Drug dose adjustment affecting

Use of suboptimal doses of drugs in serious disease, sacrificing efficacy for avoidance of serious adverse effects, has been documented. It particularly affects drugs of low therapeutic index (see Index), i.e. where the effective and toxic dose ranges are close, or even overlap, e.g. heparin, anticancer drugs, aminoglycoside antimicrobials. In these cases dose adjustment to obtain maximum benefit with minimum risk requires both knowledge and attentiveness. 

Initial regimens usually consist of two NRTIs plus either a potent PI or NNRTI. Frequent changes in therapy are required over time due to adverse effects, lack of response, or both. As a general rule, NRTIs do not require dose adjustments when combined with other ARVs. However, Pis and NNRTIs tend to have complex metabolisms and in combination affect each other s levels and potency. Drug resistance occurs with all available agents, and resistance to one agent will often confer resistance to the entire class (Table 59-1). 

Topiramate is routinely administered orally, absorbed rapidly, and metabolized minimally, but its disposition is affected by CyP 2C19. Serum concentrations of other anticonvulsant drugs are not significantly affected by the concurrent administration of topiramate, with the exception in individual patients on phenytoin who exhibit increased phenytoin plasma concentrations after addition of topiramate. Co-administration of phenytoin or carbamazepine decreases topiramate serum concentrations. Changes in cotherapy with phenytoin or carbamazepine (e.g., addition or withdrawal) for patients stabilized on topiramate therapy may require topiramate dose adjustment. As with other... 

The exact mechanism of action for the secondary TCAs is unclear, but the secondary amine TCAs exhibit substantially more affinity than the SSRIs and the tertiary TCAs for inhibiting the NE transporter. None of the secondary TCAs has significant affinity for the dopamine transporter. Blocking the reuptake of NE increases its concentration in the synaptic cleft and its ability to interact with synaptic NE receptors. When drugs are selective for a transporter, differences in potency become clinically irrelevant, because the plasma concentration can be dose-adjusted to achieve inhibition of the desired transporter without affecting the other... 

The affinity data for the SSRIs show that the SSRIs, as a group, are very potent and selective inhibitors for SERT compared with their affinity for NE and dopamine reuptake transporters (Fig. 21.6) and are more potent inhibitors of 5-HT reuptake than are the tertiary amine TCAs, with the exoeption of clomipramine. None of the SSRIs has substantial effeot on the NET or dopamine transporter. Of the SSRIs, sertraline exhibits the most potent inhibition of dopamine reuptake transporter, although it is still 100 times less potent in terms of inhibiting the dopamine versus the SERT. Therefore, the plasma oonoentration of sertraline would have to be increased by as much as 100 times to inhibit the dopamine reuptake transporter. When drugs are this selective for the reuptake transporters, differences in potency become olinioally irrelevant, because the plasma concentration oan be dose-adjusted to achieve inhibition of the desired transporter without affecting the other transporters. Clomipramine displays less affinity for SERT than oitalopram, fluvoxamine, paroxetine, or sertraline does and is more potent than fluoxetine. In terms of the ability to inhibit the NET, the SSRIs are two to three times less potent than the SNRI TCA, desipramine. 

After 16 healthy subjects took both diltiazem 60 mg and moracizine 250 mg every 8 hours for 7 days, the maximum plasma concentration of moracizine was increased by 89%, the AUC was increased by 121%, and clearance was decreased by 54%. In contrast, the maximum plasma concentration and AUC of diltiazem decreased by 36% and clearance was increased by 52%. The AUCs for the diltiazem metabolites were not sig-nifrcantly affected. No clinically signifrcant changes in ECU parameters were seen. However, the frequency of adverse events (e.g. headache, dizziness, paraesthesia) was greater on concurrent use (76%) than with either drug alone (54 and 45% for moracizine and diltiazem respectively). Diltiazem probably inhibits the hepatic metabolism of moracizine while moracizine increases that of diltiazem. The clinical signifrcance of this interaction is not known. However, particular caution is advised if diltiazem and moracizine are given concurrently, in light of the increase in adverse events. Dose adjustments may also be required to obtain optimum therapeutic responses. 

Understanding the concentration-response relationship can help predict the effects of intrinsic (e.g., cytochrome P450 isoenzyme status) or extrinsic (e.g., drug-drug PK interactions) factors, possibly affecting inclusion criteria or dosing adjustments in later phase studies. 

Again, this can affect the doses of certain dmgs that are administered to patients. Various diseases (eg, cirrhosis of the liver) can affect the activities of drug-metabohz-ing enzymes, sometimes necessitating adjustment of dosages of various drugs for patients with these disorders. 

Answer The half-life of amiodarone is 35 days. Approximately five half-Uves are required for functionally complete drug elimination. Thus, it will take approximately 6 months (5 half-lives) before the amiodarone is eliminated from the body. Since amiodarone strongly inhibits metabolism of S-warfarin (active enantiomer), it will continue to affect warfarin metabolism for 6 months following discontinuation of amiodarone. Thus, the dose of warfarin will have to be monitored approximately every month and adjusted if necessary. This monthly monitoring should be continued for at least 6 months, until the metabolism of warfarin stabilizes and a constant dose of warfarin can again be maintained. 

The equations above apply strictly to dmgs administered as a single IV bolus dose, but for drug administered as an infusion or via oral route, or after multiple dosing, the calculation of AUMC must be adjusted to account for drug input [i. e., infusion time (T) or absorption rate constant JCa and extent of bioavailability F], as shown by Straughn [3]. Although, in theory, AUC will not be affected by the route, the AUMC will be overestimated, and this will result in an overestimation of Vss. 

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