Therapeutic Response Cumulative Drug Effects And Schedule Dependence

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So far we have focused our attention on the time course of drug effect. While the study of these effects can be helpful in understanding the mechanism of drug action and factors affecting efficacy and potency, it usually does not provide information on how drug exposure influences therapeutic response.

Clinical response can be defined as the effect of drug treatment on the clinical endpoint of how the patient feels, functions, or survives. Some clinical responses can be described by composite scales that are commonly used in drug development for regulatory approval [e.g., the Unified Parkinson's Disease Rating Scale (UPDRS) and the Alzheimer's Disease Assessment Scale (ADAS)]. These scales can be treated as if they were continuous measures of drug response and, as discussed in Chapter 20, are amenable to pharmacokinetic-pharmacodynamic modeling involving delayed effects even if no concentrations are available (35). This seemingly broad

Lasix Pharmacokinetics
FIGURE 19.7 The diuretic effect of furosemide is to increase the excretion rate of sodium. The pharmacodynamics of furosemide show a steep concentration effect relationship, with a clear maximum effect (180 mmol/hr of Na+). The ECgg is 1.5 mg/L and the Hill coefficient (n) is 3.

definition of clinical response nevertheless excludes almost all of the drug effects we have discussed so far. For example, some responses are related to the cumulative effects of previous drug doses.

The acute treatment of congestive heart failure commonly involves the use of a diuretic to get rid of excess fluid that has accumulated as edema of the lungs and lower extremities. As shown in Figure 19.7, a high-efficacy diuretic such as furosemide has a steep concentration effect relationship, with a clearly defined maximum effect on sodium excretion. After an oral furosemide dose of 120 mg that causes almost maximal sodium excretion, the time course of drug concentrations reaches a peak about 6 mg/L, which is well above the ECsg of 1.5 mg/L (Figure 19.8). A lower dose of 40 mg produces concentrations that are one-third of the 120-mg dose, but the natriuretic effects are not decreased in proportion to the dose. When three 40-mg doses are given over 12 hours, the cumulative effect measured by total sodium excretion is 50% greater than that seen after a single 120-mg dose. Despite the same total dose and the same cumulative area under the concentration time curve from the two patterns of dosing, the clinical response would be less with the single 120-mg dose. This is an example of the phenomenon of schedule dependence.

Schedule dependence occurs when the drug effect is reversible, the concentrations exceed the EC5g so that effects approach Emax with proportionately less drug effect at high concentrations, and the clinical response is related to the cumulative drug effect. The phenomenon is expected to be quite common but is not often recognized clinically because of wide variability in response and other confounding factors such as disease progression.

FIGURE 19.8 The time course of furosemide concentration and natriuretic effect after 3 doses of 40 mg compared with those parameters after a single dose of 120 mg. Notice that the concentrations after 120 mg are exactly three times higher than after 40 mg, but the peak effect after 40 mg is quite close to the peak after 120 mg because the 120-mg dose is limited by effects approaching Emax. The cumulative sodium loss after 120 mg is 400 mmol, while the three 40-mg doses produce a 600-mmol loss.

FIGURE 19.8 The time course of furosemide concentration and natriuretic effect after 3 doses of 40 mg compared with those parameters after a single dose of 120 mg. Notice that the concentrations after 120 mg are exactly three times higher than after 40 mg, but the peak effect after 40 mg is quite close to the peak after 120 mg because the 120-mg dose is limited by effects approaching Emax. The cumulative sodium loss after 120 mg is 400 mmol, while the three 40-mg doses produce a 600-mmol loss.

The reduction of pain and other symptoms due to peptic ulceration may be quite closely linked to the current effect of a drug on acid secretion, but the rate of healing and eventual disappearance of an ulcer is a slow process, determined in part by the extent and duration of gastric acid secretion suppression over several weeks. The clinical response of ulcer healing is therefore a consequence of the cumulative degree of acid inhibition. Proton pump inhibitors such as omeprazole bind irreversibly to the proton pump to suppress gastric acid secretion. The extent of inhibition is close to 100% and responses are related to cumulative effects, but the irreversible nature of the drug action means that schedule dependence is not observed.

Many clinical responses are described in terms of events. An event might be death, a stroke, a myocardial infarction, an epileptic seizure, admission to hospital, need for supplementary treatment, and so on. The occurrence of an event or the time to an event can be modeled using a survival function. The word survival relates most obviously to a death event, but the term is commonly used in a much broader context to describe the probability that the event under study will not occur.

The hazard/survival approach allows complex pharmacokinetic-pharmacodynamic influences to affect the hazard and thus occurrence of an event. At the jth observation time, t[j], which follows a previous observation at time t[j — 1], a patient is observed either to have survived or to have had an event. The exact time of the event may not be known, but is between t[j — 1] and t[j]. The hazard [h(t), sometimes called instantaneous risk] of an event a time t is shown as

Cox et al. (37, 38) use a somewhat similar model for modeling the time to an event whose time is known:

where B is a set of parameters describing the hazard as a function of X (time, dose, etc). Potential time-varying covariates for the hazard are cholesterol concentrations (heart attack event), blood pressure (stroke event), or concentration of an anticonvulsant drug (seizure event). The chances of an event are related both to the size of the hazard and the time that the patient is exposed to the hazard. The cumulative hazard from 0 to t [H(t)] can be related to the probability of an event, as illustrated by Equation 19.15 for the case of a constant hazard:

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  • abel
    Does furosemide have a cumulative effect?
    7 months ago

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