emotional control, social behaviour or motivation may accompany or precede cognitive impairment. Alzheimer's and vascular (multi-infarct) disease are the two most common forms of dementia, accounting for about 80% of presentations. Alzheimer's disease is associated with deposition of beta-amyloid in brain tissue and abnormal phosphorylation of the intracellular tau proteins, causing abnormalities of microtubule assembly and collapse of the cyto-skeleton. Pyramidal cells of the cortex and subcortex are particularly affected.

In Western countries, the prevalence of dementia is below 1% in those aged 60-64 years, but it doubles with each 5-year cohort to a figure of around 16% in those aged 80-84 years. The emotional impact of dementia on relatives and carers and the cost to society in social support and care facilities are great. Hence the impetus for an effective form of treatment is compelling.

Evidence indicates that cholinergic transmission is diminished in Alzheimer's disease. All agents that benefit the condition act to enhance acetylcholine activity by inhibition of the acetylcholinesterase which metabolises and inactivates synaptically-released acetylcholine. Consequently acetylcholine remains usable for longer. Individual drugs are categorised by the type of enzyme inhibition they cause. Donepezil is classed as a 'reversible' agent as binding to the acetylcholinesterase enzymes lasts only minutes, whereas rivastigmine is considered 'pseudo-irreversible' since inhibition lasts several hours. Galantamine is associated both with reversible inhibition and with enhanced acetylcholine action on nicotinic receptors.8 Clinical trials show that these agents produce an initial increase in patients' cognitive ability. There may be associated global benefits, including improvements in non-cognitive aspects such as depressive symptoms. But the drugs do not alter the underlying process, and the relentless advance of the disease is paralleled by reduction in acetylcholine production with decline in cognition.

6 Alois Alzheimer (1864-1915) German psychiatrist who studied the brains of demented and senile patients and correlated hisological findings with clinical features.

7ICD-10 diagnostic system.

8 Irreversible antagonists exist but, not surprisingly, have no place in therapeutics (sarin nerve gas is an example).

The beneficial effects of drugs are therefore to:

• stabilise the condition initially and sometimes improve cognitive function,

• delay the overall pace of decline (and therefore the escalating levels of support required),

• postpone the onset of severe dementia.

The severity of cognitive deficits in patients suffering from, or suspected of having, dementia can be quantified by a simple 30-point schedule, the mini mental-state examination (MMSE) of Folstein. A score of 21-26 denotes mild, 10-20 moderate and less than 12 severe Alzheimer's disease. The MMSE can also be used to monitor progress.

Given the limited evidence of overall benefit in relation to cost, the use of these drugs is the subject of debate but there follows a practical position.

The UK National Institute for Clinical Excellence (NICE) recommends that donepezil, galantamine and rivastigmine should be available as adjuvant therapy for those with a MMSE score above 12 points, subject to the following conditions:

• Alzheimer's disease must be diagnosed and assessed in a specialist clinic; the clinic should also assess cognitive, global and behavioural functioning, activities of daily living, and the likelihood of compliance with treatment

• treatment should be initiated by specialists but may be continued by general practitioners under a shared-care protocol

• the carers' views of the condition should be sought before and during drug treatment

• the patient should be assessed 2-4 months after maintenance dose is established; drug treatment should continue only if MMSE score has improved or has not deteriorated and behavioural and functional assessment shows improvement

• the patient should be assessed every 6 months and drug treatment should normally continue only if MMSE score remains above 12 points and if treatment is considered to have a worthwhile effect on the global functional and behavioural condition.

donepezil 5-10 mg nocte increasing to 10 mg nocte after one month, galantamine 4 mg b.d. increasing to 8-12 mg b.d. at

4 weekly intervals, rivastigmine 1.5 mg b.d. increasing to 3-6 mg b.d. at intervals of 2 weeks.

Adverse effects inevitably include cholinergic symptoms with nausea, diarrhoea and abdominal cramps appearing commonly. There may also be bradycardia, sinoatrial or atrioventricular block. Urinary incontinence, syncope, convulsions, and psychiatric disturbances also occur. Rapid dose increase appears to make symptoms more pronounced. Hepatotoxicity is a rare association with donepezil.

The deterioration of function in dementia of Alzheimer's disease is often accompanied by acute behavioural disturbance and the development of a range of psychotic symptoms. Therapy with atypical drugs is then preferred because they provoke fewer adverse effects than classical antipsychotics.

Other substances that are being evaluated in Alzheimer's disease include the antioxidant vitamin E, the monoamine oxidase type B inhibitor, selegeline (see p. 425) and the plant extract gingko biloba, which is though to have antioxidant and cholinergic activity. Oestrogens and nonsteroidal anti-inflammatory agents may also have protective effects.

each of the three principal symptoms. It should be initiated only by a specialist in these conditions and should form part of a comprehensive treatment programme of psychological, educational and social measures. Periodic breaks in treatment once symptoms have been stabilised ('drug holidays') are recommended to allow expected improvement in function to be quantified.

Unwanted effects include anxiety, anorexia and difficulty sleeping, which usually subside. Methyl-phenidate reduces expected weight gain and has been associated with slight growth retardation. Monitoring of therapy should include height and weight, also blood pressure and blood counts (thrombocytopenia and leucopenia occur).

Methylphenidate should be avoided in children with Tourette's syndrome or where there is a family history of this disorder. Thyroid disease is also a contraindication.

Dexamfetamine is an alternative for it has similar efficacy in ADHD. Unwanted effects and contraindications are broadly similar to those of methylphenidate. Dexamfetamine is the preferred drug in children who also have epilepsy. It has a greater potential for abuse.

Clonidine, tricyclic antidepressants and antipsychotic agents (e.g. risperidone, sulpiride) may have a role in ADHD where methylphenidate and dexamfetamine are contraindicated or have failed to produce benefit.

Drugs in attention deficit/ hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, impulsivity and motor overactivity, present before the age of 7 years, and causing pervasive impairment across situations as opposed to occurring only at school or within the home. Some diagnostic systems use the narrower definition of hyperkinetic disorder rather than ADHD. Hyperkinetic disorder is reported to affect 1-2% of school-aged children in the United Kingdom and ADHD 5%.

Methylphenidate (see above) is effective in children with ADHD and hyperkinetic disorder, reducing

Drugs and skilled tasks

Drugs can affect skilled tasks and car driving, and it is convenient to consider the implications of this broad issue.

Many medicines affect performance, not only psychotropic drugs9 (amongst which sedative antidepressants, benzodiazepines, hypnotics and antipsychotics are the most obvious examples) but also antihistamines, antimuscarinics, analgesics including some NSAIDs, (e.g. indomethacin), antiepileptics, antidiabetics (hypoglycaemia) and some antihypertensives. Alcohol and cannabis are discussed on pages 178 and 190.

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