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Cognitive Burden of Common Non-antiretroviral Medications in HIV-Infected Women (WIHS)
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see below following this study information from general literature on use of ......
Anticholinergic drugs should be avoided in patients with dementia, cognitive impairment, or delirium. A study from Group Health in Seattle and published in JAMA Internal Medicine in 2015 noted that higher cumulative anticholinergic medication use was associated with an increased risk for dementia.....Anticholinergic drugs fall into many different classes of drugs, so it's hard for patients to identify or remember these specific drugs. For example, some antihistamines, antidepressants, or even muscle relaxants have anticholinergic properties. Patients with delirium, dementia, constipation, and benign prostatic hypertrophy (BPH) are particularly at risk of anticholinergic adverse drug events. Refer to the list below for a list of anticholinergic drugs to avoid in older patients.......The results of this study showed that the current use of drugs with anticholinergic properties was significantly associated with low cognitive performance among community-dwelling elderly people.
- The use of drugs with anticholinergic activity is a biologically plausible and potentially modifiable risk factor for cognitive impairment, as suggested by the cholinergic hypothesis of geriatric memory dysfunction [6]. The anticholinergic drug scopolamine has been used to model some aspects of the cognitive changes that occur with ageing. When administered to young and healthy subjects, the drug produced a pattern of reversible memory and cognitive deficits that mimic those occurring with normal ageing [24-26]. In older subjects, the impairment produced was consistent with the fact that elderly people are more sensitive than younger people to side-effects of drugs which block muscarinic receptors, including cognitive impairment [8, 9].
- Because elderly people often have multiple illnesses which are generally treated with different types of medication [27], there is a risk that more than one drug with anticholinergic properties will be given. This could lead to cumulative anticholinergic toxicity and increase the risk of adverse effects. In our study, only 6.6% of users took more than one drug with anticholinergic activity.
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Cognitive Burden of Common Non-antiretroviral Medications in HIV-Infected Women
JAIDS Sept 1 2018 - Rubin, Leah H., PhD, MPH*,; Radtke, Kendra K., PharmD; Eum, Seenae, PharmD; Tamraz, Bani, PharmD, PhD; Kumanan, Krithika N., MPH; Springer, Gayle, MLA; Maki, Pauline M., PhD*,; Anastos, Kathryn, MD**; Merenstein, Daniel, MD; Karim, Roksana, MD, PhD; Weber, Kathleen M., RN; Gustafson, Deborah, PhD, MS; Greenblatt, Ruth M., MD; Bishop, Jeffrey R., PharmD
"In conclusion, HIV+ women seem to take a greater number of non-ARV NC-AE medications as well as non-ARVs with anticholinergic properties as well as anxiolytics and anticonvulsants compared with HIV- women. Despite these differences, non-ARV NC-AE medications seem to have no general effects on global or domain-specific cognitive performance amongHIV+ and HIV- women. However, HIV+ women may have increased cognitive vulnerabilities to anticholinergic medications. Potential synergy between anticholinergic medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider anticholinergic medication use in HIV+ women."
Objective: The aging HIV population has increased comorbidity burden and consequently non-antiretroviral medication utilization. Many non-antiretroviral medications have known neurocognitive-adverse effects ("NC-AE medications"). We assessed the cognitive effects of NC-AE medications in HIV+ and HIV- women.
Methods: One thousand five hundred fifty-eight participants (1037 HIV+; mean age 46) from the Women's Interagency HIVStudy completed a neuropsychological test battery between 2009 and 2011. The total number of NC-AE medications and subgroups (eg, anticholinergics) were calculated based on self-report. Generalized linear models for non-normal data were used to examine the cognitive burden of medications and factors that exacerbate these effects.
Results: HIV+ women reported taking more NC-AE medications vs. HIV- women (P < 0.05). NC-AE medication use altogether was not associated with cognitive performance. However, among NC-AE medication subgroups, anticholinergic-acting medications, but not opioids or anxiolytics/anticonvulsants, were negatively associated with performance. HIV status moderated the association between these NC-AE medication subgroups and performance (P's < 0.05). HIV-serostatus differences (HIV- < HIV+) in global, learning, fluency, and motor function were greatest among women taking >1 anticholinergic medications. HIV-serostatus differences in performance on learning and psychomotor speed were also greatest among women taking 1 or more anxiolytics/anticonvulsants and 1 or more opioids, respectively.
Conclusions: HIV+ women have increased cognitive vulnerabilities to anticholinergic, anxiolytic/anticonvulsant, and opioid medications. Potential synergy between these medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider these specific types of medications as a contributor to impaired cognitive performance in HIV+ women and assess the cost/benefit of treatment dosage for underlying conditions.
INTRODUCTION
Increasing effectiveness and adherence to antiretroviral (ARV) therapies has led to an aging of the HIV population. To date, approximately 50% of all individuals with HIV are 50 years or older1,2 and about 90% of individuals older than 50 years have been living with HIV for the majority of their life.3 Two consequences of aging in the HIV-infected population are increases in: (1) prevalence of HIV-associated non-AIDS comorbidities; and (2) prescription and utilization of non-ARV medications to treat these comorbidities. Both consequences may cause detrimental effects on brain structure and function.
One common HIV-associated non-AIDS comorbidity is cognitive impairment, which is reported to occur in approximately 30%-60% of people with HIV at some point during their lifetime.4 The clinical features of HIV-associated cognitive impairment commonly include alterations in executive function, complex attention, processing speed, learning, and memory5-9 and these deficits are associated with dysfunction of frontostriatal networks10 and altered integrity of hippocampal and prefrontal brain regions.11-13 Interestingly, the utilization of non-ARV medications with known cognitive adverse effects may in part explain some of the cognitive complications among HIV-infected (HIV+) individuals, particularly among those individuals aged 50 years and older. Many of the non-ARV medications used among HIV+ individuals have known cognitive adverse effects (termed "NC-AE medications"), especially agents with anticholinergic properties14-18 as well as opioids,19 anxiolytics,20 and anticonvulsants.21 This is particularly concerning because older adults in general have an increased vulnerability to medication side effects due to the pharmacokinetic and pharmacodynamic changes that occur with aging.22 For example, with age, metabolism and drug elimination slows, the blood-brain barrier changes, and there are age-related deficits in neurotransmission.23 As a result, many medications with higher side effect burden are not routinely recommended in older patients.24-26
The primary aim of the present analysis was to examine the potential cognitive burden of NC-AE medications (total number) and to determine whether HIV exacerbates potentially negative effects. We were interested in both the more general, diffuse effects of NC-AE medications27 as well as the effects of commonly used non-ARV medications with known pharmacodynamic mechanisms including those with anticholinergic properties, opioids, anticonvulsants, and anxiolytics. Our overarching hypothesis was that the effects of NC-AE medications would be broad, negative influences on cognitive performance, and that HIV would exacerbate these effects. Furthermore, consistent with previous studies in older adults,16,18 we expected more specific associations with medications with known anticholinergic properties on measures of learning, memory, and attention.
DISCUSSION
To the best of our knowledge, this is the first study to examine the general effects of non-ARV NC-AE medications as well as the effects of commonly used non-ARV classes of medications such as anticholinergics, opiates, anticonvulsants, and anxiolytics with known neurocognitive effects on cognitive performance in a sample of HIV+ and HIV- women. Although we demonstrated that non-ARV NC-AE medications are more commonly used among HIV+ compared with HIV- women, differential usage of these non-ARV medications does not seem to explain greater cognitive impairment among HIV+ compared with HIV- women. However, greater use of non-ARV medications with anticholinergic properties as well as anxiolytics/anticonvulsants and opioids among HIV+ vs. HIV- women may in part explain some of the greater cognitive impairment among HIV+ compared with HIV- women, particularly on global function, learning, fluency, psychomotor speed, and motor function.
In this study, there were no overall influences of non-ARV NC-AE drugs on cognitive performance in women irrespective of HIV-serostatus. Typically, there are generalized latency effects, as well as sedative effects, of many medications39 that can result from influences on a number of neurotransmitter systems. The accumulated influence of these latency and sedative properties are likely reasons for the lower global cognitive function. However, non-ARV NC-AE burden was not associated with any cognitive outcome across all women.
Of the drug categories further examined, anticholinergic-acting medications may in part explain our previous findings of a greater persistence of impairment observed in the learning domain and the gradual decline in motor function over time in HIV+ compared with HIV- women.8 Among women taking one anticholinergic-acting drug, HIV- women showed lower performance on motor function than HIV+ women. Detailed medication review in the each group revealed that the percentage of individuals taking antidopaminergic medications (ie, antipsychotics) was higher in HIV- women than in HIV+ women (36% vs. 25%) within women taking one anticholinergic-acting medication. Because motor performance is also robustly influenced by medications with antidopaminergic properties,16 similar anticholinergic exposure but higher antidopaminergic exposure in HIV- women compared with HIV+ women may in part explain these findings on motor function. In addition, on domains where we have not previously seen an HIV-serostatus difference over time such as fluency and psychomotor speed,8 anticholinergic-acting medications may have synergistic effects with HIV to yield performance differences. The general15-17 and more specific adverse cognitive effects16,18 of medications with anticholinergic properties are thought to result from suppression of cholinergic system by direct blockade of muscarinic acetylcholine receptors in the brain. Specific cognitive effects seem to depend on selectivity of the medication for 1 of the 5 muscarinic receptor subtypes (M1-M5).40 Transgenic mouse models lacking the M1 receptor have impairments in learning, memory, and attention. Similarly, in humans, M1-selective antagonism decreases similar cognitive abilities.41
One possible explanation for medications with anticholinergic properties exacerbating HIV-serostatus differences on cognitive performance globally is that neurotoxic viral proteins may have additive or interactive effects with these medications. Effects on memory may be due to the neurotoxic effects of HIV viral proteins on brain regions important for learning such as the hippocampus.42,43 Envelope glycoprotein, gp120, is one example that may be important in HIV-induced cognitive impairment.44 It has been suggested that gp120-mediated cognitive impairment may, in part, result from impairing cholinergic function.44 It was also shown that memory impairment induced by gp120 could be reversed by hippocampal cholinergic stimulation in mice.44 Another neurotoxic viral protein that may contribute to adverse cognitive outcomes is Tat.45 Tat protein selectively enhances acetylcholine release from human and rodent cortical synaptosomes.46 The selectivity of Tat on the release of acetylcholine but not other neurotransmitters (ie, dopamine, glutamate, aspartate, GABA, serine, and norepinephrine) suggests that cholinergic neurons may be uniquely sensitive to HIV Tat proteins. These findings, taken together with this present work, suggest that there may be an additive adverse consequence of HIV neurotoxicity and anticholinergic medication burden. Although gp120 and Tat protein may be factors that contribute to these effects, there could be drug-drug interactions (eg, non-ARV drug by non-ARV drug; non-ARV drug by ARV drugs; non-ARV drugs by illicit drug use such as crack/cocaine47), as well as pharmacodynamic effects such anticholinergic-induced inflammation (eg, increases interleukin-1β expression48) that have not been accounted for in this study. Medication-induced inflammation compounded with HIV-induced inflammation49 could adversely impact global cognitive performance.
Although HIV+ women reported using more anticonvulsants than HIV- women, unexpectedly, anticonvulsant medications were not negatively associated with cognitive performance in women. Although using these medications was associated with higher impairment among HIV+ vs. HIV- women on learning, these medications were not differentially related to cognitive performance by HIV-serostatus when accounting for uncontrolled viremia among the HIV+ women. Anticonvulsant medications (eg, phenytoin, carbamazepine, valproate, etc.) are typically associated with cognitive side effects.50,51 The adverse effects of anticonvulsant medications on cognition are thought to be related to their influence on glutamate transmission in the brain.52 Although the extent and type of cognitive adverse effects may vary among anticonvulsants, many induce impairments in attention, memory, and mental speed.50,51 The lack of association in our analyses after accounting for uncontrolled viremia is likely due to the relatively higher utilization of some newer anticonvulsant drugs (ie, lamotrigine and pregabalin) that may not adversely influence cognition to a similar degree as older medications.53,54
HIV+ and HIV- women reported similar rates of opioid use and, in our study sample, we did not identify associations between these drugs and cognitive performance. We did find that opioid use was associated with worse psychomotor speed among HIV+ vs. HIV- women. However, after accounting for uncontrolled viremia, this opioid use was not differentially related to performance on psychomotor speed by HIV-serostatus. These findings were also unexpected because opioid receptors are involved with pain as well as other central neuromodulatory systems including cognition, and are generally considered to have cognitive impairing effects.55 Although there is no consensus on differential effects of opioids by cognitive domain, most previous studies have shown that opioid use is associated with decreased psychomotor speed.55,56 Opioids are commonly used for the short-term management of pain, often prescribed to take "as needed." The doses and long- vs. short-term use of opioids in our study sample were not consistently available. Thus, the lack of association observed in our study may be partially related to inconsistent or "as-needed" use, which may be less likely to induce notable cognitive adverse effects than higher-dose or longer-term exposures.
Limitations of this study include the cross-sectional study design. Longitudinal studies are underway to examine the longer-term impact of non-ARV medications with adverse cognitive effects on cognitive performance among HIV+ and HIV- womenas they age. In addition, medication dose or duration of use was not available and therefore could not be examined or accounted for in this study. Medication history interviews (eg, names, dose, times per day, route, and reason) and adherence assessments, even when conducted by trained research or medical professionals, are prone to recall bias in the absence of objective pill counts or pharmacy refill data. This may result in observed attenuation of drug-outcome relationships when there is inaccurate reporting of adherence, omission of medications, or reporting medications not actually taken.
In conclusion, HIV+ women seem to take a greater number of non-ARV NC-AE medications as well as non-ARVs with anticholinergic properties as well as anxiolytics and anticonvulsants compared with HIV- women. Despite these differences, non-ARV NC-AE medications seem to have no general effects on global or domain-specific cognitive performance amongHIV+ and HIV- women. However, HIV+ women may have increased cognitive vulnerabilities to anticholinergic medications. Potential synergy between anticholinergic medications and HIV may explain some HIV-related cognitive impairments. It may be important clinically to consider anticholinergic medication use in HIV+ women.
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The results of this study showed that the current use of drugs with anticholinergic properties was significantly associated with low cognitive performance among community-dwelling elderly people.
- The use of drugs with anticholinergic activity is a biologically plausible and potentially modifiable risk factor for cognitive impairment, as suggested by the cholinergic hypothesis of geriatric memory dysfunction [6]. The anticholinergic drug scopolamine has been used to model some aspects of the cognitive changes that occur with ageing. When administered to young and healthy subjects, the drug produced a pattern of reversible memory and cognitive deficits that mimic those occurring with normal ageing [24-26]. In older subjects, the impairment produced was consistent with the fact that elderly people are more sensitive than younger people to side-effects of drugs which block muscarinic receptors, including cognitive impairment [8, 9].
- Because elderly people often have multiple illnesses which are generally treated with different types of medication [27], there is a risk that more than one drug with anticholinergic properties will be given. This could lead to cumulative anticholinergic toxicity and increase the risk of adverse effects. In our study, only 6.6% of users took more than one drug with anticholinergic activity......https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884748/
Anticholinergic Drugs to Avoid in the Elderly
Anticholinergic drugs block (antagonize) the action of the neurotransmitter acetylcholine. A neurotransmitter is a chemical released by nerve cells to send signals to other cells. Acetylcholine is involved in transmitting messages that affect muscle contractions in the body and learning and memory in the brain.
Medications To Avoid in Elderly
Why should many anticholinergic drugs be avoided in the elderly? Chemical properties of these drugs can cause a wide array of more pronounced reactions in the elderly.
The central nervous system is very sensitive to anticholinergic side effects due to the substantial decrease in cholinergic neurons or receptors in the brain of older individuals. In addition, the lower ability of the liver and kidney to break down and excrete medications, and the increase in the blood-brain barrier permeability which allows drugs to cross more easily into the brain, are major factors contributing to anticholinergic side effects in older adults. Most commonly, anticholinergics can cause the following side effects, which may be more pronounced in the elderly:
• Drowsiness or sedation
• Blurred vision
• Dizziness
• Urinary retention
• Confusion or delirium
• Hallucinations
• Dry mouth
• Constipation
• Reduced sweating and elevated body temperature
• Falls and risk for fracture
Anticholinergic drugs fall into many different classes of drugs, so it's hard for patients to identify or remember these specific drugs. For example, some antihistamines, antidepressants, or even muscle relaxants have anticholinergic properties. Patients with delirium, dementia, constipation, and benign prostatic hypertrophy (BPH) are particularly at risk of anticholinergic adverse drug events. Refer to the list below for a list of anticholinergic drugs to avoid in older patients.
Anticholinergic drugs should be avoided in patients with dementia, cognitive impairment, or delirium. A study from Group Health in Seattle and published in JAMA Internal Medicine in 2015 noted that higher cumulative anticholinergic medication use was associated with an increased risk for dementia. Data were evaluated from a prospective, population-based cohort study using data from the Adult Changes in Thought Study. Over 3,400 participants aged 65 and older with no dementia were enrolled at study entry between 1994 and 2003. It was found the most common anticholinergic drug classes used by the elderly in the study were tricyclic antidepressants, first generation antihistamines and overactive bladder antimuscarinics. Overall, a higher cumulative use of anticholinergic medications (3 years or more) across all subclasses was linked with a 54% higher risk for developing dementia than taking the same dose for three months or less. Results also suggested that the risk for dementia with anticholinergics remain even after drug discontinuation.
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