Drugs are used to treat neurodegenerative disorders, anxiety, psychosis, depression, epilepsy and pain.
Neurodegenerative Disorders
The very limited capacity of neurons to divide and re-establish synaptic contacts means that neuronal death in the central nervous system (CNS) produces largely irreversible changes in brain function. The main neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease (PD); less common are Huntington’s chorea and motor neuron diseases (amyotrophic lateral sclerosis); prion diseases, such as variant Creutzfeldt-Jakob disease, are less common still. Another major cause of neuronal death is the acute brain ischaemia resulting from a stroke.
Many neurodegenerative diseases are associated with protein misfolding and aggregation, believed to be the first step leading to neurodegeneration. Mechanisms are not clear, but misfolded proteins can be toxic and lead to neuronal cell death. Examples are provided in Table 12.1 .
| Disease | Protein | Characteristic pathology | Notes |
|---|---|---|---|
| Alzheimer’s disease | β-Amyloid (Aβ) | Amyloid plaques | Aβ mutations occur in rare familial forms of Alzheimer’s disease |
| Tau | Neurofibrillary tangles | Implicated in other pathologies (‘tauopathies’) as well as Alzheimer’s disease | |
| Parkinson’s disease | α-Synuclein | Lewy bodies | α-Synuclein mutations occur in some types of familial Parkinson’s disease |
| Creutzfeldt-Jakob disease | Prion protein | Insoluble aggregates of prion protein | Transmitted by infection with prion protein in its misfolded state |
| Huntington’s disease | Huntingtin | No gross lesions | One of several genetic ‘polyglutamine repeat’ disorders |
| Amyotrophic lateral sclerosis (motor neuron disease) | Superoxide dismutase | Loss of motor neurons | Mutated superoxide dismutase tends to form aggregates; loss of enzyme function increases susceptibility to oxidative stress |
∗ Protein aggregation disorders are often collectively known as amyloidosis and commonly affect organs other than the brain.
Mechanisms of neurodegeneration
Excitotoxicity
This is neuronal damage produced by disproportionate action of the excitatory neurotransmitter glutamate. High concentrations of glutamate cause an excessive elevation of calcium ions [Ca 2+ ] i which leads to membrane damage and cell death ( Fig.12.1 ).
Oxidative stress
This results from the generation of reactive oxygen species following inflammatory insults or ischaemia (reactive oxygen species (ROS): oxygen and hydroxyl free radicals) which can damage proteins, membrane lipids and nucleic acids. Elevations of ROS are normally prevented by antioxidants such as glutathione and vitamins C and E and the activities of superoxide dismutase (SOD) and catalase. However, it seems that, in neurodegenerative diseases, these defence mechanisms can be overwhelmed.
Apoptosis
Programmed cell death is frequently associated with excitotoxicity. Neural apoptosis is normally prevented by neuronal growth factors such as nerve growth factor and brain-derived neurotrophic factor.
Potential drug targets to reverse neurodegeneration
These might include elements of the excitotoxic glutamate cascade: Ca 2+ entry, intracellular protease activation, free radical damage, the inflammatory response and membrane repair. Furthermore, neuroprotective strategies to induce neuro-regeneration (i.e. reverse apoptosis) might be employed.
Stroke
Brain ischaemia, usually due to thrombosis, leads to rapid cell death in the hypoxic area followed by a slower neurodegeneration in adjacent areas. The ischaemia causes depolarization of neurons, which leads to release of glutamate and the consequences shown in Fig. 12.1 . At present, there are few effective drugs available. If given soon after the vascular occlusion, fibrinolytics (tissue plasminogen activators; e.g. alteplase (see Ch. 15 )) can improve blood flow and reduce further damage; however, they can make matters worse if the stroke is due to haemorrhage rather than clot formation.
Parkinson’s Disease
Patients with PD have tremor at rest, muscle rigidity and difficulty in performing voluntary movements (hypokinesia).
Pathogenesis
The motor symptoms of PD are due to a specific loss of dopaminergic neurons in the nigrostriatal pathway, which forms an essential link in the extrapyramidal motor system involved in fine motor control. Excessive activity of the intrinsic cholinergic fibres of the striatum (unchecked by dopamine) is probably implicated in the tremor. An imbalance between the two systems is thought to be a key factor in PD. The damage to the dopaminergic neurons is caused by excitotoxicity, oxidative stress and apoptosis. Mitochondrial abnormalities have been detected in PD. (Mitochondrial effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of meperidine, are responsible for a PD-like condition induced in a number of abusers of this drug.) PD-like symptoms may be produced, as one might expect, by dopamine receptor antagonists. The pathways that are affected in PD are shown in Fig. 12.2 .
In PD, the destruction of dopaminergic fibres projecting from the substantia nigra to the corpus striatum impairs the fine control of movement exerted by the basal ganglia. This is exacerbated by a resulting enhancement in the action of striatal cholinergic neurons.
Treatment of PD
Drugs used to treat PD act by:
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redressing the loss of dopamine ( levodopa or dopamine receptor agonists, e.g. bromocriptine );
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reducing the unbalanced action of acetylcholine in the striatum (muscarinic receptor antagonists, e.g. benztropine);
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inhibiting the breakdown of dopamine in CNS neurons with monoamine oxidase-B (MAO-B) inhibitors ( selegiline );
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releasing dopamine ( amantadine ).
None of the above actions halt the progression of the disease. Drugs affecting the dopaminergic system are shown in Fig. 12.3 .
Levodopa (l-dopa)
Levodopa is the main treatment for PD.
Actions and mechanism of action
Levodopa is decarboxylated to dopamine either within surviving nigrostriatal fibres or in other monoaminergic neurons and provides some restoration of nigrostriatal pathway activity. It is more effective against the akinesia and rigidity than against the tremor. The MAO-B inhibitor selegiline reduces the breakdown of dopamine in the brain and may enhance the action of levodopa. Combining entacapone (a catechol- O -methyltransferase (COMT) inhibitor) with levodopa can improve the response.
Pharmacokinetic aspects
Levodopa is given orally and is well absorbed. It crosses the blood–brain barrier by active transport and has a half-life of approximately 2 h.
Unwanted effects
These include an acute schizophrenia-like syndrome related to an increase in dopamine concentrations and, more commonly, confusion, disorientation and insomnia or nightmares. More slowly developing effects include dyskinesia (uncontrolled movements, which occur in most patients after 2 years) and ‘on-off’ effects, which are rapid fluctuations between dyskinesia and hypokinesia/rigidity. Outside the CNS, levodopa is converted to dopamine, which causes the unwanted peripheral side effects: postural hypotension and nausea. The latter is due to stimulation of the chemoreceptor trigger zone and can be reduced by co-administration of the dopamine antagonist domperidone, whose action is confined to the periphery. These peripheral side effects can be reduced by combining levodopa with a peripheral dopa decarboxylase inhibitor such as carbidopa or benserazide. These not only decrease the production of dopamine in the periphery but also substantially reduce the required dose of levodopa.
Dopamine receptor agonists
The dopamine receptor agonists bromocriptine , lisuride and pergolide have varying agonist activities on D 1 , D 2 and D 3 receptors and can be used in place of, or as adjuncts to, levodopa. (Both D 1 and D 2 receptors are involved in the regulation of motor activity by the striatum.) They have similar side effects to levodopa.
Amantadine
Amantadine, an antiviral agent, also has a useful action in PD, possibly attributable to an increase in neuronal release of dopamine. It is less effective than levodopa or bromocriptine.
MAO-B inhibitors
Inhibition of MAO-B protects dopamine from extra neuronal degradation and MAO-B inhibitors may therefore be used with levodopa. However, Selegiline is metabolized to amphetamine, and may cause excitement, anxiety and insomnia. Rasagiline does not have this side effect and it is thought it might be neuroprotective, slowing disease progression. Safinamide inhibits both MAO-B and dopamine reuptake.
Muscarinic receptor antagonists
Muscarinic antagonists decrease the tremor of PD. The drugs used (e.g. benztropine and trihexyphenidyl (benzhexol)) show some CNS selectivity. Apart from the predictable effects due to antagonizing acetylcholine (ACh) in peripheral parasympathetic nerves, this drug class can have troublesome side effects in elderly patients such as sedation and confusion.
Alzheimer’s Disease
This age-related dementia is associated with a loss of neurons and shrinkage of brain tissue, particularly in the hippocampus and basal forebrain. Amyloid plaques and neurofibrillary tangles characterize the condition, leading to the selective loss of cholinergic fibres (in basal forebrain nuclei) that is thought to be a key factor.
Anticholinesterase drugs have a modest efficacy with predictable parasympathomimetic side effects, but do not retard or reverse disease progression. The drugs used are tacrine (short acting and can be hepatotoxic), donepezil (rather more effective and causes less liver damage), rivastigmine (fewer parasympathomimetic effects and longer lasting), and galantamine (may work partly by allosteric activation of CNS nicotinic receptors). Memantine , an N-methyl-D-aspartate (NMDA) receptor antagonist, provides some benefit probably by reducing excitotoxicity.
Other Neurodegenerative Diseases
Huntington’s disease is inherited (autosomal dominant) resulting in progressive brain degeneration and death in adults through protein misfolding of Huntington protein. Prion diseases such as Creutzfeldt-Jakob disease are transmissible through an infective agent (a prion) that causes protein misfolding (see Table 12.1 ).
Anxiety and Hypnosis
Anxiolytics are used to treat acute anxiety states. Hypnotics are drugs used to treat insomnia.
Anxiety is characterized by psychological symptoms such as nervousness and feelings of foreboding, accompanied by a variety of physical symptoms such as agitation, palpitations, sweating, sleeplessness and gastrointestinal (GI) tract disturbances. It can be a normal appropriate reaction to disturbing events but can in some circumstances be pathological and disabling, particularly if associated with panic attacks, phobic states or obsessive-compulsive disorders (OCDs). Many anxiety states, especially in the long term, may be better treated with antidepressants (e.g. the selective serotonin reuptake inhibitors (SSRIs) such as paroxetine).
Insomnia is difficulty in sleeping and may result from anxiety.
Both anxiety states and insomnia can be treated with CNS depressant drugs, which have effects that range from anxiolytic at low concentrations, to sedation and sleep at higher concentrations, to anaesthesia and, in toxic doses, coma and respiratory depression. However, some sedative and hypnotic drugs are ineffective in anxiety states.
The main drugs used are benzodiazepines, 5-hydroxytryptamine (5-HT) 1A receptor agonists and β-adrenoceptor antagonists. H 1 receptor antagonists (e.g. promethazine) may sometimes be used as hypnotics.
Benzodiazepines
Benzodiazepines have related chemical structures (e.g. clonazepam, diazepam, lorazepam ) and are the most important and widely used anxiolytics and hypnotics.
Pharmacological actions
Benzodiazepines cause:
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a decrease in anxiety (less effective in obsessional states),
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a sedative effect,
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the induction of sleep,
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a reduction in muscle tone,
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an anticonvulsant effect.
The onset of their action is generally rapid. In general, most benzodiazepines exhibit similar pharmacological actions and choice is made mainly on the basis of duration of action. Shorter-acting agents are preferred as hypnotics to avoid sedative actions throughout the day. Table 12.2 gives a selection from the large number of benzodiazepines available.
| Drug | Half-life | Main uses |
|---|---|---|
| Midazolam | Short (<10 h) | Premedication, induction |
| Zolpidem a | Short | Hypnotic (not anxiolytic) |
| Oxazepam | Short | Anxiolytic |
| Nitrazepam | Medium (10–24 h) | Hypnotic |
| Temazepam | Medium | Hypnotic |
| Flunitrazepam | Medium | Hypnotic, jet lag |
| Lorazepam | Medium | Anxiolytic, premedication |
| Alprazolam | Medium | Anxiolytic, panic disorder |
| Clonazepam | Long (>24 h) | Epilepsy |
| Diazepam | Long b | Anxiolytic, premedication, status epilepticus |
| Chlordiazepoxide | Long b | Anxiolytic |
b Long action due to slowly metabolized active metabolite. The drugs are also used in the treatment of spasticity and withdrawal from alcohol dependence.
Mechanism of action
Benzodiazepines act by binding to distinct ‘benzodiazepine regulatory sites’ on γ-aminobutyric acid (GABA) A receptors to enhance the action of GABA, effectively increasing its affinity for its site on GABA-activated chloride (Cl – ) channels ( Fig. 12.4 ; see Chapter 11 ). The increase in affinity is manifest as a shift of the GABA log dose–response curve to lower concentrations. The overall action of the benzodiazepines on the CNS is to produce a general enhancement of the neuroinhibitory actions of GABA. The actions at the GABA A receptor of benzodiazepines, competitive antagonists, such as flumazenil, and inverse agonists are shown in Fig. 12.5 . Flumazenil can be used to treat an overdose of benzodiazepine.
