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11 Cards in this Set
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Mr. Jones is admitted to the hospital with pneumonia due to gram-negative bacteria. The antibiotic tobramycin is ordered. The CL and Vd of tobramycin in Mr. Jones are 80 mL/min and 40 L, respectively.
What maintenance dose should be administered intravenously every 6 hours to eventually obtain average steady-state plasma concentrations of 4 mg/L? |
Dosing rate = TC * CL * dose rate/bioavailability
bioavailability = 1 because the drug is given IV 4 mg/L * 1 L/1000 mL * 80 mL/min * 60 min/1 hr * 6 hr = 115.2 mg |
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Mr. Jones is admitted to the hospital with pneumonia due to gram-negative bacteria. The antibiotic tobramycin is ordered. The CL and Vd of tobramycin in Mr. Jones are 80 mL/min and 40 L, respectively.
If you wish to give Mr. Jones an IV loading dose to achieve the theraputic plasma concentration of 4 mg/L rapidly, how much should be given? |
loading dose = Vd * TC
40 L * 4 mg/L = 160 mg |
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Despite your careful adherence to basic pharmacological principles, your patient on digoxin therapy has developed digitalis toxicity. The plasma digoxin level is 4 ng/mL. Renal function is normal, and the plasma t<1/2> for digoxin in this patient is 1.6 days. How long should you withhold digoxin in order to reach a safer yet probably theraputic level of 1 ng/mL?
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Plasma levels is 4 ng/mL and must drop to 1 ng/mL. Once we withhold digoxin, plasma levels will reduce by 50% in one half-life (= 2ng/mL) and by an additional 50% in two half-lives (= 1 ng/mL). So, it will take 2 half-lives to reach 1 ng/mL. Since half-life is 1.6h, it will take 3.2h to reach 1 ng/mL.
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Verapamil and phenytoin are both eliminated from the body by metabolism in the liver. Verapimil has a clearance of 1.5 L/min, approximately equal to liver blood flow, whereas phenytoin has a clearance of 0.1 L/min. When these compounds are administered alond with rifampin, a drug that increases hepatic drug-metabolizing enzymes, what will happen to the clearances of verapamil and phenytoin?
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There are two important variables to consider here: rate of delivery to the liver and rate of removal once at the liver. Treatment with rifampin will increase the latter, but has no effect on the former. Verapamil is removed from plasma as quickly as it can be delivered to the liver (CL is similar to liver blood flow), so the rate of delivery is limiting. Therefore rifampin will have no effect on verapamil clearance. Clearance of phenytoin is limited by the rate of clearance in the liver (capacity limited) and will therefore be removed more efficiently if liver metabolism is increased.
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A 60 y.o. man enters the hospital with a myocardial infarction and a severe ventricular arrhythmia. The antiarrhythmic drug chosen has a narrow theraputic window: the minimum toxic plasma concentration is 1.5 times the minimum theraputic plasma concentration. The half-life is 6 hours. It is essential to maintain the plasma concentration above the minimum theraputic level to prevent a possibly lethal arrhythmia. The most appropriate dosing regimen would be:
Once a day? Twice a day? Three times a day? Four times a day? Constant IV infusion? |
The trick here is to dose the drug in such a way that it will not drop below the therapeutic concentration (1.0) and will not spike above the toxic concentration (1.5).
Recall that IV administration will lead to a smooth rise in TC with no spikes or troughs, so IV will definitely work. The question is if any other regimen will also work. Consider 4X daily: In 4X daily dosing, drug will be administered every 6h. We know that [drug] will drop 50% over the 6h (since half-life is also 6h). If [drug] is to be 1.0 after 6h, [drug] must be 2.0 at the start. But 2.0 is above the toxic dose. Dosing 4X daily is therefore not possible. Since dosing less frequently would lead to even greater peaks and troughs, the other dosing regimens are also not feasible. |
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A 50 y.o. woman with metastatic breast cancer has elected to participate in the trial of a new chemotheraputic agent. It is given by constant IV infusion of 8 mg/h. Plasma concentrations are measured with the results shown in the table.
Time after start of infustion (hours): 1, 2, 4, 8, 10, 16, 20, 25, 30, 40 Plasma Concentration (Mg/L) 0.8, 1.3, 2.0, 3.0, 2.6, 3.7, 3.8, 4.0, 4.0, 4.0 What is the half-life? |
From the table, we can tell that half-life is 4h (the time it takes to reach 50% of maximal [drug]).
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A 50 y.o. woman with metastatic breast cancer has elected to participate in the trial of a new chemotheraputic agent. It is given by constant IV infusion of 8 mg/h. Plasma concentrations are measured with the results shown in the table.
Time after start of infustion (hours): 1, 2, 4, 8, 10, 16, 20, 25, 30, 40 Plasma Concentration (Mg/L) 0.8, 1.3, 2.0, 3.0, 2.6, 3.7, 3.8, 4.0, 4.0, 4.0 What will doubling the rate of infusion do to TC? |
We can also easily see that doubling the rate of infusion will double TC to 8.0mg/L (from Dose = CL x TC; recall that CL is constant)
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A 50 y.o. woman with metastatic breast cancer has elected to participate in the trial of a new chemotheraputic agent. It is given by constant IV infusion of 8 mg/h. Plasma concentrations are measured with the results shown in the table.
Time after start of infustion (hours): 1, 2, 4, 8, 10, 16, 20, 25, 30, 40 Plasma Concentration (Mg/L) 0.8, 1.3, 2.0, 3.0, 2.6, 3.7, 3.8, 4.0, 4.0, 4.0 What "order" is the kinetics of this drug? |
We can also tell that CL is first order (because [drug] reaches steady state, zero order would not reach steady state)
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A 50 y.o. woman with metastatic breast cancer has elected to participate in the trial of a new chemotheraputic agent. It is given by constant IV infusion of 8 mg/h. Plasma concentrations are measured with the results shown in the table.
Time after start of infustion (hours): 1, 2, 4, 8, 10, 16, 20, 25, 30, 40 Plasma Concentration (Mg/L) 0.8, 1.3, 2.0, 3.0, 2.6, 3.7, 3.8, 4.0, 4.0, 4.0 What is the clearance? |
Loading dose = TC * Vd
The steady-state plasma concentration that is reached is 4.0 mg/L, so TC = 4.0 mg/L loading dose = 8 mg/hour Vd = loading dose/TC Vd = 8 mg/hour / 4 mg/L = 2 L |
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A 50 y.o. woman with metastatic breast cancer has elected to participate in the trial of a new chemotheraputic agent. It is given by constant IV infusion of 8 mg/h. Plasma concentrations are measured with the results shown in the table.
Time after start of infustion (hours): 1, 2, 4, 8, 10, 16, 20, 25, 30, 40 Plasma Concentration (Mg/L) 0.8, 1.3, 2.0, 3.0, 2.6, 3.7, 3.8, 4.0, 4.0, 4.0 What is the volume of distribution? |
CL = kVd
t<1/2> = 0.693/k t<1/2> = 0.693Vd/CL Vd = CL * t<1/2> / 0.693 Note that Clearance at a steady state can be calculated by: Dose <steady state> = CL * TC, so CL = Dose <ss> / TC CL = 4.0 mg/h / 8 mg/L = 2.0 L/h We can get Vd from: t1/2 = 0.693 x Vd/CL; solving for Vd gives 4 x 2/0.693 = 11.5L |
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A nineteen y.o. woman is brought to the hospital with severe asthmatic wheezing. You decide to use IV theophylline for treatment. The pharmacokinetics of theophylline include the following average parameters: Vd = 35 L, CL = 48 mL/min, half-life = 8 hours. If an IV infusion of theophylline is started at a rate of 0.48 mg/min, how long will it take to reach 93.75% of the final steady state?
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We know that continuous dosing produces 50% of steady state [drug] in one half-life, 75% in 2 half-lives, 87.5% in 3 half-lives and 93.75% in 4 half-lives. Since half-life of theophylline is 8h, it will take 32h to reach 93.75% of steady state.
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