Selegiline selectively inhibits the MAO_B enzyme in the brain that is normally responsible for the degradation of dopamine (see Fig. 5.3). By reducing the catabolism of dopamine, the actions of l-dopa are potentiated, thus allowing the dose to be reduced by up to a third. There is evidence to suggest that selegiline may slow the progression of the underlying neuronal degeneration in Parkinson’s disease.

Route of administration

Oral.

Indications

MAO_B inhibitors can be used on their own in mild cases of parkinsonism or in conjunction with l-dopa to reduce ‘end-of-dose’ deterioration in severe parkinsonism.

Adverse effects

The adverse effects of MAO_B inhibitors are those that might be expected by potentiation of l-dopa.

Hints and Tips

Note that with the possible exception of selegiline, none of the drugs used in Parkinson’s disease affect the inevitable progressive degeneration of nigrostriatal dopaminergic neurons. The disease process is unaffected, just compensated for by drug therapy.

Communication

Mrs Patches, a 62-year-old barrister, presents to her GP complaining of shaking arms, the right arm more prominently so than the left. She notes that alcohol does not help to steady the shaking and that people at work have started complaining about her handwriting becoming too small to read. She also mentions her body muscles have been feeling rather stiff.

She is referred to a neurologist, who observes her face to be expressionless, a resting tremor and increased muscle tone. Her power, reflexes, coordination and sensation are found to be normal. Examination of her gait shows she is slow getting started and has difficulty stopping and starting.

A diagnosis of Parkinson’s disease is made and the implications discussed with Mrs Patches. She returns 3 months later and says she now wishes to commence treatment; she has the same symptoms as before, however, they are interfering more with her daily life. She is given co-beneldopa and this helps to control her symptoms.

Drugs that inhibit striatal cholinergic activity

Anticholinergic agents

Benzatropine, procyclidine and orphenadrine are examples of anticholinergic (antimuscarinic) agents.

Mechanism of action

Benzatropine, procyclidine and orphenadrine are antagonists at the muscarinic receptors that mediate striatal cholinergic excitation (see Fig. 5.3). Their major action in the treatment of Parkinson’s disease is to reduce the excessive striatal cholinergic activity that characterizes the disease.

Route of administration

Oral.

Adverse effects

Typical peripheral anticholinergic effects, such as a dry mouth and blurred vision, are less common. More often, patients experience a variety of CNS effects, ranging from mild memory loss to acute confusional states.

Therapeutic notes

Termination of anticholinergic treatment should be gradual, as parkinsonism can worsen when these drugs are withdrawn. Anticholinergic drugs are most effective in controlling tremor rather than other symptoms of Parkinson’s disease.

Transplantation

The transplantation of cells from the substantia nigra of human fetuses into the putamen of patients with Parkinson’s disease has shown some success in controlling parkinsonian symptoms.

Transplantation in the treatment of Parkinson’s disease is still experimental, and its role is highly controversial.

Dementia

Alzheimer’s disease is a specific process that results in dementia and is unrelated to the dementias associated with stroke, brain trauma and alcohol. Its prevalence increases markedly with age.

Alzheimer’s disease is progressive and it is associated with atrophy of the brain substance, loss of neuronal tissue and deposition of amyloid plaques. The clinical features include deterioration in cognitive function, disorientation and generalized confusion.

Loss of neurons in the forebrain is most marked and a relative selective loss of cholinergic neurons most likely accounts for the features of this dementia. The obvious therapeutic target is, therefore, restoration of cholinergic function.

Anxiety and sleep disorders

Anxiety and anxiolytics

Anxiety is a state characterized by psychological symptoms such as a diffuse, unpleasant and vague feeling of apprehension, often accompanied by physical symptoms of autonomic arousal such as palpitations, light-headedness, perspiration, ‘butterflies’ and, in some people, restlessness.

While occasional anxiety is perfectly normal, it is a common and disabling symptom in a variety of mental illnesses including phobias, panic disorders and obsessive compulsive disorders. Drugs used to treat such anxiety disorders are called anxiolytics.

Sleep disorders and hypnotics

Insomnia is a common and non-specific disorder that may be reported by 40–50% of people at any given time.

Causes of insomnia include medical illness, alcohol or drugs, periodic limb movement disorder, sleep apnoea and psychiatric illness. Without an obvious underlying cause, it is known as primary or psycho-physiological.

Hypnotics are drugs used to treat psycho-physiological (primary) insomnia. The distinction between the treatment of anxiety and that of sleep disorders is not clear-cut, particularly if anxiety is the main impediment to sleep.

γ-Aminobutyric acid receptor

The γ-aminobutyric acid (GABA) receptors of the GABA_A type are involved in the actions of some classes of hypnotic/anxiolytic drugs, notably:

• The benzodiazepines, which are currently the most commonly used clinically

• Newer non-benzodiazepine hypnotics, e.g. zopiclone

• The now obsolete barbiturates.

The GABA_A receptor belongs to the superfamily of ligand-gated ion channels. It consists of several subunits – α, β, γ and δ – which form the GABA/Cl^– channel complex, as well as containing benzodiazepine and barbiturate modulatory receptor sites. The GABA binding site appears to be located on the α and β subunits whereas the benzodiazepine modulatory site is distinct and located on the γ subunit.

GABA released from nerve terminals binds to postsynaptic GABA_A receptors, the activation of which increases the Cl^– conductance of the neuron. Occupation of the benzodiazepine sites by benzodiazepine receptor agonists enhances the actions of GABA on the Cl^– conductance of the neuronal membrane. The barbiturates similarly enhance the action of GABA, but by occupying a distinct modulatory site (Fig. 5.4).

Fig. 5.4 Diagrammatic representation of the GABA_A receptor and how its activity is enhanced by benzodiazepines and similarly by barbiturates. (BDZ, benzodiazepine; Cl^–, chloride ion; GABA, γ-aminobutyric acid.)

(Redrawn from Page et al. 2006.)

Anxiolytic and hypnotic drugs

The pharmacotherapy of anxiety and sleep disorders involves several different classes of drug, as shown in Figure 5.5, and non-pharmacological management relying on cognitive and behaviour psychotherapy.

Fig. 5.5 Drugs used to treat anxiety and sleep disorders

Benzodiazepines

Benzodiazepines are drugs with anxiolytic, hypnotic, muscle relaxation and anticonvulsant actions that are used in the treatment of both anxiety states and insomnia.

Benzodiazepines are marketed as either hypnotics or anxiolytics. It is mainly the duration of action that determines the choice of drug (see below).

Mechanism of action

Benzodiazepines potentiate the action of GABA, the primary inhibitory neurotransmitter in the CNS. They do this by binding to a site on GABA_A receptors, increasing their affinity for GABA. This results in an increased opening frequency of these ligand-gated Cl^– channels, thus potentiating the effect of GABA release in terms of inhibitory effects on the postsynaptic cell (Fig. 5.4).

Indications

Benzodiazepines are used clinically in the short-term relief of severe anxiety and severe insomnia, preoperative sedation, status epilepticus and acute alcohol withdrawal.

Route of administration

Oral is the usual route. Intravenous, intramuscular and rectal preparations are available.

Contraindications

Benzodiazepines should not be given to people with bronchopulmonary disease, and they have additive or synergistic effects with other central depressants such as alcohol, barbiturates and antihistamines.

Adverse effects

Benzodiazepines have several adverse effects:

• Drowsiness, ataxia and reduced psychomotor performance are common; therefore, care is necessary when driving or operating machinery.

• Dependence becomes apparent after 4–6 weeks, and is both physical and psychological. The withdrawal syndrome (in 30% of patients) comprises rebound anxiety and insomnia, tremulousness and twitching.

Although in overdose benzodiazepines alone are relatively safe when compared with other sedatives, such as barbiturates, if benzodiazepines are taken in combination with alcohol the CNS-depressant effects are potentiated and fatal respiratory depression can result. Treatment is with the benzodiazepine antagonist flumazenil.

Therapeutic notes

Benzodiazepines are active orally, and they differ mainly in respect of their duration of action (Fig. 5.6). Short-acting agents (e.g. lorazepam and temazepam) are metabolized to inactive compounds, and these are used mainly as sleeping pills because of the relative lack of ‘hangover’ effects in the morning. Some long-acting agents (e.g. diazepam) are converted to long-lasting active metabolites with a half-life longer than the administered parent drug. With others (e.g. nitrazepam) it is the parent drug itself that is metabolized slowly. Such drugs are more suitable for an anxiolytic effect maintained all day long, or when early morning waking is the problem.