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(6) Drug Toxicity or Adverse Reactions:  Drug therapy has contributed significantly to the management of numerous medical conditions in older patients, a substantial number of these individuals will experience some sort of Adverse Drug Reaction (ADR). ADRs have been recognized as a serious health problem, and one US Government report estimated that 10% to 15% of geriatric hospital admissions were caused by ADRs.

The relative odds of an ADR specifically related to cognitive impairment in older individuals have also been found to increase as the number of prescription drugs increased.

Cognitive impairment is a broadly definable ADR, which is extremely important in older people and one to which they seem to have heightened susceptibility. Symptomatology includes disorders that can be termed “psychiatric” and/or “neurologic,” and often occurs on a continuum. Some drugs that are linked with discretely classifiable outcomes, such as depression and suicide or seizures, are often also noted to cause a variety of more subtle central nervous system (CNS) disturbances as well, such as confusion or decreased sensory gain. Such symptoms are more difficult to assess and could clearly have an impact on cognitive abilities.

However, these drugs may more routinely be considered in the context of their most dramatic adverse sequelae, and may be overlooked when considering drugs that can impair “cognition.”[13]

Drugs used for sedation, for example, may impair cognition in the course of exerting their therapeutic effect without an undesired outcome if the setting is proper and the effect terminates in a predictable and expected manner.

Figure.3: Consequences of reduced clearance in the elderly. For any given drug, impairment of the capacity for drug elimination (reduced clearance) will cause an elevation in steady-state concentrations (Css) with a resulting increase in the likelihood of toxicity. Reduced clearance also may cause a prolongation of elimination half-life, and a consequent delay in the rate of attainment of the steady-state condition. An increase in volume of distribution (Vd) may also contribute to a prolongation of elimination half-life.[14]

Aged individuals are commonly on multiple medications increases the risk of all ADRs, including those resulting in impaired cognition. Many of the commonly used medications, such as digoxin, psychotropics, and those with anticholinergic (muscarinic-blocking) properties, have been well documented as causes of cognitive disturbances, even when used alone.

A number of intrinsic physiologic alterations also put older individuals at increased risk for cognitive toxicity, including changes in neuroplasticity with resulting changes in drug sensitivity, and changes in drug distribution and elimination with subsequent pharmacokinetic toxicity. These factors form the basis for the age’s increased risk for the development of cognitive problems from medications. [15]

Manifestations of cognitive toxicity:
As with many ADRs, a clear association between drug and cognitive disturbance can be difficult to definitively establish, particularly if the disturbance is subtle and if the impairment is in fact multifactorial in origin. Acute confusional states (delirium) have been most clearly documented by clinical report, but dementia has also been shown to be a presentation of drug toxicity. Delirium is characterized by disturbed consciousness with reduced ability to focus, sustain, or shift attention. Onset is usually rapid with fluctuations in levels of impairment over the course of a day. Such patients also frequently exhibit confusion, agitation, delusions, and/or hallucinations. Many medications have been reported to cause delirium, such as those with anticholinergic activity, as well as opioids, sedatives, anxiolytics, and others. It is also important to recall that withdrawal from some sedative-hypnotics and anxiolytics, has also been reported to precipitate delirium.

Dementia associated with medication use involves multiple cognitive deficits, including memory impairment with accompanying deficits in speech, recognition, motor and sensory ability, or other executive functions (such as planning, organizing, or abstracting). Onset is generally insidious, and progression is slow. Drug treatment may not be ongoing at the time the condition is identified, but, in general, has previously been prolonged and intensive. Sedative-hypnotics, anxiolytics, anticonvulsants, and intrathecal methotrexate have all been reported to cause dementia.[17]

Investigators examining the effect of particular drugs in controlled settings are able to assess less global or drastic, but still definitive effects by using formal testing to measure effects on memory, attention/concentration, reaction time, and executive function in relation to drug exposure. For example, impairment of mental skills in older subjects has been found to be greater and more persistent than in younger subjects following administration of some benzodiazepines, such as triazolam and alprazolam .Some data suggest that the aged are more sensitive to the effects of any given plasma level of these drugs. Similarly, cognitive decrements have been measured following oxybutynin and diphenhydramine .These deficits can be assessed using various methods such as arithmetic calculation, digit recognition, simple reaction time, and the digit symbol substitution test.

Sedating drugs can clearly impair awareness of hazards and diminish reaction time, and overall sedation and reaction time have been recognized as two potentially important factors in falls.

An anticholinergic drug administered to an aged person, for example, blocks postsynaptic acetylcholine receptors in a CNS that already has compromised cholinergic system activity. The result can be confusion, disorientation, and memory loss, which would not occur in a younger person with more baseline acetylcholine neurotransmission.[18]

Drug classes implicated in the concurrence of cognitive toxicity:
The following drugs or drug classes have been implicated in the concurrence of cognitive toxicity:
Selegiline:The most frequent problems include delirium, hallucinations, agitation, and overall sedation.

2. L-dopa: Used as a sole agent or in combination with carbidopa, a variety of cognitive problems have been reported to be associated with its use.

3. Amantadine:Used as an antiviral as well as in Parkinson’s disease, therapy has been linked to suicide attempts in patients with and without previous psychiatric problems. These patients exhibit a variety of abnormal mental states, including confusion, depression, paranoia, personality changes, and aggressive behavior. In aging populations, where its use would most likely occur, clearance is reduced and plasma levels are higher at standard doses.

4. Phenytoin:The CNS is the most common site of toxicity, which appears to be dose-related, but can occur even within the usual effective serum concentration  range of 40 to 79 µmol/L. Confusion as well as speech and coordination difficulties are common.

5. Digoxin: Some data indicate that this drug ranks first in the number of prescriptions made out to the elderly in the US. A spectrum of CNS-related effects can occur, including depression and anxiety as well as confusion and delirium with hallucinations. Such symptoms may appear in the absence of cardiac toxicity and at therapeutic plasma levels (0.6–2.6 nmol/L). Clearance of digoxin correlates with renal function as determined by creatinine clearance, which generally declines with age.

6. Alpha Blockers: Symptoms ranging from depression to memory disturbances and pseudodementia have been attributed to individual drugs, including propranolol and local use of timolol in glaucoma.

7. Lidocaine: Symptoms ranging from confusion to delirium are common manifestations of toxicity.

8. Antibiotics: Penicillins, cephalosporins, quinolones, and imipenem/cilastatin have all been shown to cause cognitive disturbances, particularly at high doses in renal insufficiency, severely ill patients, and/or patients with increased blood–brain barrier permeability. Quinolones such as ciprofloxacin can cause events such as anxiety and agitation, while imipenem can precipitate confusion (as well as convulsions).

9. Corticosteroids:Particularly at higher doses, drugs such as prednisone can precipitate psychosis. Memory and attention deficits have also occurred during chronic therapy.

10. Immunochemotherapy: Both interferon-alpha and interleukin-2 have been linked with serious depression.

11. Opiate analgesic: Symptoms ranging from overt sedation to depression and delirium have occurred with many of the narcotics and vary with the clinical setting (postoperative vs. chronic pain management). Some investigators feel that meperidine may be more likely to cause symptoms because of the anticholinergic nature of its metabolite, normeperidine.[19]

Therapeutic implication of Neurotransmitter deficits:
1. Acetylcholine precursors:

1. Choline oral source: Natural food contains little choline salts most is found as lecithin in eggyolk, meat, fish and soyabean oil. Lecithin (phosphatidyl choline).
2. Inhibition of acetylcholine hydrolysis: Physostigmine(esterase blocker), Centrally acting AchE inhibitor: improves long term memory and reverse the scopolamine induced memory deficiency.[21]

2. Direct Cholinegic agonists: Arecholine.

3. Noradrenegic Agonists:
1. Levodopa
2. Ritalin
3. Metrazol
4. Adrafinil
5. modafinil :  medications improving alertness
(Ritalin and metrazol causes adrenergic “mood elevation”)

4. Other Neuromodulating drugs for cerebral aging:
1. Hydergine (6mg):It has high affinity for NA receptors in brain causing increase in Cyclic AMP at receptor level relating improve in metabolic functioning of brain cells. Also increases cerebral blood flow. Indicated for mild to moderate dementia. Improves cognitive functions, self care abilities, motivation and mood disorders   in elders.[22]
2. Nootrophil: Cyclic derivative of GABA. Increase energy stores in the brain and promotes interhemispheric transfer of information.
3. Vasopressin: First neuropeptide used for improving cognitive functions in elders. Nasal Spray used for amnesic and demented patients. Act by stimulation of ACTH secretion which in turn improves attention arousal system of elderly. Causes release of other peptide modulators too e.g. endorphins.[23]

Figure.4: Potential physiological pathways to Alzheimer’s Disease, APOE, apolipoprotein E , CSF , PET, fMRI .[24]

Figure.5: Typical clinical course current and future therapeutic. AACD, age- associated cognitive decline; AD, Alzeimer's disease; MCI, mild congitive impairment.

Table showing possible drug therapy for the particular neurological disorder characterized by the reason behind:[25]

Ayurvedic Treatment:
1. Brahmihelps to dilate the cerebral blood vessels improving circulation to the brain.
2. Bacopa, bhringaraj and shankhapushpihelp enhance mental performance and promote    intelligence.[26]
3. Nasya oilhas been used for centuries to improve voice, vision and bring clarity of Mind.
4. Tulsi tailam, use on scalp and having 3-5 leaves of the “wonder drug” is may prove benificial in Neurocognitive disorders.[27]

Non Pharmacological treatment:
Treatment includes providing older adults with memory supports that bypass the need to encode items actively or deliberately, thus lessening the executive processing requirements of the tasks.

Specific examples in which environmental supports have effectively repaired the memory of older adults include:
1. Using matching picturesto support memory for sentences, resulting in dramatically better memory in older adults (probably due to dual coding of the material) and
2.Providing older adults with memory cuesthat are conceptually related to target words, resulting in larger memory improvements for the words in the old compared with the young.[28]

Further practice of Yoga is the beneficial part to revive the dead cells and potential of body efficiently. Utilizing Brahamri Pranayam is one of best possible outcome to be in future since it revitalizes the neuronal cells by vibration(OM) lead to their utmost efficiency and thus the age related cognitive decline can be combated.

Proper lifestyle, the healthy one will lead to the normal aging (the rule of life-aging-death) without impairing the cognitive actions to large extent. So, advisable part is to stop using tobacco, have a nice breath full of oxygen to revitalize the cells of body, perform yoga and exercise.


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