Harrisburg University of Science and Technology Digital Commons at Harrisburg University Harrisburg University Faculty Works 12-8-2016 Pharmacotherapeutic Considerations for Individuals with Down Syndrome Erik Hefti Follow this and additional works at: http://digitalcommons.harrisburgu.edu/faculty-works Part of the Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, and the Medicinal and Pharmaceutical Chemistry Commons R EVIEW O F T HERAPEUTICS Pharmacotherapeutic Considerations for Individuals with Down Syndrome Erik Hefti,* and Javier G. Blanco* Department of Pharmaceutical Sciences, The School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York Down syndrome (DS; trisomy 21) is the most common survivable disorder due to aneuploidy. Individ- uals with DS may experience multiple comorbid health problems including congenital heart defects, endocrine abnormalities, skin and dental problems, seizure disorders, leukemia, dementia, and obesity. These associated conditions may necessitate pharmacotherapeutic management with various drugs. The complex pathobiology of DS may alter drug disposition and drug response in some individuals. For example, reports have documented increased rates of adverse drug reactions in patients with DS treated for leukemia and dementia. Intellectual disability resulting from DS may impact adherence to medication regimens. In this review, we highlight literature focused on pharmacotherapy for individu- als with DS. We discuss reports of altered drug disposition or response in patients with DS and explore social factors that may impact medication adherence in the DS setting. Enhanced monitoring during drug therapy in individuals with DS is justified based on reports of altered drug disposition, drug response, and other characteristics present in this population. KEY WORDS Down syndrome, trisomy 21, pharmacotherapeutics, medication adherence, gene dosage effect, seizure disorder, leukemia, adverse drug reactions. (Pharmacotherapy 2016;**(**):**–**) doi: 10.1002/phar.1880 Down syndrome (DS), also known as trisomy wide imbalances with a range of phenotypic con- 21, is the most common survivable chromosomal sequences.2 Individuals with DS often exhibit disorder due to aneuploidy.1 The incidence of associated disorders that contribute to elevated DS in the United States is ~1 per 700 live births, health care needs and financial costs.3 In spite of and the worldwide incidence is ~1 per 1000 live the high incidence of multiple adverse health births.1 DS is caused by the presence of an addi- conditions, the life expectancy of individuals tional whole or partial copy of chromosome 21 with DS has increased to ~60 years of age.4 Indi- in affected individuals that results in genome- viduals with DS will likely have increased health care needs as they age.5 The complex pathobiology of DS results in Support: physical deficits and biochemical changes that This review was supported by the National Institute of can lead to multiple comorbid conditions. Gas- General Medical Sciences and the Eunice Kennedy Shriver trointestinal malformations such as duodenal National Institute of Child Health and Human Development stenosis and Hirschsprung disease are associated of the National Institutes of Health under awards with DS.6 DS can impact immune responses, R01GM073646 and R03HD076055. *Address for correspondence: Erik Hefti, Department of resulting in individuals being more susceptible to Pharmaceutical Sciences, The State University of New York certain infections (e.g., upper respiratory tract at Buffalo, 471A Kapoor Hall, Buffalo, NY 14214; e-mail: infections).7 Celiac disease and other food intol- [email protected] or Javier G. Blanco, Department of erances are also more common in individuals Pharmaceutical Sciences, The State University of New York with DS.8, 9 Congenital heart defects are common at Buffalo, 470 Kapoor Hall, Buffalo, NY 14214; jgblanco@ buffalo.edu. in those with DS, whereas the incidence of coro- Ó 2016 Pharmacotherapy Publications, Inc. nary artery disease (CAD) is lower than in 2 PHARMACOTHERAPY Volume **, Number **, 2016 10 subjects without DS. One study found that Alterations in Drug Disposition and Drug 9.9% of persons with DS older than 40 years died Response as a result of CAD.11 A lower level of homocys- teine in individuals with DS is thought to con- Dementia and Psychiatric Disorders tribute to the reduced incidence of CAD; however, this has yet to be confirmed.12 The fre- Individuals with DS have a greater risk of quency of congenital hypothyroidism is 28 times developing Alzheimer’s-like dementia earlier in higher in individuals with DS in comparison with life compared with individuals without DS.19 those without DS.13 Multiple skin conditions are Rivastigmine, galantamine, memantine, and done- also associated with DS and can lead to recurrent pezil have been used to treat Down syndrome– skin and soft tissue infections.14 DS is a leading associated dementia (DSAD).20 Donepezil has cause of intellectual disability.15 Neurologic con- shown significant therapeutic efficacy in multiple ditions such as seizure disorders and early-onset reports. One small study showed improvement in dementia are prevalent in the DS population. dementia scores in subjects treated with donepe- Children with DS are at an increased risk for zil during the 3- to 5-month time period hematologic disorders such as acute myeloid leu- (p=0.03). Subjects were treated with initial doses kemia, acute lymphoblastic leukemia, and ane- of donepezil 5 mg/day for 50 days, followed by mia.16 Obesity, dental problems, and apnea are 10 mg/day for 60 days.21 Other studies did not also associated with DS.17 show significant improvement in subjects with Although some physical deficits in DS may be DSAD who were treated with donepezil.22 Ele- corrected with surgery, medications are often vated frequencies of adverse effects from donepe- used to manage various comorbid health condi- zil have been reported in subjects with DSAD.23 tions in individuals with DS. This results in high For example, in two separate reports, a total of rates of medication use by those with DS.18 six individuals with DSAD developed gastroin- Unfortunately, there is often a lack of prospec- testinal disturbances, altered mental status, or uri- tive research to make evidence-based recommen- nary incontinence following treatment with dations for all DS-associated conditions and donepezil of varying duration (weeks to anomalies. Thus the treatment of comorbid con- months).24, 25 A small group of 14 healthy sub- ditions associated with DS can be a daunting task jects with DS did show higher donepezil plasma for health care providers and often requires mul- concentrations than a comparator group of 6 tiple approaches. This concise review highlights healthy subjects without DS.25 In this study, the the literature that focuses on pharmacotherapy mean donepezil plasma concentration (while for individuals with DS, indicates incidences of receiving donepezil 3–5 mg/day for 5 days) in altered drug disposition or response, and justifies subjects with DS was 17.9 and 28.2 ng/ml at the need for further investigation of drug therapy doses of 3 mg/day and 5 mg/day, respectively, in individuals with DS. This information may be versus a mean plasma concentration of 7.8 and relevant for health care professionals who man- 17.7 ng/ml in the group of subjects without DS age patients with DS. taking similar doses, respectively (p<0.001). The authors speculated that altered pharmacokinetics of donepezil could play a role in the increased Literature Review incidence of adverse effects in subjects with Published reports concerning medication use, DSAD and suggested that donepezil doses as low adherence, disposition, and effect in subjects as 3 mg/day should be adequate for most patients with DS were considered for this review. The with DSAD. It has been postulated that initiating PubMed and Ovid databases were used to search treatment with donepezil at a lower dose and then and identify the reports. These keywords were titrating this dose, if necessary, may reduce the used: Down syndrome, trisomy 21, pharmacother- frequency of adverse effects in individuals with apy, adverse drug reaction, drug treatment, phar- DSAD.20 Rivastigmine, a cholinergic agent used macokinetics, pharmacodynamics, and drug for the treatment of mild to moderate dementia, metabolism. The search was performed from has also been studied in subjects with DSAD. In March 2016 through July 2016 and yielded pri- one double-blind placebo-controlled trial in 22 mary research articles as well as other relevant children and adolescents with DS, rivastigmine reviews on related topics. The publication dates treatment did not improve cognition, language, of reports used in this review spanned from or overall function.26 It was noted that subjects 1981 to 2016. with DSAD tolerated rivastigmine therapy well. PHARMACOTHERAPY FOR DOWN SYNDROME Hefti and Blanco 3 Patients with DS can have high utilization effects of pharmacotherapy with anticonvulsants rates of antidepressant and antipsychotic medica- in individuals with DS may necessitate gradual tions.18 These medications are given to some titration to effect and enhanced monitoring.36 patients with DS and dementia to manage sym- ptoms as well as other psychological disorders.27 Respiratory Disorders One case series explored the efficacy of admi- nistering antidepressants such as sertraline, Respiratory