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  • Review specific neurological disease states and the pharmacogenomics of these.
  • Discuss how pharmacogenomics affects response to drug therapy and its implications.
  • Outline how pharmacogenomics and pharmacogenomic testing will have an impact on diagnosis and treatment of neurological disease states.

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Knowledge of pharmacogenomics is becoming increasingly important in neurology, as in many fields of medicine, for practicing pharmacotherapeutics. The effectiveness and toxicities of medications used in secondary stroke prophylaxis, dementia, seizure disorders, multiple sclerosis (MS), and Parkinson disease (PD) are all influenced by genetic polymorphisms. These include but go beyond variability in metabolism by Phase I/II enzymes. Genetic variability plays a role in how prodrugs work by controlling metabolism to their active form, as in the case of clopidogrel; how drugs bind to receptors, as in the case of MS; or how drugs are eliminated or inactivated as in the case of anticonvulsants and agents for Alzheimer's disease (AD).1 In recent AD clinical trials, for example, it has been found that a certain apolipoprotein E (APOE) allele can affect whether patients respond positively to a drug treatment. Susceptibility to life-threatening hypersensitivity reactions is also related to specific polymorphisms. Future research may provide genetic explanations for multiple drug resistance in epileptic patients.

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Antiplatelet therapy is the standard of care for prevention and treatment of atherothrombotic events, including myocardial infarction and stroke prophylaxis.2 Variability in antiplatelet response to all classes of these drugs has been well documented and lack of response to antiplatelet therapy has been established as a risk factor for developing secondary atherothrombotic events. While pharmacokinetics and disease severity play a role in the variability in response to antiplatelet agents, genetic polymorphisms contribute to variability in response to aspirin, the thienopyridines, and the GPIIb/IIIa inhibitors. Patients with certain genotypes may benefit from individualized therapy to reduce their risk of secondary thrombotic events.

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Thienopyridines

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Clopidogrel is commonly used and indicated for acute myocardial infarction, myocardial infarction prophylaxis, stroke prophylaxis, and percutaneous coronary intervention.3 It is administered as an inactive drug that requires activation, largely by CYP2C19, CYP3A4 and CYPA12, to an active metabolite for a therapeutic effect to be produced (Figure 16–1). Antiplatelet effect is produced by the active metabolite of clopidogrel irreversibly inhibiting adenosine diphosphate (ADP)–induced platelet aggregation by preventing ADP binding to its P2Y12 platelet receptor. It is estimated that up to 40% of patients do not achieve an optimal antiplatelet effect with clopidogrel, which puts these patients at higher risk of developing an atherothrombotic event.4

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FIGURE 16–1
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Genetic polymorphisms associated with clopidogrel.127 (With permission from Vance JM., Tekin D. Genomic medicine and neurology. Continuum: lifelong learning in neurology. Neurogenetics. 2011;17(2):249–267. Copyright © 2011, American Academy of Neurology).

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Mega et al. tested the association between genetic variants in CYP genes and antiplatelet response in 162 healthy patients ...

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