B978-0-7234-3630-0.00005-4, 00005 Central nervous system 5 Objectives After reading this chapter, you will: ● Understand the functions of the central nervous system and the diseases that can occur ● Know the drug classes used to treat these conditions, their mechanisms of action and adverse effects. Parkinson’s disease is progressive, with continued BASIC CONCEPTS loss of dopaminergic neurons in the substantia nigra correlating with worsening of clinical symptoms. The The central nervous system consists of the brain and the possibility of a neurotoxic cause has been strengthe- spinal cord, which are continuous with one another. ned by the finding that 1-methyl-4-phenyl-1,2,3, The brain is composed of the cerebrum (which consists 6-tetrahydropyridine (MPTP), a chemical contaminant of the frontal, temporal, parietal and occipital lobes), of heroin, causes irreversible damage to the nigrostriatal the diencephalon (which includes the thalamus and dopaminergic pathway. Thus, this damage can lead hypothalamus), the brainstem (which consists of the mid- to the development of symptoms similar to those of brain, pons and medulla oblongata) and the cerebellum. idiopathic Parkinson’s disease. Drugs that block The brain functions to interpret sensory information dopamine receptors can also induce parkinsonism. obtained about the internal and external environments Neuroleptic drugs (p. 000) used in the treatment of TS1 and send messages to effector organs in response to a schizophrenia can produce parkinsonian symptoms as situation. Different parts of the brain are associated an adverse effect. Rare causes of parkinsonism are cere- with specific functions (Fig. 5.1). However, the brain is a bral ischaemia (progressive atherosclerosis or stroke), complex organ and is not yet completely understood. viral encephalitis or other pathological damage. PARKINSON’S DISEASE HINTS AND TIPS AND PARKINSONISM RATS in the parking lot! Symptoms of parkinsonism include Rigidity, Akinesia, Tremor and Shuffling gait. Parkinsonism is characterized by a resting tremor, slow initiation of movements (bradykinesia), and muscle rigidity. A patient with parkinsonism will present with Pathogenesis characteristic signs including: • A shuffling gait Post-mortem analysis of brains of parkinsonian pati- • A blank ‘mask-like’ facial expression ents shows a substantially reduced concentration of • Speech impairment dopamine (less than 10% of normal) in the basal • An inability to perform skilled tasks. ganglia. The basal ganglia exert an extrapyramidal neural influence that normally maintains smooth Parkinsonism is most commonly caused by Parkinson’s voluntary movement. disease, though other causes exist. The main pathology in Parkinson’s disease is a pro- Parkinson’s disease is a progressive neurological gressive degeneration of the dopaminergic neurons of disorder of the basal ganglia that occurs most com- the substantia nigra, which project via the nigrostriatal monly in elderly people. pathway to the corpus striatum (Fig. 5.2). The inhibi- tory dopaminergic activity of the nigrostriatal pathway Aetiology is, therefore, considerably reduced (by 20–40%) in The cause of Parkinson’s disease is unknown in most people with Parkinson’s disease. cases (idiopathic) although both endogenous and The reduction in the inhibitory dopaminergic environmental neurotoxins are known to be responsi- activity of the nigrostriatal pathway results in unop- ble for causing parkinsonism. posed cholinergic neuron hyperactivity from the corpus © 2012 Elsevier Ltd. 69 DOI: 10.1016/B978-0-7234-3630-0.00005-4 Battista, 978-0-7234-3630-0 B978-0-7234-3630-0.00005-4, 00005 Central nervous system Fig. 5.1 Parts of the brain and their known functions. Untreated Parkinson’s eventually results in dementia and death. Treatment of parkinsonism The treatment of parkinsonism is based on correcting the imbalance between the dopaminergic and choliner- gic systems at the basal ganglia (Fig. 5.3). Two major groups of drugs are used: drugs that increase dopami- nergic activity between the substantia nigra and the corpus striatum, and anticholinergic drugs that inhibit striatal cholinergic activity. Drugs that increase dopaminergic activity Dopamine precursors An example of a dopamine precursor is levodopa (L-dopa). Fig. 5.2 Basal ganglia systems involved in Parkinson’s disease. Mechanism of action—L-dopa is the immediate (ACh, acetylcholine; DA, dopamine; GABA, g-aminobutyric precursor of dopamine and is able to penetrate the acid.) blood–brain barrier to replenish the dopamine content (Redrawn from Page et al. 2006.) of the corpus striatum. L-dopa is decarboxylated to dopamine in the brain by dopa decarboxylase, and it striatum, which contributes to the pathological features has beneficial effects produced through the actions of of parkinsonism. Frank symptoms of parkinsonism ap- dopamine on D2 receptors (see Fig. 5.3). Dopamine pear only when more than 80% of the dopaminergic itself is not used, owing to its inability to cross the neurons of the substantia nigra have degenerated. blood–brain barrier. 70 Battista, 978-0-7234-3630-0 B978-0-7234-3630-0.00005-4, 00005 Parkinson’s disease and parkinsonism 5 Fig. 5.3 Drugs used to treat parkinsonism and their site of action. (ACh, acetylcholine; DA, dopamine; L-dopa, levodopa; MAOB, monoamine oxidase B; COMT, catechol-O-methyl transferase.) the area postrema (p. 000), which lies outside the TS1 Route of administration—L-dopa is administered blood–brain barrier. orally. It reaches peak plasma concentrations after Psychiatric side-effects are common limiting factors 1–2 hours and only 1% reaches the brain, owing to in L-dopa treatment; these include vivid dreams, confu- peripheral metabolism. sion and psychotic symptoms more commonly seen in Indications—L-dopa is used in the treatment of schizophrenia. These effects are probably a result of parkinsonism (excluding drug-induced extrapyramidal increased dopaminergic activity in the mesolimbic area symptoms). of the brain, possibly similar to that found patho- Contraindications—Closed-angle glaucoma. logically in schizophrenia (dopaminergic overactivity Adverse effects—The extensive peripheral metabolism is implicated in schizophrenia, p. 000). TS1 of L-dopa means that large doses have to be given to Hypotension is common but usually asymptomatic. produce therapeutic effects in the brain. Large doses are Cardiac arrhythmias are due to increased catecholamine more likely to produce adverse effects. These include: stimulation following the excessive peripheral metabo- • Nausea and vomiting lism of L-dopa. • Psychiatric side-effects (schizophrenia-like symptoms) Dyskinesias can often develop and tend to involve • Cardiovascular effects (hypotension) the face and limbs. They usually reflect over-treatment • Dyskinesias. and respond to simple dose reduction. Nausea and vomiting are caused by stimulation of do- Three strategies have been developed to optimize pamine receptors in the chemoreceptor trigger zone in L-dopa treatment, to maximize the central effects of 71 Battista, 978-0-7234-3630-0 B978-0-7234-3630-0.00005-4, 00005 Central nervous system L-dopa within the brain, and minimize its unwanted produces profound nausea and vomiting. Ergot-derived peripheral effects. These strategies involve co-adminis- dopamine agonists (bromocriptine, cabergoline, lisuride tration of: and pergolide) can cause fibrosis. • Carbidopa (given with L-dopa as co-careldopa) or Therapeutic notes—Currently bromocriptine is the benserazide (given with L-dopa as co-beneldopa), most used of the dopamine agonists in the treatment inhibitors of dopa decarboxylase in the periphery, of Parkinson’s disease. that cannot penetrate the blood–brain barrier. Hence, extracerebral conversion of L-dopa to dopa- Drugs stimulating release of dopamine mine is inhibited. Amantadine is an example of a drug that stimulates the • Domperidone, a dopamine antagonist, that does release of dopamine (see Fig. 5.3). not penetrate the blood–brain barrier and can, Mechanism of action—Facilitation of neuronal dopa- therefore, block the stimulation of dopamine recep- mine release and inhibition of its reuptake into nerves, tors in the periphery. and additional muscarinic blocking actions. • Selegiline and entacapone, monoamine oxidase Route of administration—Oral. (MAO)B and catechol-O-methyltransferase (COMT) Indications—Amantadine has a synergistic effect inhibitors, respectively, which inhibit dopamine when used in conjunction with L-dopa therapy in degradation in the central nervous system (CNS). Parkinson’s disease. Therapeutic notes—Initially, treatment with L-dopa is Adverse effects—Anorexia, nausea, hallucinations. effective in 80% of patients with possible restoration of Therapeutic notes—Amantadine has modest antipar- near-normal motor function. Although L-dopa restores kinsonian effects, but it is only of short-term benefit, dopamine levels in the short term, therapy has no effect since most of its effectiveness is lost within 6 months on the underlying degenerative disease process. of initiating treatment. As progressive neuronal degeneration continues, the capacity of the corpus striatum to convert L-dopa to dopamine diminishes. This affects the majority of pa- MAOB inhibitors tients within 5 years and manifests itself as ‘end of dose Selegiline is an example of a MAOB inhibitor. deterioration’ (a shortening of duration of each dose of Mechanism of action—Selegiline selectively inhibits L-dopa), and the ‘on-off effect’ (rapid fluctuations in the MAOB enzyme