Pharmacology - An Illustrated Review
14. Treatment of Neurodegenerative Diseases
14.1 Parkinson Disease
Parkinson disease is a chronic, progressive, age-related neurodegenerative disease resulting from loss of dopamine-containing neurons in the substantia nigra (Fig. 14.1). This affects the complex release of excitatory and inhibitory neurotransmitters in the basal ganglia and subthalamic nucleus which culminates in excessive inhibition of the thalamus. Inhibition of the thalamus suppresses voluntary movement and accounts for the signs and symptoms of Parkinson disease including
– Pill-rolling tremor that is present at rest and that increases with stress
– Bradykinesia (slow initiation of movements) and decrease of spontaneous movements
– Masked facies
– Increased muscle tone and cogwheel rigidity
– Postural disturbances occurring in later phases. (The patient adopts a stooped position and a festinating gait.)
– Lewy body dementia (LBD) in one third of patients
Lewy body dementia
LBD is the second most common form of dementia after Alzheimer disease. It occurs as a result of abnormal proteins (Lewy body proteins) being deposited throughout the cortex of the brain. If this deposition occurs in the substantia nigra, dopamine stores become depleted, resulting in parkinsonian symptoms. LBD manifests with cognitive impairment and increasing difficulty in performing tasks, as well as memory problems and visual hallucinations. There is no cure for this disease, so treatment aims to reduce symptoms by using cholinesterase inhibitors, levodopa, and antipsychotic (neuroleptic) drugs. Dangerous reactions can occur in 50% of patients taking antipsychotic (neuroleptic) drugs.
Fig. 14.1 Parkinson disease.
In Parkinson disease, there is death of dopaminergic neurons in the substantia nigra. This causes less dopamine to be available to neurons in the striatum. Ultimately, these changes cause excess inhibition of the thalamus (via gamma-aminobutyric acid [GABA]) and are responsible for the symptoms of Parkinson disease. Treatment aims to increase dopamine in neurons.
Nigrostriatal Tract and Parkinson Disease
In a normal, healthy person, there is a balance between inhibitory dopamine components and excitatory acetylcholine components in the nigrostriatal tract. In Parkinson disease, howeve r, there is a deficiency of the dopamine component; therefore, the goal of therapy is to restore dopamine levels. Alternatively, you can decrease the acetylcholine component (Fig. 14.2).
The basal ganglia are made up of the corpus striatum (which is composed of the caudate nucleus and putamen), globus pallidus, subthalamic nucleus, and substantia nigra. It functions to control movement in conjunction with the cerebellum and motor cortex (Fig. 14.2).
Control of movements
The pyramidal and extrapyramidal motor systems are involved in the control of movement. The pyramidal system is involved in initiation and termination of movement. Disorders of the pyramidal system are characterized by paralysis and spasticity. The extrapyramidal motor system consists of the basal ganglia (caudate putamen, globus pallidus, subthalamic nuclei, and substantia nigra), with connections to the thalamus, cortex, reticular formation, and spinal cord (Fig. 14.2). The extrapyramidal system integrates and coordinates impulses arising in the pyramidal system. Disorders of this system are characterized by dyskinesias.
Dopamine cannot be given directly because it is rapidly metabolized in the periphery, has adverse side effects on the cardiovascular system, and very little penetrates the CNS. Strategies to combat the dopamine deficiency include increasing dopamine precursor levels (levodopa), decreasing dopamine breakdown (entacapone, tolcapone, selegiline, and rasagiline), enhancing dopamine release (amantadine), and administering dopamine receptor agonists (bromocriptine, pramepixole, and ropinirole).
Mechanism of action. Levodopa, or l-3,4-dihydroxyphenylalanine (l-dopa), is a precursor in dopamine synthesis. It is formed from L-tyrosine and is transformed to dopamine by aromatic l-amino acid decarboxylase (dopa decarboxylase). Levodopa itself is pharmacologically inert; its effects are a result of decarboxylation to dopamine (Fig. 14.3).
– Levodopa is rapidly absorbed from the intestine by active transport. Administration with meals reduces absorption.
– It has a short plasma half-life of 1 to 3 hours.
– It undergoes peripheral decarboxylation.
– Small amounts enter the central nervous system (CNS).
– It is converted to dihydroxyphenylacetic acid and homovanillic acid and excreted in the urine.
Fig. 14.2 Basal ganglia.
Neurons in the cortex release glutamate, which activates striatal neurons. Neurons within the basal ganglia communicate mainly via the inhibitory neurotransmitter, GABA. Glutamate (an excitatory neurotransmitter) is also released by neurons of the subthalamic nucleus, which acts on neurons in the inner pallidum and substantia nigra to release GABA. GABA is responsible for the inhibitory effect on the thalamus. Dopamine, released from the substantia nigra, may have an excitatory or inhibitory effect on the striatum. Acetylcholine activates striatal neurons.
Effects. Table 14.1 describes the effects of levodopa.
Table 14.1 Effects of Levodopa
Relieves bradykinesia and rigidity preferentially over relieving tremor
Secondary improvements are seen in posture, gait, ability to modify facial expression, speech, and handwriting.
There is no relief of dementia.
Postural (orthostatic) hypotension and cardiac stimulation occur, although tolerance usually develops (mechanism unknown).
Prolactin secretion is inhibited.*
Growth hormone release may also be observed in healthy individuals but not in patients with Parkinson disease.
* Dopamine is a prolactin-inhibiting hormone.
Abbreviation: CNS, central nervous system.
Side effects. Table 14.2 lists the side effects experienced by most patients who take levodopa.
Table 14.2 Side Effects of Levodopa*
Nausea and vomiting
Abnormal movements such as tics, grimacing, head bobbing, and oscillatory movements of the limbs are seen in 50% of patients within 2 to 4 months and in 80% of patients by 1 year. No tolerance develops to these effects, and they will worsen if the dose is not reduced.
Psychiatric disturbances (serious in 15% of patients): hallucinations, paranoia, mania, i nsomnia, anxiety, nightmares, and depression
False-positive test for ketoacidosis by the dipstick test due to the presence of levodopa metabolites
Red-colored urine that changes to black on exposure to air or alkali
* All side effects are seen in the majority of patients. These are reversible and can be controlled by reducing the dose.
– Pyridoxine, a form of vitamin B6 found in multivitamins, is a cofactor for dopa decarboxylase and may enhance the metabolism of levodopa.
– Antipsychotics antagonize dopamine receptors and are thus contraindicated with levodopa.
– Reserpine is contraindicated because it depletes dopamine.
– Monoamine oxidase inhibitors (MAOIs) block dopamine breakdown and may exaggerate effects (hypertensive crisis and hyperpyrexia). MAOIs should be withdrawn at least 2 weeks prior to levodopa administration.
– Anticholinergics may slow gastric emptying.
Contraindications. Care must be exercised in patients with heart disease, cerebrovascular disease, or neurological disease.
Aromatic l-Amino Acid Decarboxylase Inhibitors: Carbidopa and Benserazide
Carbidopa is the only type available in the United States. Benserazide, which is available in Europe and Canada, has similar properties.
Mechanism of action. These agents inhibit the peripheral production of dopamine from levodopa by inhibiting dopa decarboxylase. This allows more levodopa to be available to the CNS (Fig. 14.3).
Uses. Carbidopa and benserazide are usually administered with levodopa. They confer the following advantages:
– They allow for a dose reduction of levodopa and for a reduced number of doses.
– The effective dose is achieved more rapidly.
– A larger percentage of patients responds favorably.
– Pyridoxine interaction is avoided.
Side effects. No side effects are seen when these agents are given alone. All side effects are associated with the increased effect of levodopa.
– CNS side effects may appear more frequently or earlier in therapy.
– There are fewer peripheral side effects, such as nausea, vomiting, and cardiac effects.
Entacapone and Tolcapone
Mechanism of action. Entacapone and tolcapone are selective and reversible inhibitors of catechol-O-methyltransferase (COMT), which is the enzyme responsible for the peripheral breakdown of levodopa. This allows more levodopa to be available in the CNS (Fig. 14.3). They act mainly in the periphery.
Uses. These agents are given as adjunctive therapy to patients experiencing fluctuations in disability related to levodopa and dopa-decarboxylase inhibitor combinations.
Side effects. These agents do not cause any adverse effects alone, but they enhance the adverse effects of levodopa.
– Acute liver failure may occur with tolcapone.
Drug interactions. These agents may potentiate the actions of drugs metabolized by COMT (i.e., dopamine, epinephrine, and methyldopa).
Mechanism of action. Amantadine probably enhances dopamine release in the CNS (Fig. 14.3).
– Used in early stages of parkinsonism or as a supplement to levodopa.
– Neurologic: restlessness, irritability, insomnia, and headache at lower doses, progressing to agitation and delirium at higher doses
– Gastrointestinal: nausea and diarrhea
Bromocriptine, Pramipexole, and Ropinirole
Mechanism of action. These agents are dopamine agonists.
– Parkinson disease
– Restless leg syndrome (pramipexole and ropinirole)
– The same as levodopa
Fig. 14.3 Antiparkinsonian drugs.
The dopamine precursor levodopa (l-dopa) penetrates the blood–brain barrier (unlike dopamine), where it can directly replenish striatal dopamine levels. Carbidopa inhibits dopa decarboxylase and thus prevents the peripheral production of dopamine that can cause adverse effects (e.g., vomiting). Carbidopa cannot cross the blood–brain barrier; thus, central decarboxylation is unaffected. Bromocriptine is a dopamine agonist in the central nervous system (CNS). Entacapone is a catechol-O-methyltransferase (COMT) inhibitor that prevents the peripheral breakdown of levodopa, allowing more levodopa to be available for the CNS. Benztropine is a muscarinic receptor antagonist that blocks acetylcholine in the striatum and thereby counteracts excessive cholinergic activity that results from dopamine deficiency. Selegiline inhibits the degradation of dopamine by monoamine oxidase type B (MAOB) in the striatum, and amantadine is thought to block central N-methyl-d-aspartate (NMDA) glutamate receptors in the brain, causing a decreased release of acetylcholine in the striatum.
Selegiline and Rasagiline
Mechanism of action. Selegiline and rasagiline are selective inhibitors of MAO-B, the enzyme involved in dopamine metabolism in the CNS (Fig. 14.3).
Side effects. These agents potentiate the effects of dopamine in the brain but do not potentiate the effects of catecholamines to produce a hypertensive crisis.
Trihexyphenidyl, Benztropine, Procyclidine, and Diphenhydramine
These anticholinergics were the primary agents prior to the introduction of levodopa.
– Useful in early stages, in patients who are intolerant to levodopa, or as a supplement to levodopa therapy
– More effective in relieving tremor than either rigidity or bradykinesia
– Cycloplegia, constipation, and urinary retention
– CNS: confusion, delirium, and hallucinations
– Paralysis of the ciliary muscle of the eye
14.2 Alzheimer disease
Alzheimer disease is a progressive neurodegenerative disorder producing marked atrophy of the cerebral cortex. It is the most common cause of dementia. It produces the following signs and symptoms:
– Impairment of short-term memory
– Impairment of cognition and language
– Increasing difficulty performing the activities of daily living
– Personality changes, e.g., anxiety, depression, aggression, social withdrawal
– Immobility leading to death
Cognitive and memory impairment in Alzheimer disease has been linked to the progressive loss of cholinergic neurons and the subsequent loss of cholinergic transmission within the cerebral cortex. Other neurodegenerative processes may result from damage to neurons due to over-stimulation by glutamate, particularly at N-methyl-D-aspartate (NMDA) receptors.
Tacrine, Donepezil, Rivastigmine, and Galantamine
Mechanism of action. These agents are centrally-acting, reversible inhibitors of cholinesterase. They prevent the hydrolysis of ACh thus increasing the concentration of ACh available to neurons.
Uses. Improves cognition in mild to moderate Alzheimer disease.
– Nausea, diarrhea, vomiting.
– Hepatotoxicity (Tacrine only)
Mechanism of action. Memantine is an NMDA receptor antagonist. It protects neurons from damage caused by glutamate.
Uses. Moderate to severe Alzheimer disease.
Side effects. Confusion and dizziness
14.3 Spasticity and Muscle Spasms
Spasticity and muscle spasms can result from lesions at various levels of the CNS. Dysfunction in the descending pathways controlling motor neurons results in hyperexcitability of the tonic stretch reflexes. The mechanisms by which drugs can affect skeletal muscle tone are illustrated in Fig. 14.4.
Mechanism of action. Baclofen is a gamma-aminobutyric acid type B (GABAB) receptor antagonist that acts in the spinal cord to hyperpolarize afferent nerve terminals and thus inhibit synaptic transmission.
– Treatment of spasticity in multiple sclerosis and spinal trauma
– Cerebral palsy (given intrathecally)
Note: It is not used for stroke.
– Sedation, insomnia, dizziness, weakness, and ataxia
– The threshold for seizures is decreased.
– Causes hallucinations, anxiety, and tachycardia
Fig. 14.4 Mechanisms influencing skeletal muscle tone.
Myotonolytics lower muscle tone by increasing the activity of intraspinal inhibitory neurons. Benzodiazepines augment the action of GABA at GABAA receptors, which are ligand-gated CI– ion channels. Baclofen is an antagonist at GABAB receptors, which are G-protein coupled. Dantolene acts on muscle cells to reduce Ca2+ release from the sarcoplasmic reticulum, causing muscle relaxation. Muscle relaxants themselves also act on muscle cells to cause relaxation. Antiepileptics and antiparkinsonian drugs act centrally to affect muscle tone. These agents are used to treat various spasticity disorders, as well as painful muscle spasms. Convulsants, such as tetanus toxin and strychnine, inhibit glycine, which is an interneuronal synaptic inhibitor. This allows impulses to propagate unchecked along the spinal cord, leading to convulsions.
Mechanism of action. Diazepam enhances presynaptic inhibition in the spinal cord.
– Spinal lesions
– Some cases of cerebral palsy
Mechanism of action. Dantrolene acts directly on skeletal muscle to apparently decrease Ca2+ release from the sarcoplasmic reticulum, thus reducing skeletal muscle contractions (Fig. 14.5).
– Reduces spasticity in paraplegics and hemiplegics
– Cerebral palsy (improvement seen in 50% of cases)
Muscular dystrophy is a term used to describe a group of inherited muscle diseases. Each individual type of muscular dystrophy has its own genetic defect. The most common type of muscular dystrophy is due to a genetic defect that causes a mutation in dystrophin, part of a protein complex that conveys force from the Z disks to connective tissue on the surface of the fiber. Dystrophin mutations result in degeneration of muscle fibers with increasing muscle weakness. As the disease progresses there will be muscular contractures with loss of mobility of joints. There is no cure for this group of diseases, but drugs are sometimes used to provide symptomatic relief or to slow its progression. Drugs that help with contractures include phenytoin, carbamazepine, and dantrolene. Prednisone, cyclosporin, and azathioprine may also be used to protect muscle cells from damage. Physical therapy is the mainstay of treatment for muscular dystrophy to try to preserve mobility. Surgery may be used for the relief of contractures.
Fig. 14.5 Inhibition of neuromuscular transmission and electromechanical coupling.
Acetylcholine (ACh) is released from motor neurons upon stimulation. It then binds to nicotinic receptors in the motor end plate, causing it to depolarize and propagate an action potential to the surrounding sarcolemma. The sarcoplasmic reticulum then releases Ca2+, which causes myofilaments to contract. This electromechanical coupling can be inhibited at different stages. Mg2+ and botulinum toxin inhibit acetylcholine release from motor neurons, muscle relaxants inhibit the generation of action potentials, and dantrolene inhibits Ca2+ release from the sarcoplasmic reticulum.