Therapeutic Response, Cumulative Drug Effects, and Schedule Dependence

THERAPEUTIC RESPONSE, CUMULATIVE DRUG EFFECTS, AND SCHEDULE DEPENDENCE 

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. 

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 EC q is 1.5 mg/L and the Hill coefficient (n) is 3. 

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, wliile 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. 

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