Objectives Description of Parkinson's disease The neurotransmitter model Use of levodopa Agents which enhance dopaminergic activity Anticholinergic agents New approaches..

Description Signs of the disease muscular rigidity (cog-wheel) bradykinesia resting tremor (pill-rolling) characteristic flexed posture and shuffling gait loss of normal associated movement little spontaneous movement slow initiation of voluntary movement..

Historical evidence - a great story - the first piece Biogenic amines - amphetamine originally given for excess sleepiness found to relieve symptoms Clue ==> enhanced biogenic amine activity is a positive factor Atropine given for excess salivation anticholinergic agents relieved symptoms Clue ==> enhanced cholinergic activity is a negative factor..

The second piece - drug-induced extra-pyramidal disorders Drugs which deplete dopamine (reserpine) or block receptors (antipsychotics: chlorpromazine, haloperidol, etc.) cause Parkinson effects A decrease in dopamine in the basal ganglia MPTP - may be related to cell damage caused by excitatory amino acids at NMDA receptors..

Neurotransmitter model Disorder

Treatment approaches Dopaminergic drugs Anticholinergic agents augment defective inhibitory systems: l-DOPA probably involves D2 receptors D2 agonists: Pramipexole, Ropinirole and Bromocriptine, are used for effective treatment potent D2 blockers, butyrophenones (other anti-schizophrenic drugs), cause the syndrome Anticholinergic agents may be used for mild cases used as adjunctive therapy with dopaminergic drugs for drug-induced extrapyramidal effects Treatment does not reverse the disease process..

The dopamine picture Rotigotine

The use of levodopa Stimulating dopamine synthesis Therapy with levodopa Side/toxic effects Combination of a peripheral dopa-decarboxylase inhibitor - Carbidopa Interactions/precautions..

Rate-limiting step in dopamine synthesis ( ) Tyrosine hydroxylase is the rate-limiting step in the synthesis dopamine By-pass the bottleneck in the remaining healthy neurons by giving dopa to synthesize more dopamine..

Therapy with levodopa Goal: low doses at small intervals - side-effects are then reduced Improvement may take several weeks 70% respond well 90% obtain relief for 5 years neuronal deterioration occurs levodopa can no longer be converted to dopamine new dopaminergic agonists are important agents Fluctuations in therapeutic response may occur..

Side/toxic effects Gastrointestinal - nausea, vomiting (Chemoreceptor Trigger Zone) Cardiovascular/autonomic orthostatic hypotension in 30% - tolerance occurs ß-adrenergic stimulation of the heart in patients with pre-existing problems Endocrine - growth hormone increases, prolactin decreases..

Side/toxic effects Abnormal involuntary movements choreiform or faciolingual problems after 5-8 years, many patients have dose-related dyskinesias (chorea, dystonia) Psychiatric/behavioral problems - about 15% the dopamine hypothesis for schizophrenia reports of increased compulsive behavior cognitive defects may be related to decreased cholinergic activity..

Addition of carbidopa Much of the l-dopa is converted to dopamine in the periphery which doesn't cross the blood-brain-barrier>> Carbidopa

Addition of carbidopa Without carbidopa, large doses are administered to obtain small amounts in the CNS which are converted to the necessary dopamine With cabidopa, smaller overall doses are effective half-life is 60-90 min. daily amount is divided into 3-6 doses to reduce side effects Prevention of peripheral conversion allows for lower doses>>

Addition of carbidopa

Cost/benefit ratio to the combination Advantages Can reduce the effective dose of levodopa by 75% Nausea and vomiting are reduced Effective dose levels are achieved more rapidly Control is more even - diurnal variation is reduced Per cent of patients helped is greater..

Benefit/cost ratio to the combination Disadvantages Orthostatic hypotension is not helped Involuntary movements may occur earlier, be more severe, and last longer Adverse mental effects occur earlier Combination of levodopa and carbidopa is SINEMET..

Interactions/precautions Acute psychosis, psychoneurosis Caution with other adrenergic agents in asthma or emphysema MAO-A inhibitors act primarily on norepinephrine and serotonin effects of dopamine (converted to norepinephrine) may be exaggerated or unpredictable - hypertension, hyperpyrexia..

Peripheral enhancers of dopaminergic activity COMT inhibitors (similar approach to Carbidopa) Entacapone (COMTAN) prevents the conversion of dopa to 3-O-methyl DOPA peripherally thereby prolonging its half-life and enhancing entry into the CNS other COMT-metabolized drugs will have an increased duration of activity a useful adjunct especially in patients with an "end of dose" fluctuating response to treatment >>

Peripheral enhancers of dopaminergic activity

Peripheral enhancers of dopaminergic activity Tolcapone (TASMAR), a similar more potent agent is more hepatotoxic is reserved for patients not responding to entacapone There is now a combination product available Stalevo is a combination of levodopa, carbidopa and entacapone

Central enhancers of dopaminergic activity Dopaminergic agonists Pramipexole (MIRAPEX) and Ropinirole (REQUIP) are agonists at D2 and D3 receptors may be used as initial treatment, fewer on/off issues, longer duration of action, less likely to induce dyskinesias (movement difficulties) can reach therapeutic levels more rapidly reduces levodopa requirement and smoothes the response Both drugs have been approved for “restless leg syndrome”..

Central enhancers of dopaminergic activity Dopaminergic agonists Rotigotine (NEUPRO) is a D3/D2/D1 dopamine agonist Used in a once daily patch Side effects include irritation at the site of application CNS - dizziness, headache, somnolence GI - nausea, vomiting poor impulse control - pathologic gambling, excessive shopping, binge eating or hypersexuality (previously reported with levodopa)..

Central enhancers of dopaminergic activity These have largely replaced Bromocriptine (PARLODEL) - D2 agonist (ergot derivative).. DOPA induction of free radicals may contribute to cell death; agonists do not change the course of the disease..

Central enhancers of dopaminergic activity Amantidine antiviral agent - NMDA -antagonist the exact mechanism in PD is unknown usual CNS dopaminergic side-effects, psychosis..

Central enhancers of dopaminergic activity Deprenyl/selegiline - an MAO-B inhibitor - affects predominately dopamine at the doses used preserves dopamine in the basal ganglia allows for lower doses of l-dopa and more even drug effect probably does not slow the disease progression as originally thought..

Enhancers of dopaminergic activity Rasagiline (AZILECT) - another MAO-B inhibitor that is completing clinical trials may not be as selective for dopamine, as there are major precautions against use with antidepressants that raise serotonin - serotonin syndrome (tachycardia, hypertension, hyperthermia, muscular rigidity) should not be used with meperidine, propoxyphene, tramaol, methadone, mirtazapine, cyclobenzaprine, dextromethorphan and St. John’s Wort because their breakdown is slowed should not be used with sympathomimetics..

Central enhancers of dopaminergic activity About MAO-B inhibitors early thoughts were that they were neuroprotective and slow the advancement of PD this was later dispelled, particularly because selegiline is metabolized to amphetamine derivatives that may be neurotoxic Rasagiline may have neuroprotective and anti-apoptotic effects on dopaminergic neurons distinctive benefits remain to be seen..

Central enhancers of dopaminergic activity Apomorphine has been introduced in advanced Parkinson patients with significant “off” periods A specific dopamine agonist at the CTZ causing nausea Other typical dopaminergic side effects occur orthostatic hypotension confusion and other CNS effects..

Anticholinergic agents Historical background - the use of atropine Effective anticholinergic agents trihexyphenidyl (ARTANE) benztropine (atropine/diphenhydramine) others: antihistamines, phenothiazines..

Anticholinergic agents Only approach for drug-induced Parkinson effects>> Benztropine Trihexyphenidyl

Anticholinergic agents Effectiveness - 25% begun with small doses until side-effects are too severe may be used with dopaminergic agents Side/toxic effects dry mouth, failure to accommodate constipation, urinary retention heat stroke (no sweating) elderly: delirium, confusion Precautions/interactions glaucoma, prostatic hypertrophy..

New approaches Lesions/microstimulators Tissue implants a return to an older approach, now more precise for relieving tremor and rigidity Tissue implants adrenal medullary tissue fetal brain tissue - MPTP patients..

Review of Rotigotine therapy

Initial therapy - NEJM ‘05, Treatment Guidelines ‘07 First-line dopaminergic agents Carbidopa plus levodopa Carbidopa plus levodopa plus entacapone Dopamine agonists Non-ergot: pramipexole, ropinirole, rotigotine Ergot: pergolide Second-line agents Anticholinergic: trihexyphenidyl, benztropine Selective MAO-B antagoinist - selegiline NMDA antagonist: amantadine..

Considerations on management Effectiveness of levodopa diminishes with time Adverse l-DOPA effects increase Some suggest avoiding treatment until symptoms or disability affect lifestyle Suggest using dopamine agonists instead of levodopa in younger patients..

Considerations on management With disease progression, begin dopaminergic therapy levodopa/carbidopa/entacapone and an agonist a peripheral COMT inhibitor can be added as levodopa control is difficult or wanes consider adding selegiline as control becomes more difficult apomorphine may be added to deal with “off” drug periods in advanced patients..

Costs