CNS: Pharmacological Management of Parkinson's Disease Flashcards
Degenerative Diseases of the Nervous System
Chronic neurological conditions associated with progressive loss of neurons
No evidence of inflammation
No evidence of cellular necrosis
Examples:
Alzheimer’s disease
Parkinson’s disease
Motor neuron disease (ALS)
Parkinson’s Disease
2nd most common neurodegenerative disease
Mean onset = 57 years of age
Affects 1-2% of population over 60 years of age
Etiology is unknown
Disease progression is highly variable
Can be early onset in some cases
Patient’s afflicted with Parkinson’s disease are described as exhibiting a ‘classic triad’:
Resting tremor
Muscle rigidity
Bradykinesia
Symptoms related to selective loss of pigmental neurons in the midbrain
Substantia nigra pars compacta – Dopaminergic neurotransmission to caudate nuclei (i.e., striatum) and putamen
MPTP and Dopaminergic Neurons
MPTP – induces oxidative damage to dopaminergic neurons
Effect identified in 1976 due to incorrect synthesis of MPPP, an analogue of pethidine (Demerol – opioid analgesic)
Symptoms of Parkinson’s disease observed within 3 days
Effect on dopaminergic neurons is indirect MPTP itself is not a neurotoxin Enzymatically converted (via MAO-B) in the CNS to MPP+, which selectively targets dopaminergic neurons in the substantia nigra MPP+ - high-affinity substrate for dopamine reuptake transporters localized to the pre-synaptic membrane of neurons in the substantia nigra
Oxidative stress and Parkinson’s Disease
Dopamine metabolism results in reactive oxygen species (oxidative deamination of dopamine by MAO => H2O2)
Glutathione (primary CNS antioxidant) levels are depressed in Parkinson’s disease
Renders neurons more susceptible to ROS toxicity
Observed in workers exposed to insecticides/pesticides
Coenzyme Q10 study: 1200 mg/day may slow progression
Pharmacological Treatment of Parkinson’s Disease
Goals:
Primary = restore dopamine receptor function
Secondary = inhibition of muscarinic cholinergic receptors
Several types of drugs:
Levodopa
Dopamine Receptor Agonists
Monoamine Oxidase Inhibitors (MAOIs)
Catechol-O-Methyltransferase (COMT) inhibitors
Muscarinic Cholinergic Receptor Antagonists
Amantidine
Levodopa
Prodrug – immediate metabolic precursor of dopamine
Levodopa can cross the blood-brain barrier while dopamine cannot
CNS – enzymatically converted to dopamine by L-aromatic amino acid decarboxylase
1-3% of Levodopa actually enters the brain
Primarily due to extracerebral metabolism
Extracerebral metabolism can be reduced by administering a non-BBB permeating peripheral L-aromatic amino acid decarboxylase inhibitor
Sinemet® = levodopa + carbidopa
MOA: restoration of synaptic concentrations of dopamine
Activation of post-synaptic D2 receptors = inhibit adenylyl cyclase = promote voluntary movement via indirect pathway
Additional benefit obtained via activation of post-synaptic D1 receptors = stimulate adenylyl cyclase = facilitate voluntary movement via direct pathway
Therapeutic Effectiveness
Best results obtained in first few years of treatment
80% of patients show marked initial improvement (primarily in terms of resolution of muscle rigidity and bradykinesia)
20% show virtually normal motor function
Over time, levodopa therapy becomes less effective
Progressive loss of dopaminergic neurons
Downregulation of D1/D2 receptors on post-synaptic terminals
Some patients require reduced doses of levodopa to prevent side effects
Levodopa – Adverse Drug Effects
Dyskinesias – occur in 80% of patients on long-term levodopa therapy
Choreiform movements
Dose-related – higher doses = increased risk
Occur more frequently in younger Parkinson’s patients
“On-off” Effect – fluctuations in clinical response to levodopa
“Off” = marked akinesia
“On” = improved mobility but marked dyskinesia
Thought to be related to fluctuations in levodopa plasma concentrations
Fluctuations can be “smoothed out” by incorporating a dopamine receptor agonist into pharmacotherapy
Pramipexole (Mirapex®)
Ropinirole (Requip®)
Acute side effects – related to increased peripheral concentrations of dopamine
Nausea
Anorexia – treated with peripherally-acting dopamine antagonist (i.e., Domperidone)
Hypotension – particularly in patients on anti-hypertensives
Other common side effects: Confusion Insomnia Nightmares Schizophrenic-like syndrome – delusions and hallucinations due to enhanced CNS concentrations of dopamine
Dopamine Receptor Agonists
Pergolide Mesylate (Permax®) – directly stimulated both D1 and D2 receptors
Associated with valvular heart disease (33%)
Loses efficacy over time
Pramipexole (Mirapex®) – preferential affinity for D3 receptor (also D2/D4)
Used primarily in patients with advanced Parkinson’s disease
Possibly neuroprotective – scavenge H2O2
Ropinirole (Requip®) – D2 receptor agonist
Effective as monotherapy in patients with mild disease
Bromocriptine (Parlodel) – selective D2 receptor agonist
Apomorphine – potent D1/D2 agonist
Given via subcutaneous injection to provide temporary relief of “off” periods of akinesia
Short period of effectiveness ( ~ 2 h)
Associated with several side effects (i.e., dyskinesias, drowsiness, sweating, hypotension)
Monoamine Oxidase Inhibitors (MAOIs)
Two types of MAO have been characterized
MAO-A – primarily metabolizes NE and 5-HT
MAO-B – primarily metabolizes dopamine
Selegiline (Eldepryl®) and Rasagiline (Azilect®)
Selective, irreversible inhibitors of MAO-B
Selegiline – MAO-B Inhibitor
Therapeutic Effectiveness
Effective in early Parkinson’s disease (as monotherapy or in combination with levodopa)
Enables reduction in levodopa dose or may smooth the “on-off” fluctuations associated with levodopa
Metabolite = Desmethylselegiline – neuroprotective
Adverse Effects
Selectivity for brain MAO-B makes selegiline less likely to produce ADRs involving peripheral tyramine (i.e., wine, cheese, and chopped liver syndrome)
Tyramine = catecholamine releasing agent
Blocks MAO-A at high doses
Hypertensive crisis due to peripheral accumulation of NE
Fatal hyperthermia – may occur when administered in conjunction with meperidine, cocaine, or fluoxetine
Catechol-O-Methyltransferase (COMT) Inhibitors
Inhibition of L-aromatic amino acid decarboxylase is associated with compensatory activation of COMT
Increased plasma levels of 3-OMD = poor response to levodopa (competition for active transporter in the gut and at the BBB?)
Adjunctive therapy in patients treated with levodopa
Tolcapone and Entacapone
Selective COMT inhibitors – diminish peripheral metabolism of levodopa
May also reduce “on-off” fluctuations
Adverse Effects:
Related to increased plasma concentrations of levodopa
Include dyskinesias, nausea, and confusion
Other side effects: diarrhea, abdominal pain, orthostatic hypotension, sleep disorders, orange urine discoloration
Tolcapone – potentially hepatotoxic
Muscarinic Cholinergic Receptor Antagonists.
Muscarinic Receptors – localized to striatal neurons
Mediate cholinergic tremor
May cause presynaptic inhibition of dopamine release
Trihexyphenidyl (Artane®) and Benztropine (Cogentin®)
Therapeutic Effectiveness –
Useful in patients administered neuroleptics as anti-dopaminergic properties of these drugs antagonize effects of levodopa
Improve muscle rigidity and tremor but have little effect on bradykinesia
Adverse Effects –
Characterized as “atropine-like” = dry mouth, inability to sweat, impaired vision, urinary retention, constipation, drowsiness, confusion
Amantidine (Symmetrel®)
Antiviral drug with anti-Parkinsonian properties
Mechanism of action is unclear
Potentiates dopaminergic function by modifying synthesis, release, or reuptake of dopamine
Therapeutic Effectiveness –
Less effective than levodopa or bromocryptine
Therapeutic benefits are short-lived
Adverse Effects –
Primarily CNS = restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, confusion
Overdoses = acute toxic psychosis
Others = headache, edema, postural hypotension, heart failure, GI disturbances
Considerations for Rehabilitation
Coordinate the therapy session with the peak effects of drug therapy
Maintain patient mobility for those patients on drug holiday
Monitor blood pressure due to orthostatic hypotension (dizziness and syncope)
Aggressive program of gait training, balance activities, and other exercise can help promote optimal health and function in patients with Parkinson’s
