Psychotropics side effects

In the search for new anti-inflammatory drugs structurally derived from indomethacine [147], Pravadoline showed psychotropic side effects in clinical trials. It became apparent that these effects are mediated through the cannabinoid receptor. Optimization of the structure Anally led to WIN-55,212-2 (8.6), which has a higher affinity to the CBl receptor than THC [148]... 

PRS-211,096 (8.8) is a CB2-selective agonist, thus avoiding the psychotropic side effects related to CBl. It is currently in clinical trial for the treatment of multiple sclerosis. 

HU-210 is (8.1) among the most potent cannabinoids known. Its enantiomer HU-211 (8.2) does not bind to the cannabinoid receptor and lacks psychotropic side effects (as long as optical purity is guaranteed). In animal models it shows analgesic and antiemetic activity. It also shows neuroprotec-tive effects after brain injury and was tested in humans as anti-traiuna agent, where it did not meet the expectations in a clinical phase III trial. 

Concerns about psychotropic side effects, which can vary cross-culturally, often lead to premature cessation of psychotropics. This may be related to different propensities for and values placed on somatic experiences in different cultures. Transcultural research indicates that patients from non-Western cultures are more likely to present with predominantly somatic symptoms of psychiatric disorders (Ng, 1997 Parker, Gladstone 8c Chee, 2001), as cultural explanatory models and social demands may serve to bias information processing in the various domains of subjective experience (Angel 8c Thoits, 1987). Several studies have shown that the perception and reporting of side effects are influenced by cultural beliefs... 

Fortunately, for most psychotropics, side effects are minimal, usually involving nuisance complaints. With some agents, such as clozapine, however, the potential for more serious adverse effects does exist and must be carefully explained to the patient and family. Although managed care has successfully controlled overall financial costs, it is our responsibility to advocate for the optimal delivery of treatment, which necessarily takes into consideration not only the immediate expense of treatment but the impact of appropriate care in the long-term. As importantly, one should always factor in the cost of not providing adequate treatment, including ... 

Psychotropic side effects that are more pronounced in the elderly are sedation, anticholinergic reactions, extrapyramidal symptoms, delirium, postural hypotension, cardiotoxicity, and cognitive impairments. Constipation is common and particularly... 

Differentiating Psychotropic Side Effects from Psychiatric Symptoms... 

Some of the compounds of general formula (I) are disclosed in U.S. Pat. Nos. 4,179,517 and 4,876,276. As disclosed in said U.S. patents, these essentially pure synthetic (-i-)-(3S,4S)-THC derivatives and analogues are devoid of any undesired cannabimimetic psychotropic side-effects. These known compounds have been described as having analgesic, antiemetic and antiglaucoma activity. 

Recent work has aimed at developing cannabinoids that lack psychotropic side effects, which limit dosing. One example of this may be found in fhe THC and cannabidiol acid derivatives ajulemic acid (CT-3) and HU-320. These compounds were reported to produce anti-inflammatory effects with a reduced side effect profile (Burstein et al. 1998 Burstein et al. 2004 Sumariwalla et al. 2004), perhaps because they possess either poor (ajulemic acid) or virtually no (HU-320) affinity for either CBIR or CB2R. Consequently, the mechanism by which they produce analgesic effects is not clear. In a recent clinical trial of patients suffering from neuropathic pain, ajulemic acid possessed some efficacy (Karst et al. 2003). While many questions about these and similar compounds are awaiting further research, this appears to be an important line of inquiry. 

There is now substantial evidence for the presence of endocannabinoid and endovanilloid systems in the GI tract. The anti-inflammatory, anticancer, antiulcero-genic and antiemetic responses to CBi receptor activation holds promise for the future management of gastrointestinal diseases. Thus, exploitation of the endocannabinoid system by facilitation at sites of endocannabinoid activity by preventing cellular re-uptake or reducing EC degradation may enhance beneficial endocannabinoid effects without the psychotropic side-effects found with systemic administration of exogenous cannabinoids. Manipulation of the endocannabinoid... 

Ethnic differences in CYP2D6 have been more thoroughly documented than with the other isoenzyme (Bradford, 2002). Over 70% of Caucasians but only about half of Asians, Sub-Saharan Africans, and African Americans have fully functional CYP2D6 alleles - alleles that code for normal metabolic activity. Approximately 50% of Asian and people of African ancestry have reduced function or nonfunctioning alleles. As a consequence, many older psychotropic medications are metabolized more slowly and plasma levels would be higher. Thus individuals of African and Asian ancestry would have an increased risk of side effects and should receive lower dose for a therapeutic response when compared to Caucasians of European descent (Lin, 2001 Lawson, 2000). 

What Is a Side Effect This chapter picks up where Chapters 1 and 2 left off. As we discussed in the earlier chapters, all medications, psychiatric and otherwise, have multiple effects. One takes a medication to achieve a therapeutic effect. Occasionally, a single medication may have more than one therapeutic effect. All other effects are side effects. Different medications may have differing therapeutic and side effects depending on the intended use. For example, trazodone and quetiapine are often prescribed to aid in sleep, and in this instance sedation is the desired effect, yet when used as an antidepressant and antipsychotic, respectively, the sedation is often an unwanted effect. Psychotropic medications typically have multiple effects. First, they usually interact with more than one nerve cell protein, be it a transporter or a receptor. Quite often, one of the medication s receptor or transporter interactions produces the therapeutic effect. The other interactions tend to not be involved in the therapeutic effect and only serve to produce side effects. Sometimes a neurotransmitter will have multiple different receptor types, but the medication interacts with... 

As we move forward with our discussion, we ll devote a section of this chapter to each of the key neurotransmitter systems that psychotropic medications interact with. We will discuss the following systems norepinephrine, dopamine, serotonin, GABA, acetylcholine, and histamine. Within each of the sections is a description of the effects that can be anticipated when a medication enhances the activity of that transmitter (reuptake inhibitors or agonists), and the effects to expect when a medication interferes (receptor antagonists) with the activity of that same transmitter. We will then describe strategies that can be implemented to help minimize and/or manage these side effects. 

Parkinsonism. As will be discussed later, dopamine-blocking antipsychotics and rarely other psychotropic medications can produce symptoms that resemble Parkinson s disease. This includes an expressionless face, slowed movement, and a stooped posture. In many respects, medication-induced parkinsonism resembles both depression and the negative symptoms of schizophrenia. Again, one must decide if it is the illness or the medication. Do you decrease the medication to remedy the side effect Or do you increase the medication to treat the illness, anticipating that a higher dose may prove more beneficial (though this is not always what is found) ... 

Hopefully these few examples will serve to emphasize the importance of a knowledge of the pharmacokinetic features of psychotropic drugs in order to avoid the potentially serious side effects that can result from drug interactions. 

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