Neurodegenerative diseases
Dr. Entisar Al-Mukhtar
Include Parkinson disease (PD), Alzheimer disease, multiple sclerosis (MS) and
amyotrophic lateral sclerosis (ALS).
• They are characterized by the progressive loss of selected neurons in brain areas,
resulting in characteristic disorders of movement, cognition, or both.
Parkinson disease (Parkinsonism)
• Progressive neurological disorder of muscle movement, characterized by tremors,
muscular rigidity, bradykinesia & postural & gait abnormalities.
• Most cases involve people over the age of 65.
Etiology
• For most patients the cause is unknown.
• Genetic factors &unidentified environmental factor may play a role in the loss of
dopaminergic neurons.
• In PD, the destruction of dopaminergic neurons (in substantia nigra) significantly
diminished dopamine secreted into the neostriatum, thus overproduction or a relative
overactivity of Ach (by stimulatory neurons), result in loss of muscle movements control.
Secondary parkinsonism:
• Viral encephalitis or vascular lesions or drugs such as phenothiazines and
haloperidol may produce Parkinsonian symptoms.
• These drugs should not be used in parkinsonian patients.
Drugs used in PD
• They offer temporary relief of symptoms, but they do not arrest or reverse the neuronal
degeneration caused by the disease.
A. Levodopa & carbidopa
Levodopa
• A metabolic precursor of dopamine, in new patients, response to levodopa is
consistent, & the patient rarely complains the drug effects “wear off ”. With time, the
number of neurons decreases & fewer cells are capable of taking up exogenous
levodopa & converting it to dopamine as a result, motor control fluctuation develops.
• levodopa effects can be enhanced by carbidopa.
Mechanism of action:
a. Levodopa: is actively transported into the brain and converted to dopamine.
Note: dopamine itself does not cross the BBB.
• Levodopa is decarboxylated to dopamine in the periphery thus, large doses are
required, that can result in side effects (nausea, vomiting, cardiac arrhythmias and
hypotension).
b. Carbidopa: A dopa decarboxylase inhibitor that does not cross the blood-brain barrier
(BBB) can diminish metabolism of levodopa in GIT and peripheral tissues, thereby
increasing its availability to the CNS.
• Carbidopa use lowers Levodopa dose by 4 - 5 fold thus, decreases the severity of the
side effects arising from peripherally formed dopamine.
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Uses:
• Levodopa- carbidopa combination is an efficacious drug regimen.
• Withdrawal from the drug must be gradual.
Absorption and metabolism:
• Levodopa has an extremely short half-life (1 to 2 hours) which causes fluctuations
in plasma concentration, that may produce fluctuations in motor response.
• Protein rich meal interferes with the transport of levodopa into the CNS.
• Also large, neutral amino acids (eg. leucine & isoleucine) compete with levodopa for
absorption from the gut & for transport across the BBB. Therefore, levodopa should be
taken on an empty stomach, usually 30 minutes before a meal.
Adverse effects:
1. Peripheral effects:
• Anorexia, nausea & vomiting.
• Tachycardia & ventricular extrasystoles. Hypotension may also develop.
• Mydriasis, blood dyscrasias & a positive reaction to the Coombs test are seen.
• Brownish saliva and urine (due to melanin produced from catecholamine oxidation).
2. CNS effects:
• Visual & auditory hallucinations & dyskinesias (abnormal involuntary movements).
• Mood changes, depression, psychosis & anxiety.
Interactions:
• Pyridoxine (vitamin B6) increases peripheral breakdown of levodopa.
• Concomitant use of levodopa & non-selective MAOIs (e.g., phenelzine) can cause
hypertensive crisis (concomitant administration of these agents is contraindicated).
• Cardiac patients should be carefully monitored due to possible cardiac arrhythmias.
• In psychotic patients levodopa exacerbates the symptoms which can be treated with
low doses of atypical antipsychotics.
• In PD, the antipsychotic drugs are contraindicated (potently block dopamine receptors).
• Levodopa can increase IOP in patients with glaucoma.
B. Catechol-O-methyltransferase (COMT) inhibitors: Entacapone & Tolcapone
Normally, methylation of levodopa by COMT to 3-O-methyldopa is a minor pathway.
But, when peripheral dopamine decarboxylase is inhibited (by carbidopa), a significant
concentration of 3-O-methyldopa is formed & competes with levodopa for transport into
the CNS. Thus use of entacapone or tolcapone increases central uptake of levodopa.
Pharmacokinetics:
• Tolcapone has a relatively long duration of action, while entacapone requires frequent
dosing.
• Dose adjustment may be needed in patients with moderate or severe cirrhosis.
Adverse effects:
• Tolcapone cause fulminating hepatic necrosis therefore, entacapone has largely
replaced tolcapone.
C. Selegiline & Rasagiline
Selegiline: Selectively inhibits MAO type B (which metabolizes dopamine), selegiline high
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doses, may cause hypertensive crises (due to inhibition of MAO type A which metabolizes
NE & serotonin).
• Selegiline is metabolized to methamphetamine & amphetamine, that may produce
insomnia.
Rasagiline
• Irreversible & selective inhibitor of brain MAO type B.
• More potent than selegiline.
D. Dopamine-receptor agonists
• Include an ergotamine derivative ( Bromocriptine) & nonergot drugs ( Ropinirole,
Pramipexole, Rotigotine & Apomorphine).
• Durations of actions are longer than that of levodopa.
• Bromocriptine, pramipexole & ropinirole are effective for PD complicated by motor
fluctuations & dyskinesias, but are ineffective in patients who don’t responded to levodopa.
• Side effects (sedation, hallucinations, confusion, nausea & hypotension) limit the utility
of the dopamine agonists
1. Bromocriptine:
• Comparing to levodopa dyskinesia is less prominent ,whereas other side effects are
more common with bromocriptine.
• Mental psychiatric illness may be worsened.
• Used cautiously in patients with MI or peripheral vascular disease history.
• Bromocriptine, has the potential to cause pulmonary & retroperitoneal fibrosis.
2. Apomorphine, Pramipexole, Ropinirole & Rotigotine:
• Apomorphine & rotigotine are available as injectable & transdermal formulations
respectively.
• Apomorphine is used for acute management of the hypomobility “off” phenomenon in
severe and advanced PD to supplement oral medications.
• Dopamine agonists may delay levodopa use in early PD & may decrease the dose of
levodopa in advanced PD.
• Rrenal dysfunction necessitate pramipexole dosage adjustments, also cimetidine
inhibits renal tubular secretion of pramipexole.
• Fluoroquinolone antibiotics or fluoxetine may inhibit ropinirole metabolism.
E. Amantadine
• Antiviral drug with antiparkinsonism action.It (1) increases dopamine release, (2) blocks
cholinergic receptors & (3) inhibits the N-methyl-D-aspartate (NMDA) type of glutamate
receptors.
• Its high doses may induce acute toxic psychosis.
• Less efficacious than levodopa.
• Less effective against tremor, but more effective than anticholinergics against rigidity &
bradykinesia.
F. Antimuscarinic agents : Benztropine, Trihexyphenidyl, Procyclidine & Biperiden
• Less effective than levodopa & play only an adjuvant role.
• Contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis.
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