Week 4 - Pharmacokinetics Continued Flashcards

Question

Question: ## Footnote Assume an infusion of 80 units/hr achieves the desired average steady-state concentration for a drug. Now assume that you’d like to achieve the same average concentration using an oral formulation, given once every 6 hours. Finally, assume that the oral drug has a fractional biovailability of 0.5 (50%). What would you prescribe as a maintenance dose?

Answer 1

Answer: ## Footnote Maint. Dose = dosing rate x interval/f = 80 units/h x 6 h/0.5 = 960 units, once every 6 h So bascally with a bioavailability of .5 the drug must be doubled and be accounted for time

Answer 2

If a drug takes a long time to get to steady state, can give a loading dose to incerease quicken this process... It is the concentration we want to achieve multiplied by the volume of distribution devided by the bioavailability factor... **Loading dose = Css Vd / f \*\*\***

Answer 3

Answer: ## Footnote First you need to know what the VD is for your particular patient, expressed in liters. Multiplying 2 L/kg times 100 kg gives a VD of 200 L. Next, recall our relationship: Loading Dose (LD) = CSS VD/f Doing the math, the LD = (5 mg/L)(200 L)/0.5 = 2000 mg

Answer 4

* For most drugs (esp. those with a large TI), recommended dosing regimens based on “population” kinetic parameters (taking into account things like age, gender, etc.) can be used as a first step in patient care with relatively little concern for toxicity. These compounds have a **LARGE TI** (therapudic index) * Under these circumstances optimization of drug dosage may be achieved by **measurement of a clinically defined endpoint\*** that is responsive to the drug (e.g., blood pressure - can change drug based on results, clotting time, serum cholesterol). * **\*As opposed to measurement of the drug itself which requires periodic blood sampling and is generally expensive**

Answer 5

Refers to patient-specific monitoring of serum drug levels and optimization of the dosing regimen as a means of tailoring treatment to the individual When required (one or more of the following): - Drugs with a narrow TI - Poor correlation between administered dose and observed effects - Large individual differences in CL - A toxicity profile that is difficult to recognize clinically before serious damage occurs Drugs that are commonly monitored include: Aminoglycoside antibiotics (e.g., gentamicin) Antiepileptics (e.g., phenytoin) Cardioactive agents (e.g., digoxin, lidocaine) Theophylline, lithium, methotrexate, cyclosporine Involves a close relationship between the attending physician, a clinical pharmacy department, and (as needed) other specialists (e.g., for neonates, the elderly, dialysis patients)

Answer 6

Population kinetic parameters appropriate to a patient’s age, gender, weight, etc., are used in along with knowledge of a compound’s kinetic behavior (e.g., principle route of elimination) and routine measures of organ function (e.g., creatinine clearance) to design a dosing protocol (i.e., the same approach used for other drugs). **Measured drug concentrations **are then used to monitor the patient and, if necessary, develop patient-specific kinetic parameters for use in adjusting the dosing regimen.

Answer 7

Others occur only in susceptible patients and may be difficult to predict prior to a drug’s approval for use. These are likely to have, at least in part, a genetic basis and include: **Intolerance;** a lower dose threshold for the drug’s normal action. May have CL or VD basis. **Allergic reactions**; effect unrelated to normal pharmacological action. Typically requires prior exposure which elicits an immune response. **Idiosyncratic reactions;** effect unrelated to normal pharmacological action. Mechanism often unclear although some are probably immune responses

Answer 8

Some can be expected to occur in anyone (no special susceptibility is required). These include: * *Overdose** - Generally (but not always\*) results in extreme manifestation of a drug’s usual pharmacological action * *Drug-drug interactions;** recall various mechanisms - One drug impacts the CL or VD of a second - Two drugs operate on the same or opposing signaling pathways - Physiological antagonism **\*Recall: a higher dose may “unmask” a different effect**

Answer 9

* Makes no assumptions about the “compartmental” nature of a system * Based on statistical approaches * Increasingly popular for drug development because it facilitates simple comparisons among drugs * Gives Cl, VD, and Mean Residence Time (MRT): average time that a drug resides within the body following i.v. dosing * MRT is conceptually similar to the elimination t ½

Answer 10

Clearance and volume of distribution are now very important relationships we derived.

Answer 11

Numbers here are too complicated for exam so numbrers would be much simpler

Answer 12

The compound is likely to be filtered by the kidney and the plasma Cl of 5.0 L/h estimated from your elimination experiment is somewhat smaller than the GFR. We might speculate, therefore, that this compound is partially reabsorbed in the kidney tubule, decreasing its renal clearance Instructors note: In this absence of other information, however, this type of speculation must be regarded with extreme caution)

Answer 13

Yes. When you increase urine pH by adding base you tend to trap weak acids by shifting the equilibrium between the neutral and ionized forms toward the ionized form (which cannot be reabsorbed). This finding suggests that by adding base you have trapped all of the drug that is being filtered at the glomerulus (accounting for the fact that Cl now equals the GFR) and is consistent with the suggestion that this drug is eliminated primarily in urine

Answer 14

Possibly. If the patient had unusually high levels of plasma binding protein (esp. the protein responsible for binding this particular drug) this would tend to decrease the VD. For drugs that are very highly bound to plasma proteins the theoretical minimum VD is approximately equal to the plasma volume. The plasma volume is about 4% of total body volume. In this particular case the solved-for VD is about 10% of total body volume, which is still quite small. This would suggest a high level of plasma binding.

Answer 15

If you express this VD in weight-normalized terms you get a value of 55 L/75 kg, or about 0.73 L/kg. This is approximately equal to a person’s whole-body water content. Based on this finding one might speculate that the drug distributes evenly into whole-body water.

Answer 16

Yes, potentially. Smoking tends to induce CYP activity. If the patient quits smoking CYP activity could decline over time which could cause the Cl to decrease. It might be necessary, therefore, to reduce the drug dosing rate. Factors such as the drug’s therapeutic index and potential for toxicity would factor into the decision.

Answer 17

The most likely reason is that the drug’s oral bioavailability in this patient is lower than expected resulting in a reduced average concentration in plasma

Answer 18

Reduced bioavailability may be due to higher-than-expected metabolism in the liver and/or GIT as well as dietary habits that promote retention of the drug in the gut contents (e.g., eating fatty foods, assuming that the drug is lipophilic). So, you might want to know how this drug is metabolized and whether there is any reason to think that metabolism would be induced in this patient (occupational exposures, other drugs they may be taking, etc.). You also might inquire about their dietary habits.

Answer 19

Now let’s suppose that by some means you determine that oral bioavailability in this patient is 80% (as originally expected). What else could explain the patient’s poor response to this drug? Hint: while doing your research you find that the elimination t1/2 is 2 hr. Recall that you have prescribed a pill that is to be taken once every 8 hr.

Answer 20

Given the drug’s lipophilic character and the fact that this patient is obese we might expect the VD for this drug in this patient is greater than the average value. Recalling that the L.D. is impacted by VD we question the table value. Finally, noting that L.D. = CSS (VD)/f we can speculate that the required L.D. (to achieved the desired CSS) will have to be increased