Adverse interactions

Pha.rma.ceutica.1 Purity. A safety profile of a generic dmg can differ from that of the brand-name product because different impurities may be present in each of the dmgs (154). Impurities can arise out of the manufacturing processes and may be responsible for adverse interactions that can occur. Eor example, serious adverse reactions (LyeU syndrome) were observed upon the use of isoxicam in 1985. These seemed to have resulted from trace elements of a manufacturing by-product that was within the manufacturing quaUty control specifications. 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

The disulfiram-ethanol interaction is described above. Depending on the dose of disulfiram, sensitivity to disulfiram, amount of alcohol consumed, and metabolism, patients may be at risk to have an adverse interaction with alcohol for 2 to 14 days after stopping disulfiram (5 days on average) and... 

These differences may become particularly germane if co-prescribing with some antipsychotics is undertaken. For example, in certain individuals, combinations of clozapine with benzodiazepines may lead to unexpected adverse events, including delirium and augmented respiratory depression (Jackson, Markowitz Brewer-ton, 1995 Grohmann et al, 1989). Presumably if there are additive or synergistic effects of ethnicity on clearance of one or both substances, adverse events may be enhanced. Similar interactions are theoretically possible with olanzapine, as adverse interactions have been described between olanzapine and benzodiazepines, at least in the elderly (Kryzhanovskaya etal, 2006). 

The results, shown in Table II, quantify the adverse effect of common well fluid ions on permeability. Especially relevant are the data indicating that even calcium chloride/calcium bromide fluids cause some permeability reduction, although the cause of the adverse interaction is obscure. 

Callaway JC, Grob CS. (1998). Ayahuasca preparations and serotonin reuptake inhibitors a potential combination for severe adverse interactions. J Psychoactive Drugs. 30(4) 367-69. 

Investigation of potential adverse interactions with drugs likely to be co-prescribed with the test drug may also be required. A generalised approach, such as the determination of effects on hepatic drug metabolising enzymes, may be sufficient, but in most cases, a number of drug-specific interaction studies will also be required. 

Adverse interactions occurring in at least 3% of patients include dizziness dyspnea headache nausea fatigue palpitation chest pain asthenia tremor constipation edema abdominal pain visual disturbances. 

B. Anticholinergic agents, such as procainamide and disopyramide, are relatively contraindicated in patients with glaucoma. Procainamide is hypotensive rather than hypertensive. The local anesthetic activity of procainamide would have no adverse interaction with the diabetes mellitus. 

Coadministration of beta-blockers can potentiate rebound hypertension upon discontinuation of medications, and it is therefore recommended that the beta-blocker be withdrawn before the tt2 agonist (Physicians Desk Reference, 2001). Tricyclic antidepressants may also produce changes in sinus node and AV conduction, and it is recommended that they be used cautiously in combination with tt2 agonists (Physicians Desk Reference, 2001). However, in child psychiatric practice, there has been debate about whether there are adverse interactions related to concomitant use of tricyclics and tt2 agonists. Finally, the tt2 agonists may potentiate the effects of CNS depressants (e.g., barbiturates) or other medications that produce sedation, so lower doses of each may be warranted. 

Barbiturates create dependency, have an unsuitable therapeutic safety margin and exhibit adverse interactions with other medicaments. 

If type A inhibitors eventually prove to be as efficacious as other MAOIs and non-MAOIs, there is no doubt that some clinicians will prescribe them with increasing frequency. In addition, if there is minimal risk of adverse interactions with tyramine and other substances (e.g., sympathomimetics), medical and legal concerns about their use will be appreciably reduced. 

Likelihood of pharmacokinetic or pharmacodynamic interactions, with the goal of minimizing adverse interactions with other drugs or medical conditions... 

In comparison with TCAs, SSRIs cause fewer pharmacodynamic drug-drug interactions but some (i.e., fluvoxamine, fluoxetine, paroxetine) cause more CYP enzyme mediated pharmacokinetic drug-drug interactions. Unlike TCAs, SSRIs do not potentiate alcohol and perhaps even slightly antagonize its acute CNS effects. Nevertheless, there are some important adverse interactions. 

Because nefazodone does inhibit the 5-HT uptake pump, it has the same class warning against combined use with an MAOl. Nevertheless, there are several reasons to suspect that there may be less risk of this interaction with nefazodone than other serotonin uptake pump inhibitors. First, trazodone, an analogue of nefazodone, is one of the few antidepressants that can be used in combination with an MOAI with minimal risk of an adverse interaction. Second, the most potent action of nefazodone is 5-HT2a receptor blockade, rather than 5-HT uptake inhibition. Nonetheless, we recommend the conservative approach of avoiding this combination, particularly when using high doses (i.e., > 450 mg per day), at which appreciable serotonin uptake inhibition is produced by nefazodone. 

As noted earlier, lithium is contraindicated in patients with unstable congestive heart failure or the sick sinus node syndrome ( 307, 328). In older patients or those with prior cardiac histories, a pretreatment ECG should be obtained. Except for the potential adverse interactions with diuretics, the concomitant use of other cardiac drugs is generally safe. Because verapamil may lower serum levels of lithium, however, more careful monitoring may be required to assure continued therapeutic effects (329). Some data also indicate that verapamil may predispose to lithium neurotoxicity. Conversely, increased lithium levels leading to toxicity has occurred with methyidopa and enalapril. When antihypertensive therapy is necessary, b-blockers are a reasonable choice when lithium is coadministered. 

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