With the globalization of the “silver wave”, the prevalence and incidence of neurodegenerative diseases in middle-aged and elderly people are rapidly increasing. Alzheimer’s disease (also known as dementia) and Parkinson’s disease (PD) are the main neurodegenerative diseases with a long course, progressive development, high disability rate and heavy disease burden, which are second only to tumors and cardiovascular diseases in terms of their impact on patients’ ability to live.
To date, the etiology of neurodegenerative diseases is not fully understood, and there is a lack of curative measures, but the application of a series of targeted therapeutic drugs has played a significant role in improving and maintaining the quality of life of patients. However, the risk of adverse drug reactions is increased by organ atrophy, reduced function and altered pharmacokinetics in the elderly; in addition, multiple drug use is common in elderly patients, with superimposed toxic effects and adverse reactions between drugs. Therefore, the medication safety of elderly patients with neurodegenerative diseases should not be ignored.
1. Clearly identify the disease and reasonably regulate the use of drugs
Elderly patients who are clearly diagnosed with neurodegenerative diseases should take into account the efficacy and adverse effects of the selected drugs. At present, there are at least 6 types of anti-PD drugs commonly used in clinical practice, among which anticholinergic drugs (such as benzhexol hydrochloride) have been clearly listed as one of the 10 drugs to be avoided or used with caution in the elderly by the Beers standard of the American Geriatrics Society. According to the latest international and national treatment guidelines, compounded levodopa (L-dopa) should be preferred in elderly PD patients, and the medication should be started in small doses and adhered to a “dose titration” regimen.
However, although L-dopa is regarded as the “gold standard” of PD medication, after a “honeymoon period” of 3-5 years, patients may develop motor complications such as motor fluctuations and dyskinesia, which can affect about 90% of patients treated with L-dopa after 10 years. This complication can affect about 90% of those treated with L-dopa after 10 years, making it a serious challenge for the treatment of PD in the elderly.
The combination of catecholamine oxygen methyltransferase (COMT) inhibitors with L-dopa may increase the half-life and bioavailability of L-dopa and alleviate motor complications in some patients, but the addition of COMT inhibitors in elderly PD patients requires careful monitoring of liver function. Another commonly used drug that may alleviate late motor complications is dopamine agonists ( DA), including ergot and non-ergot drugs.
Similar to L-dopa, DA causes recent adverse effects such as nausea, vomiting and postural hypotension in most patients, and while such adverse effects are generally tolerated and effectively managed, the more serious safety concerns are more frequent with DA. Ergot DAs can cause tissue fibrosis and have been rarely used or even withdrawn from the market in clinical practice. One such drug, pergolide, was added to the U.S. black box warning in 2006 and withdrawn from the market in 2007 because it can increase the risk of heart valve fibrosis by up to five times.
Currently, non-ergot DAs are more commonly used clinically. Of these, ropinirole and pramipexole were first reported to cause daytime sleepiness and sleep attacks. Although the types and incidence of adverse reactions of non-ergot DA reported in existing studies are not the same (3%-7% for sleep attacks, 5%-20% for psychiatric symptoms, and 5%-15% for impulse control disorders), it is still possible to collect possible adverse reactions through different studies and inform patients in a timely manner to improve the safety of drug use.
Studies on motor complications due to L-dopa have been carried out successively. Amantadine is the only drug that has been reported to be effective in double-blind studies for allodynia, but the clinical application of this drug has revealed more adverse effects, especially on cognitive function, and it is not recommended now as a drug for elderly PD patients. In addition, the emergence of new treatment options such as continuous pumping of apomorphine or parenteral application of levodopa will bring more benefits for the safe and effective treatment of motor complications in elderly PD patients.
2. Multi-medication to optimize treatment strategy
The neurotransmitter and neural network associations in the brain are complex, and patients with neurodegenerative diseases may exhibit multiple symptoms coexisting. In recent years, some studies have found that the impact of non-motor symptoms on the quality of life of PD patients, especially those with advanced PD, is more prominent than that of motor symptoms, and dopaminergic drug therapy is ineffective, which makes how to take into account the treatment of non-motor symptoms a hot spot in the treatment of PD at present.
In 2013, the latest guidelines published by the European Federation of Neurological Societies (EFNS) based on evidence-based medical evidence have provided recommendations for the treatment of non-motor symptoms in PD patients, and a study by Andersen et al. showed that tricyclic antidepressants were more effective in treating non-motor symptoms in PD patients treated with L-dopa.
However, the above recommendations and studies did not take into account the specificity of elderly patients themselves, such as tricyclic antidepressants have anticholinergic effects that can affect cognitive function and are not suitable for use in elderly patients. Therefore, the treatment of non-motor symptoms in elderly PD patients needs to be combined with guidelines and clinical reality to reasonably optimize the treatment strategy.
In clinical practice, pharmacological treatment of motor and non-motor symptoms in elderly PD patients should be streamlined, and if the situation requires multiple doses, we recommend.
(1) Prohibit the combination of contraindicated drugs. In elderly PD patients with comorbid depression, the use of 5-hydroxytryptamine reuptake inhibitors as antidepressants has less adverse effects, but the combination of this drug with monoamine oxidase inhibitors is prohibited.
(2) Drugs that can treat multiple symptoms are preferred. Pramipexole can exert some antidepressant effects while improving motor symptoms in PD patients, and can be considered for the treatment of mild to moderate depression in elderly PD patients.
(3) Avoid choosing drugs that can aggravate other symptoms. For example, when elderly PD patients develop psychiatric symptoms, the possibility of psychiatric systemic adverse effects due to anti-PD drugs should be ruled out first, and the order of anti-PD drugs to be reduced or discontinued in sequence should be: anticholinergics, amantadine, monoamine oxidase inhibitors, DA and L-dopa.
(4) Prefer drugs with clear evidence-based medical evidence. For example, in elderly PD patients with combined psychiatric symptoms, if the effect of the above anti-PD medications is not satisfactory or must be adjusted at the expense of aggravating PD symptoms, the use of an appropriate amount of L-dopa and the combination of antipsychotic drugs recommended for PD patients following evidence-based medical evidence – clozapine – can be considered, and the blood routine should be monitored during the medication.
3. Individualization of medication regimens with emphasis on differences
Individualized treatment is currently the mainstream direction of clinical practice, which is conducive to maximizing the therapeutic effect and minimizing adverse effects. The main challenge in the clinical treatment of PD is the large variability of drug efficacy and adverse effects, and individual differences due to genetic variation may be the main determinant. It has been found that the risk of distant adverse reactions to L-dopa may be associated with genetic variants in the receptors, metabolic enzymes and transporters encoding the drug.
PD patients carrying the dopamine D2 receptor ( DRD2) Taq IAA1 genotype present a low striatal DRD2 density and an increased risk of motor fluctuations compared to PD patients who do not carry this genotype (33% vs. 10%. Studies with large samples have shown that variants in the 40 bp variable number of tandem repeats of the dopamine transporter gene can significantly increase the risk of heterokinesis.
Currently, anti-PD drugs are not included among the 80 drugs for which the FDA has approved a requirement to disclose genetic information, but their associated pharmacogenetic studies have been rapidly developed and the impact of genetic information on drug effectiveness is being studied.
Studies have found that PD patients with the SLC22AI gene rs622342, which encodes the organic cation transporter, with genotype AC or CC have lower sensitivity to L-dopa and require higher doses of L-dopa. It has also been suggested that PD patients carrying the Ser9 Gly position DRD3 ser/ser genotype may show better response rates to pramipexole.
As research progresses, pharmacogenomics may become a powerful tool to guide clinical drug use in the future, thus truly realizing the shift from individualized drug use to individualized drug use and improving drug safety for patients with neurodegenerative diseases.
4. Trinity, mobilize family strength
Good compliance is also crucial to medication safety. As the ability of elderly patients with neurodegenerative diseases decreases in daily life, clinical workers should give more humanistic care to patients and actively mobilize the strength of family members and caregivers to obtain timely and comprehensive feedback on medication adherence and efficacy while making diagnosis, treatment and prevention recommendations.
For example, patient and careful explanation should be given to PD patients who are “levodopa-phobic” and caregivers of PD patients who are unable to take care of themselves should be mobilized. Family members’ care and assistance in life and spirit can help reduce the occurrence of anxiety and depression, and also reduce the impact of the disease on patients’ quality of life. The integrated model of physician, patient, family and biological-psychological-social trinity is a guarantee to improve the safety of medication for elderly patients with neurodegenerative diseases.