C-JR is supported by a 2019 NARSAD Small Investigator Award
C-JR is supported by a 2019 NARSAD Small Investigator Award. Biography ?? Dr Jose de Leon is a native of Bilbao, Spain. doubt Bilobalide that in spite of halving the dose there are still indicators of clozapine intoxication, completely stopping clozapine may be indicated. Once the indicators of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level. strong class=”kwd-title” Keywords: schizophrenia, psychopharmacology Introduction This forum article reviews the multifaceted relationship of clozapine and inflammation and its impact on the clinical care of patients. After briefly critiquing clozapine metabolism, four major topics are discussed: (1) inflammation can increase clozapine levels; (2) clozapine can cause inflammation, particularly during titration; (3) clozapine may increase the risk of contamination; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. This data provides a consistent pattern, but the studies are limited by their observational nature. Obviously for ethical reasons, it is not possible to randomise clozapine patients to infections versus placebo. There is no data on COVID-19 in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia evolves, the clozapine dose should be slice in half to decrease the risk Bilobalide of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still Fli1 indicators of clozapine intoxication, completely stopping clozapine may be indicated. Once the indicators of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level. Clozapine metabolism In 1989 before pharmacokinetic studies were required, the United States (US) Food and Drug Administration (FDA) approved clozapine with very limited information on clozapine metabolism. In 1994, Bertilsson em et al /em 1 explained CYP1A2 as its major metabolic pathway. CYP1A2 pharmacology is usually highly relevant in clozapine dosing. Norclozapine is the main metabolite of clozapine and appears to be mainly eliminated by the kidney, since its conjugated metabolites are present in the urine and the serum free norclozapine is usually excreted by an unknown renal transporter that can be inhibited by gemfibrozil. With geriatric age, clozapine clearance from the body decreases; this is probably explained by the decrease in renal function and subsequent decrease in renal clearance of norclozapine and other metabolites eliminated in the urine. Tobacco smoke has polycyclic aromatic hydrocarbons which bind to the aryl hydrocarbon receptor and induce CYP1A2 expression, increasing the levels of CYP1A2, which is mainly expressed in the liver. Therefore, smokers tend to have serum concentration values that are approximately 0.80 that of non-smokers when using the same clozapine dose.2 Conversely, oestrogens have inhibitory effects on CYP1A2 activity. Male patients, then, tend to have serum concentration values that are approximately 0.86 that of females when using the same clozapine dose.2 Co-medication with inducers such as carbamazepine, phenytoin or rifampicin increase clozapine metabolism and decrease clozapine levels. The most important inhibitors Bilobalide of clozapine metabolism are ciprofloxacin, oral contraceptives, fluvoxamine and caffeine in high doses. Valproic acid can be an inducer and/or an inhibitor of clozapine metabolism; this varies from patient to patient and over time. During clozapine titration, clinicians should be more concerned about the potential of valproic acid to act as an inhibitor. Clozapine is usually prone to cause side effects, called adverse drug reactions (ADRs) by pharmacologists. Some of these clozapine ADRs, such as sedation, hypersalivation, constipation and seizures, are dose-related. It is probably more accurate to describe them as serum concentration-related. An expert guideline recommends for efficacy in schizophrenia trough steady-state clozapine concentrations of 350C600?ng/mL.3 This indicates a narrow therapeutic index. The serum concentration of norclozapine does not contribute to antipsychotic efficacy since norclozapine has no antipsychotic activity. On the other hand, it is.