Interactions, drug pharmacokinetics

TABLE 37-5. Pharmacokinetic Drug Interactions with Benzodiazepines44... 

SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.28,48,49 With similar efficacy reported and no trials comparing SSRIs with other SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 35 for more discussion). The most common side effects of SSRIs include headaches, irritability, nausea and other gastrointestinal complaints, insomnia, sexual dysfunction, increased anxiety, drowsiness, and tremor.49 SSRIs should not be discontinued abruptly to avoid a withdrawal syndrome characterized by dysphoric mood, irritability, and agitation. 

Gillum JG, Israel DS, Polk RE Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 1993,25 450-482. 

It is believed to have a low potential for pharmacokinetic drug interactions. 

TABLE 68-11 Pharmacokinetic Drug Interactions with the Benzodiazepines ... 

Some indications for plasma level monitoring include inadequate response, relapse, serious or persistent adverse effects, use of higher than standard doses, suspected toxicity, elderly patients, children and adolescents, pregnant patients, patients of African or Asian descent (because of slower metabolism), cardiac disease, suspected noncompliance, suspected pharmacokinetic drug interactions, and changing brands. 

Pharmacokinetic Drug Interactions Involving Tricyclic Antidepressants (TCAs)... 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

The first factor lead to the studies of drug interactions. These had been preceded by studies of factors that modified drug metabolism and were focused primarily on pharmacokinetic drug interactions... 

Brouwers JRB, de Smet PAG. Pharmacodynamic-pharmacokinetic drug interactions with nonsteroidal antiinflammatory drugs. Clin Pharmacokinet 1994 27 462-85. 

Greiff JMC, Rowbotham D. Pharmacokinetic drug interactions with gastrointestinal motility modifying agents. Chn Pharmacokinet 1994 27 447-1. 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinei 1996 31 198-214. 

Tanaka E, Hisawa S. Clinically significant pharmacokinetic drug interactions with psychoactive drugs antidepressants and antipsychotics and the cytochrome P450 system. J Clin Pharm Ther 1999 24 7-16. 

Jonkman JH, Upton RA. Pharmacokinetic drug interaction with theophylline. Clin Pharmacokinei 1985 9 309-334. 

For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22. 

Buspirone tends to be used preferentially in patients with chronic and persistent anxiety, in patients with comorbid substance abuse, and in elderly patients, because it is well tolerated and has no significant pharmacokinetic drug interactions. What is clear is that buspirone shows reproducible efficacy in certain animal models of anxiety and in GAD, which points to a potentially important role of serotonin in mediating anxiety symptoms through 5HT1A receptors. Buspirone also has a role as an augmenting agent for the treatment of resistant depression, as discussed in Chapter 7. 

Back DJ, Orme ML. Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990 18(6) 472-84. 

Wilbur K, Ensom MH. Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. Clin Pharmacokinet 2000 38(4) 355-65. 

Wood M. Pharmacokinetic drug interactions in anesthetic pratffiteB.Pharmacokinet, 1991 21 285-307. 

Brosen, K. Are pharmacokinetic drug interactions with SSRls an issue Int.. Psychopharmacol. 11 (Suppl. 1) (1996) 23-27. 

Martin P et al (2011) Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole. Drugs R D 11 37-51... 

Lane RM. Pharmacokinetic drug-interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 1996 11 31-61. 

Hill G, Cihlar T, Oo C, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos 2002 30 13-19. 

Swaisland HC, Ranson M, Smith RP, et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 2005 44(10) 1067—1081. 

Phillips J, Antal E, Smith R. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol 1986 6 297-299. 

Richelson E. Pharmacokinetic drug interactions of new antidepressants a review of the effects of the metabolism of other drugs. Mayo Clin Proc 1997 72 835-847. 

Figure 1 Schematic representation of the mechanism of pharmacokinetic drug interactions. Plasma concentrations of the victim drug are determined by its dosing rate and metabolic clearance. Plasma levels, in turn, determine drug concentrations at the receptor site and ultimately its pharmacodynamic effect. A pharmacokinetic drug interaction involves the effect of the perpetrator on the metabolic clearance of the victim. When the perpetrator is an inducer, clearance of the victim is increased, plasma levels are diminished, and pharmacological effect is reduced. Conversely, when the perpetrator is an inhibitor, clearance of the victim is reduced, plasma levels are increased, and pharmacodynamic effect is enhanced.

Clinical pharmacokinetic drug interaction protocols increasingly incorporate pharmacodynamic endpoints into the study design such that the dynamic... 

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