors (con’t) -Drug-food interaction: NG or NJ (naso jejunal feeding when you want to by pass acidic content In stomach ) feeds Continuous vs. intermittent Site of optimal drug absorption in GI tract must be considered

Answer 5

Absorption PO/NG administered drugs may have altered absorption due to: Alterations in pH Edema of GI mucosa Delayed or enhanced gastric emptying Alterations in blood flow Presence of an ileus Coadministration with formulas (I.e. Phenytoin)

Answer 6

Drug distribution may be affected: -Altered organ perfusion due to hemodynamic changes: May effect delivery to site of action, site of metabolism and site of elimination. Inflammation and changes in capillary permeability may enhance delivery of drug to a site -Hypoxemia affecting organ function: Altered hepatic function and drug metabolism

Answer 7

-Alterations in protein synthesis: If serum albumin and other protein levels are low, there is altered Vd(volume of distribution) of free fraction of drugs that typically are highly protein bound therefore a higher free concentration of drug. The bound form does not freely cross cell membranes to enter tissues.Free (Unbound) Drug: This is the portion of the drug that is not attached to proteins. It is the free drug that is pharmacologically active and capable of entering tissues to exert its effects. -Substrate deficiencies: .Exhaustion of stores .Metabolic stress

Answer 8

-Up regulation of receptors: ### Upregulation of Receptors: - **Definition**: When cells sense that there aren't enough receptors to respond to a certain signal (like a hormone or neurotransmitter), they can make more receptors. - **Example**: Imagine a cell that normally has a few "locks" (receptors) for a specific "key" (signal). If the cell senses it needs more of that signal, it can make extra locks to catch more keys. This is upregulation. -Down regulation of receptors Decreased number of drug receptors: ### Downregulation of Receptors: - **Definition**: Sometimes, cells have too many receptors or are getting too much of a signal. To protect themselves, they can take some locks away. - **Example**: If a cell has too many locks for a signal, it might remove some to avoid being overwhelmed. This is downregulation. ### Clinical Implications: - **Drug Effects**: Drugs can influence these processes. For example, some drugs might cause cells to upregulate their receptors, making them more sensitive to a signal. Others might lead to downregulation, reducing the cell's response to a signal. Upregulation and downregulation of receptors refer to adaptive changes in the number or sensitivity of receptors on cell surfaces in response to various stimuli, including drugs. -Altered endogenous production of a substance may affect the receptors. The factors below are how altered endogenous production of a substance can affect drug receptors or This altered endogenous production of a substance affecting receptors will due to : Acid-base status(alkalosis and acidosis influencing how receptors respond to signals and this influences your drug choice) Electrolyte abnormalities Altered intravascular volume: changes in blood volume and blood pressure can affect receptor responsiveness. Low blood volume can reduce receptor activation in response to hormones like aldosterone Tolerance: Prolonged exposure to certain substances (like drugs or hormones) can lead to receptor desensitization or downregulation, reducing their responsiveness over time. - **Mechanism**: Tolerance develops as cells adapt to constant stimulation by reducing the number or sensitivity of receptors, requiring higher doses to achieve the same effect. ### Clinical Considerations: - Understanding how these factors influence receptor function helps clinicians manage conditions where receptor signaling plays a crucial role. - Monitoring acid-base balance, electrolytes, and intravascular volume is essential for optimizing receptor responsiveness in various physiological and pathological states.

Answer 9

Target-effect” strategy: Either you get a Pre-determined efficacy endpoint or you Titrate drug to desired effect so in titrating: -Monitor for efficacy and If plateau occurs, you may need to add additional drug or choose alternative agent -Monitor for toxicity and in this case you May require decrease in dose or alternative agent

Answer 10

Target-concentration strategy: -There is a Pre-determined concentration goal. This goal is Based on population-based PK and the Target concentration is also based on efficacy or toxicity -you need to Know the PK of the drug you are prescribing: answer questions like Is there a Presence of an active metabolite? Should the level of the active metabolite be measured? is it Zero-order or first-order kinetics?(Does it change with increasing serum concentrations?) Does it follow linear kinetics or it follows Michael mentens kinetic principles In pharmacokinetics, the terms "first-order" and "zero-order" refer to different types of kinetics that describe how drugs are eliminated from the body: 1. **First-Order Kinetics**: - **Definition**: First-order kinetics describe a process where the rate of elimination of a drug is directly proportional to its concentration in the body. - **Characteristics**: In first-order kinetics, as the concentration of the drug decreases over time (due to metabolism and excretion), the rate of elimination also decreases proportionally. - **Example**: Most drugs follow first-order kinetics because enzymes responsible for drug metabolism and renal clearance are usually not saturated at therapeutic doses. 2. **Zero-Order Kinetics**: - **Definition**: Zero-order kinetics describe a process where the rate of elimination of a drug remains constant regardless of its concentration in the body. - **Characteristics**: In zero-order kinetics, the enzymes responsible for drug metabolism or the mechanisms of drug excretion become saturated at higher concentrations. Therefore, the rate of elimination does not increase with increasing drug concentrations. - **Example**: Some drugs, especially at high doses or when the enzymes responsible for their metabolism are saturated, exhibit zero-order kinetics. For instance, alcohol metabolism follows zero-order kinetics when the alcohol dehydrogenase enzyme is saturated. Zero-Order Kinetics: Also known as saturation kinetics. • Michaelis-Menten Kinetics: Describes both zero-order (at saturation) and first-order (at low concentrations) processes.

Answer 11

Critical aspects of “target-concentration” therapy -Know indications for monitoring serum concentrations AND when you do not need to monitor levels especially when doing therapeutic drug monitoring -Know the appropriate time to measure the concentration -If the serum concentration is low, know how to safely achieve the desired level -Be sure the level is not drawn from the same line in which the drug is administered -Be sure drug is administered over the appropriate time AND Treat the patient, not the drug level cuz some patients will need a higher dose to achieve therapeutic effect while some will need lower dose to achieve therapeutic effect

Answer 12

In the case of JB, a 5-year-old male with pneumonia and renal insufficiency requiring an aminoglycoside, the best choice would be: **b) Give a normal dose with an extended interval.** ### Rationale: 1. **Renal Insufficiency**: Since JB has renal insufficiency (BUN/SCr of 39/1.5 mg/dL) and reduced urine output (0.4 cc/kg/hr), the clearance of aminoglycosides would be impaired. Aminoglycosides are primarily eliminated by the kidneys, so adjusting the dosing regimen is necessary to avoid toxicity. 2. **Dosing Adjustments**: - Aminoglycosides have a narrow therapeutic window, and the risk of nephrotoxicity and ototoxicity increases with accumulation due to impaired renal function. - Extended-interval dosing is often preferred in patients with renal impairment because it allows for higher peak concentrations while reducing the risk of accumulation and toxicity during the trough phase. 3. **Dosing Recommendations**: - Starting with a normal dose would not be safe due to the risk of accumulation. - A lower dose with a normal interval may not provide adequate therapeutic levels for treating the infection effectively. 4. **Contraindications**: Aminoglycosides are not strictly contraindicated in renal insufficiency but require careful dosing adjustments based on renal function. ### Conclusion Thus, **b) Give a normal dose with an extended interval** is the best option to manage JB's pneumonia while accounting for his renal insufficiency.

Answer 13

In the case of MJ, a 3-year-old female with congenital heart disease who is on digoxin and has been started on amiodarone, the best choice would be: **b) Decrease the digoxin dose by 50% and monitor levels.** ### Rationale: 1. **Drug Interactions**: Amiodarone can significantly increase the serum concentration of digoxin. This is because amiodarone inhibits P-glycoprotein, which can lead to increased absorption and reduced clearance of digoxin, raising the risk of digoxin toxicity. 2. **Dosage Adjustment**: - Given the interaction between digoxin and amiodarone, it is advisable to reduce the digoxin dose to avoid potential toxicity. - A reduction of 50% is a common practice when starting amiodarone in a patient already taking digoxin. 3. **Monitoring**: Close monitoring of digoxin levels is essential after making any adjustments. This ensures that the levels remain within the therapeutic range and helps to detect any signs of toxicity early. 4. **Other Options**: - **a) Continue digoxin at the current dose**: Not advisable due to the risk of increased digoxin levels from the interaction with amiodarone. - **c) Increase the digoxin dose by 50%**: This would further increase the risk of toxicity, which is contraindicated. - **d) Discontinue the digoxin**: This is not appropriate as MJ requires digoxin for her heart condition. ### Conclusion Therefore, the best course of action is **b) Decrease the digoxin dose by 50% and monitor levels** to ensure safe and effective management of her treatment.

Answer 14

In the case of AC, a 4-year-old male on a midazolam infusion for sedation in the PICU who is becoming increasingly agitated, the best choice would be: **a) Increase the infusion to 0.5 mg/kg/hr.** ### Rationale: 1. **Midazolam Infusion**: Midazolam is a short-acting benzodiazepine commonly used for sedation in pediatric patients. An increase in agitation suggests that the current dose may not be providing adequate sedation. 2. **Dose Adjustment**: - **Increasing the infusion rate**: Given that AC is showing signs of agitation while on 0.4 mg/kg/hr, increasing the infusion to 0.5 mg/kg/hr is a reasonable step to enhance sedation. - **Safety and Efficacy**: Increasing the infusion rate allows for a continuous effect rather than a bolus, which may lead to fluctuations in sedation levels. 3. **Considerations for Bolusing**: - **b) Bolus with 0.1 mg/kg and increase the infusion to 0.5 mg/kg/hr**: While this could provide a quick effect, it may not be necessary to bolus if the goal is to achieve more consistent sedation through the infusion. - **c) Bolus with 0.4 mg/kg and increase the infusion to 0.5 mg/kg/hr**: This is too high a bolus dose and could lead to oversedation and respiratory depression. - **d) Bolus with 0.1 mg/kg and maintain the infusion at 0.4 mg/kg/hr**: This does not address the underlying issue of increasing agitation effectively. ### Conclusion Therefore, the most appropriate action is **a) Increase the infusion to 0.5 mg/kg/hr** to provide better sedation while monitoring the patient closely for response and any potential side effects.

Answer 15

In the case of JD, a 10-year-old child on phenytoin who continues to have seizures and has a low phenytoin level of 6 mcg/ml, the best choice would be: **c) Change his feeds so they are held 1 hour before and 2 hours after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day, and recheck a level in 2 days (sooner if seizures persist).** ### Rationale: 1. **Phenytoin Level**: JD's phenytoin level of 6 mcg/ml is below the therapeutic range (typically 10-20 mcg/ml for seizure control). This indicates that his current dosing regimen is insufficient to maintain effective drug levels. 2. **Nutritional Interference**: Continuous NG feeds can interfere with the absorption of phenytoin. Holding the feeds for 1 hour before and 2 hours after administering the phenytoin will help improve its absorption and effectiveness. 3. **Loading Dose**: Administering a loading dose of 10 mg/kg is appropriate to quickly raise the serum phenytoin level into the therapeutic range. The current maintenance dose of 10 mg/kg/day may then be reassessed after ensuring proper absorption. 4. **Other Options**: - **a) Increase his phenytoin dose to 12 mg/kg/day divided bid**: This option does not address the absorption issue and may not adequately resolve the low levels and persistent seizures. - **b) Load him with phenytoin 5 mg/kg and increase his dose to 12 mg/kg/day**: A 5 mg/kg loading dose is insufficient given his current low level. - **d) Add another anticonvulsant**: While this may be a consideration if phenytoin levels are optimized and seizures persist, it is important first to address the absorption issue and raise the phenytoin level. ### Conclusion Thus, the most appropriate action is **c) Change his feeds so they are held 1 hour before and 2 hours after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day, and recheck a level in 2 days (sooner if seizures persist)** to ensure adequate phenytoin absorption and therapeutic effect.

Answer 16

In the case of LF, a 12-year-old with sepsis and low serum albumin, who is experiencing clonus and seizure-like activity, the best choice would be: **d) Order a total and free serum phenytoin level now.** ### Rationale: 1. **Low Serum Albumin**: LF's serum albumin level is significantly low (1.2 mg/dL), which can affect the binding of phenytoin. Since phenytoin is highly protein-bound, a low albumin level will increase the free (unbound) fraction of the drug in the serum, potentially leading to toxicity, even if the total phenytoin level appears to be in the therapeutic range. 2. **Seizure Activity**: The presence of clonus and seizure-like activity suggests that LF may be experiencing breakthrough seizures. It's important to assess the current status of phenytoin therapy. 3. **Total and Free Levels**: Ordering both total and free phenytoin levels will provide critical information to evaluate whether she is in the therapeutic range for the free fraction of the drug, which is the pharmacologically active form. This will help guide further treatment decisions. 4. **Other Options**: - **a) Administer phenytoin 5 mg/kg IV now**: This option might be considered later, but without knowing the current free level of phenytoin, it could risk further increasing toxicity if the free levels are already high. - **b) Order a serum phenytoin level now**: This would only give the total level, which is not sufficient due to her low albumin. It’s important to get both total and free levels. - **c) Obtain an EEG now**: While this may be useful for monitoring seizure activity, it does not address the immediate concern of phenytoin levels and the potential need for adjustment of her medication. ### Conclusion Therefore, the most appropriate action is **d) Order a total and free serum phenytoin level now** to assess her current drug status and make informed decisions regarding her treatment.

Answer 17

In the case of KD, a 12-year-old child with status asthmaticus who is being treated with theophylline and is starting erythromycin for presumed Mycoplasma pneumoniae, the best choice would be: **b) Lower her dose of theophylline and monitor daily serum concentrations.** ### Rationale: 1. **Drug Interaction**: Erythromycin is known to inhibit cytochrome P450 enzymes (specifically CYP1A2), which are involved in the metabolism of theophylline. This inhibition can lead to increased serum concentrations of theophylline, raising the risk of toxicity. 2. **Current Theophylline Level**: KD's current theophylline concentration is 18 mcg/ml. While this level is within the therapeutic range for asthma, starting erythromycin could increase theophylline levels significantly, potentially leading to adverse effects such as nausea, vomiting, tachycardia, and CNS stimulation. 3. **Monitoring and Dose Adjustment**: Lowering the theophylline dose is prudent to account for the potential increase in its concentration due to the erythromycin interaction. Monitoring daily serum concentrations is essential to ensure that theophylline levels remain safe and effective. 4. **Other Options**: - **a) Continue her current dose of theophylline. There is no need to monitor serum concentrations.**: This is not appropriate because it ignores the risk of elevated theophylline levels due to erythromycin. - **c) Increase her dose of theophylline by 10% and monitor daily serum concentration.**: This is contraindicated because it would further elevate the risk of toxicity in the context of a drug interaction. - **d) Continue her current dose of theophylline and monitor daily serum concentrations.**: This does not account for the interaction with erythromycin and the potential for increased levels. ### Conclusion Therefore, the most appropriate action is **b) Lower her dose of theophylline and monitor daily serum concentrations** to mitigate the risk of toxicity while ensuring effective management of her asthma.

Answer 18

In the case of BJ, a 13-year-old female with a history of bone marrow transplant (BMT) for acute lymphoblastic leukemia (ALL) who is now in septic shock and has renal insufficiency, let's analyze the medications she is receiving: ### a) Drugs That May Worsen Her Renal Function 1. **Cyclosporine**: This immunosuppressant can cause nephrotoxicity, especially in patients with existing renal impairment. 2. **Vancomycin**: This antibiotic is associated with nephrotoxicity, particularly at higher doses or with prolonged use, especially in the setting of renal insufficiency. 3. **Acyclovir**: High doses or rapid infusion can lead to crystalline nephropathy, which can worsen renal function, especially in the context of dehydration or renal impairment. 4. **Cefepime**: While generally safe, cefepime can cause neurotoxicity and renal impairment in cases of significant renal dysfunction. ### b) Drugs Requiring Dosage Adjustment Due to Renal Dysfunction 1. **Vancomycin**: Dosing should be adjusted based on renal function. It is crucial to monitor renal function and adjust the dose accordingly to avoid toxicity. 2. **Acyclovir**: Dosage should be adjusted in renal impairment due to the risk of nephrotoxicity. 3. **Fluconazole**: The dose of fluconazole may need to be reduced in patients with renal insufficiency. 4. **Cefepime**: The dose of cefepime should be adjusted based on creatinine clearance to avoid toxicity. 5. **Cyclosporine**: Dosing may need adjustment based on renal function and therapeutic drug monitoring, but the need for adjustment may depend on the specific renal status and target levels. ### c) Drugs Requiring Serum Concentration Monitoring and When to Obtain Levels 1. **Cyclosporine**: Requires monitoring of trough levels to maintain therapeutic efficacy and avoid toxicity. Levels should be obtained just before the next dose (trough) and may need to be monitored frequently (daily or every other day) in the setting of renal insufficiency. 2. **Vancomycin**: Monitoring of serum levels (troughs) is essential to ensure effective dosing while minimizing toxicity, especially in the context of renal impairment. Trough levels should be obtained just before the next dose, ideally after a few doses (typically after the third or fourth dose). 3. **Acyclovir**: Monitoring is not typically routine unless there are concerns for toxicity; however, levels can be checked if there is suspicion of renal-related toxicity. 4. **Fluconazole**: While routine monitoring may not be required, it can be helpful in adjusting the dose based on renal function. ### Summary: - **Drugs that may worsen renal function**: Cyclosporine, vancomycin, acyclovir, cefepime. - **Drugs requiring dosage adjustment**: Vancomycin, acyclovir, fluconazole, cefepime, cyclosporine. - **Drugs requiring serum concentration monitoring**: Cyclosporine (daily or every other day), vancomycin (trough levels after a few doses). In BJ's case, it’s essential to closely monitor her renal function and adjust her medication regimen accordingly to manage her septic shock while preventing further renal deterioration.