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76 Cards in this Set
- Front
- Back
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What is the objective in therapeutic drug monitoring?
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To achieve a safe and effective Cp.
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What is the quote by Ehrich?
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"A drug will not work unless it is bound"
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What makes individualized dosing necessary sometimes?
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Variations in individual pharmacokinetic (ADME) and pharmacodynamics. This is especially true for drugs with a narrow therapeutic index.
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Why is therapeutic monitoring important for drugs with non-linear kinetics?
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Because a small increase in dose could result in large increases in effect and, possibly, toxicity.
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Why is monitoring Cp not always useful immediately?
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Because sometimes there is no direct relationship between Cp and the desired effect.
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The avg population therapeutic Cp ranges are published. What should be noted about these?
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The values are probabilistic can should not be viewed as absolute values.
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Therapeutic drug monitoring is a part of what?
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Clinical pharmacokinetic services.
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List the 6 functions of therapeutic drug monitoring?
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1. Select drug
2. Design dose schedule 3. Evaluate patient response 4. Assay drug conc in biologic fluid (plasma, urine, etc) 5. Monitor and evaluate concentrations kinetically 6. Make dose adjustments and other needed recommendations |
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What considerations are made when selecting a drug?
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Therapeutic, kinetic (all concepts), and cost considerations.
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What is often needed to clarify adequacy of tx?
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Several blood samples.
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In practice what kind of concentrations are easier to obtain?
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Trough conc.s are easier to obtain than peak or avg concentrations. (trough is before each next dose)
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When is plasma sampling better? Why?
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It is better during the post-distributive phase better because there is better correlation with tissue concentrations
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What is a better approximate of the steady-state concentration?
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Samples taken 3, 4 or even 5 half-lives later.
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See table 20.4 in text and review factors to consider when interpreting Cp data.
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See table 20.4 in text and review factors to consider when interpreting Cp data.
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Sometimes how do physicians make decisions?
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Based on their experience and on clinical observations rather than solely on kinetic considerations.
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Give 2 examples of what might cause a higher than expected Cp?
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An increased dose or a small first-pass effect.
(see table 20.4) |
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Give 2 examples of what might cause a lower than expected Cp?
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May have an overactive liver or increased distribution to tissues.
(see table 20.4) |
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When determining a dose what is calculated?
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Typically the dose is calculated so as to obtain a steady-state avg C (Cav) in the therapeutic range.
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When Cav at steady state is used as a therapeutic indicator, an optimum ? must be chosen.
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Dosing interval
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How long is the dosing interval? What is the exception?
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The dosing interval is between on to two half-lives. Unless the drug has a narrow therapeutic index, then we use less then a half-life.
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In determination of the dose if the therapeutic index is narrow what is done?
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Smaller doses and smaller dosing intervals or IV infusions are used.
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What is the relationship of k and half-life?
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k = 0.693/half-life
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What is the reciprocal of k?
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1/k = half-life/0.693
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Cav at steady state is a good indicator for what?
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For therapeutic levels because it is based on a set of points and fluctuates less than Cmin at steady state adn Cmax at steady state.
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If a drug has a wide TI and a long half-life what does it indicate about dosing?
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There is a lot more flexibility in changing the dose and dosing interval.
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What do large doses and intervals between them cause?
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More fluctuations even if the Cav at steady state is the same.
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Drugs administered extravascularly need to be ?.
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Absorbed
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Im absorption is generally more rapid for drugs that are not what?
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For drugs that are not very soluble.
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For max therapeutic effect what route should be chosen?
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The route that gives the most consistent and greatest bioavailability should be chosen.
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It is often necessary to convert from an IV infusion to what?
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oral dosing
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What does fe represent?
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The fraction of drug excreted unchanged.
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Drugs with a low fe tend to have what?
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A high fraction of metabolized (by liver elimination) drug (1 - fe)
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What drugs are more effected by liver disease?
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Highly metabolized drugs.
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See table 21.10 for specific factors that need to be considered in determining dosage for hepatic disease.
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See table 21.10 for specific factors that need to be considered in determining dosage for hepatic disease.
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Drug with a high fe are generally ? by liver disease. Why?
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Generally unaffected by liver disease because the liver is not very involved in the elimination so metabolism does not play a major role.
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Patients with hepatic disease should not be given drugs with a ? fe. Why?
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With a low fe. Because this indicates a drug excreted by the liver. You should choose a drug excreted by the kidneys.
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Dosage adjustments during hepatic disease are based upon what?
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Residual hepatic function.
(should also consider renal clearance) |
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What does RL represent?
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Residual liver function
RL = hepatic clearance in hepatitis subject / hep cl in normal subj |
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What has to take place for a prodrug to be active? How is this effected in hepatic disease?
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metabolism. In hepatic disease there is less metabolism so there is a greater concentration of unmetabolized (inactive) drug.
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In hepatic disease, if a parent drug is more potent than its metabolite, what could happen?
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The overall pharmacologic activity increases because of higher parent drug concentrations (assuming the kinetic parameters of parent and metabolite and parameter are similar)(b/c not broken down to metabolites by liver)
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In hepatic disease if a metabolite is more potent, then what happens to the pharmacologic effect?
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It will decrease (lower levels of active metabolite produced) (b/c not broken down to metabolites as much by the liver)
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What is a nomogram?
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A chart that consist of several lines marked off to scale and arranged in such a way that by using a straight edge to connect known values on two lines an unknown value can be read at the point of intersection with another line. They may be used to estimate dosage regimens.
(see 21-3) |
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What is creatine clearance in normal pts?
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about 100ml/min. Anything lower indicates kidney problems.
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Whar is Clcr used as a measure of?
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GFR
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Patients with kidney failure = ? Clcr = ? AUC.
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decreased Crcl = increased AUC
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Once the Clcr is known what adjustments can be made?
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Adjustments in the maintenance dose can be made (based on the degree of kidney impairment and the fraction of the clearance that is renal). Once the Clcr if known, the new renal clearance of a pt can be calculated by multiplying Clcr by the (normal renal clearance)/(normal Clcr) ratio.
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What is LBW?
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Lean body wt. Also used for dosage adjustments in renally impaired patients.
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Women with normal kidney function have a ? ? ? than men with normal kidney function.
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smaller Clcr (80-85% of men's)
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What is the method of Crockcroft and Gault? What consideration is taken for females?
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It is used to determine Clcr given a patients age, weight (LBW), and serum creatinine level.
(see formula on p. 7 notes) The value in females is 90% of that in males. |
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Uremic or renally impaired pts should have their ? ? ?.
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Drug dosages adjusted.
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What does uremic dose equal?
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Uremic dose = (ku/kn) X normal dose
ku = elimination rate constant in uremic patient (found in literature, see 21.4 or 21.5) kn = elim r const in normal pt |
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When is complete hepatic function attained?
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Not until the third week post natal.
(see fig 11.11) |
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Many drugs have ? plasma albumin binding in infants.
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Reduced
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Neonates have what percentage of adult renal activity per unit of body wt? What does this indicate?
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Only 30-50%. So drug is not eliminated as fast as it would in an adult.
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For infants and children even when body weight is factored into the dose (dose/unit of body wt), what else has to be adjusted?
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The frequency of administration
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What should dosage forms facilitate in infants and children?
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compliance and dosing accuracy.
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What is used to determine Clcr in children?
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A number of equations. See chpt 21 slides p 9)
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What does the Gault-Crockcroft rule indicate about elderly patients?
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Decrease in clearance with age.
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Many studies show a ? in GFR with age.
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Decrease in GFR
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Age related changes in the levels of ? ? and ? ? also affect the binding of drugs?
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Age related changes in the levels of plasma albumin and alpha-1-acid glycoprotein also affect the binding of drugs.
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On avg as pts age the ? ? represents a ? ? or their body wieght and ? ? decreases.
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On avg muscle mass represents a lower proportion of their body weight and Clcr decreases
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In elderly pts since muscle mass and Creatinine excretion decrease at nearly the same rate what can be said about the mean serum creatinine concentrations (Ccr).
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They remain about the same
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Clcr measured only by Ccr (without the measurement of urinary creatinine excretion) may give what?
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An inaccurate indication of GFR.
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What can be said about an elderly patients sensitivity?
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They have an increased sensitivity (incl. increased adverse effects) have been observed in the elderly (approx 65+). This is attributable to pharmacodynamic and kinetic changes.
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What is the 'dynamic hypothesis about elderly pts increased sensitivity?
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Due to changes in the qty and quality of target receptors. Number of receptors may decline with age but changes in affinity also occur.
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What do 'kinetic hypotheses say about increased sensivity in elderly patients?
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Increases in adverse reactions are attributable to physiologic changes in absorption, distribution and elimination (renal and/or hepatic)
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One of the issues seen in obese patients is that compared to muscle tissue, adipose tissue has a ? ? of water.
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Smaller proportion.
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What does BMI normalize?
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Body wt based on ht.
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Generally, obese pts weigh greater than ? more the ideal body weight (IBW).
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20%
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What is an obese patients BMI?
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Greater than 30 (greater than is needed for normal body functions).
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What does obesity affect?
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The distribution kinetics and the apparent volume of distribution of drugs. Most lipophilic drugs are associated with larger Vd in the obese (on the contrary, polar drugs distribute into water, like extracellular fluids rather than fat)
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Clcr is sometimes normalized to what?
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To body surface area (avg 1.73m^2) or to body wt (avg 70kg).
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In obese pts, Clcr should not be based on what? Why?
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The total body wt. Studies show that total body weight (TBW) overestimates (while IBW underestimates) renal function in the morbidly obese. An adjusted body wt (somewhere between the two) is used to estimate renal function in morbidly obese individuals.
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Emaciated subjects tend to have disproportionately greater loss of muscle mass. Thus the ? rather than the ? should be used to determine Clcr. Why?
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The actual rather than the IBW should be used, in order to avoid overstatements of Clcr.
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Dosing in obese pts should not be based on what? What should be used?
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Actual body wt. The IBW or the lean body wt (LBW) should be used.
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What is third spacing of fluids?
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In patients with third spacing (like edema or ascites) the wt or the excess fluid should mostly not be included in the total body weight.
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