Levodopa (Dopar): Overview

• Dopamine:

  • does not cross: blood-brain barrier

  • ineffective if administered peripherally

• L-DOPA:

  • crosses the blood-brain barrier

  • metabolic precursor dopamine

  • L-DOPA:

    1. enters the brain

    2. decarboxylation to dopamine

• Receptor classification:

  • D₁:

    • adenyl cyclase stimulation

    • increased cyclic AMP levels

  • D₂:

    • adenyl cyclase inhibition

    • decreased cyclic AMP levels

• Receptor Localization:

  •  D₁:

    •  substantia nigra zona compacta

    •  presynaptic concentration in striatal axons from cortical neurons and from dopaminergic substantia nigral cells

  • D₂:

    •  postsynaptic localization on striatal neurons

    •  presynaptic localization of substantia nigral axons (basal ganglia neurons)

• Beneficial Drug Effects:

  • enhanced D₂ receptor simulation;enhanced benefit may require D₁ receptor simulation

  • Dopamine agonist/partial agonists (bromocryptine & lergotrile) antiparkinsonian ® effects

  • Dopamine antagonists induce Parkinsonism.

• Pharmacokinetics:L-DOPA

  • rapid absorption from small intestine, influenced by:

    • gastric emptying rate

    • local pH

    • food will delay the rise in plasma levodopa

    • Peak plasma levels: 1-2 hours after oral dose; half-life between one and three hours

  • 2/3 of levodopa dosage: urinary metabolites:

    • Major metabolites: homovanillic acid (HVA) & dihydroxyphenylacetic acid (DOPAC)

  • About 1%-3% of administered levodopa reaches the brain (the rest metabolized extracerebrally {namely decarboxylation to dopamine}

  • To achieve therapeutic brain levels, either:

    • large quantities of levodopa must be given or

    • levodopa must be given along with a dopa decarboxylase inhibitor, such as carbidopa (does not penetrate the brain)

  • With carbidopa (Lodosyn)

    •  peripheral decarboxylation of levodopa is lessened

    • levodopa plasma half-life: longer

    • more levodopa available for brain entry

    • use of a peripheral dopa decarboxylase inhibitor ® 75% reduction in daily levodopa.

• Clinical Use:levodopa (Dopar)

  • Tolerable doses diminish with time, i.e. adverse effects develop to previously tolerated dosages

  • Efficacy to L-DOPA diminishes with time (after approximately 3-4 years)

  • L-DOPA: does not stop disease progression

    • early L-DOPA treatment may reduce Parkinson's disease mortality rate

  • Long-term therapy associated with:

    • difficulties in clinical management

  • L-DOPA usage: Combination with dopa decarboxylase inhibitor

    • levodopa plus carbidopa

  • L-DOPA -- Clinical Efficacy:

    • most effective in diminishing bradykinesia; improves all Parkinson's disease symptoms

•  Adverse Effects:levodopa

  • Gastrointestinal Effects:levodopa

    • 20% frequency: when administered in combination with carbidopa

    • 80% frequency: what administered as monotherapy

      •  vomiting: stimulation of brain stem emetic center (tolerance to this effect often develops)

      •  Phenothiazines: avoid -- reduce efficacy of levodopa/disease exacerbation

  • Cardiovascular Effects:levodopa

    •  Arrhythmias: low incidence; possibly due to increased catecholamine peripheral synthesis

    • Incidence reduced further when levodopa is combined with carbidopa

    • Postural/orthostatic hypotension: Common side effect

      • less frequent a problem with continuing therapy

    •  Hypertension may occur if very large doses of levodopa, sympathomimetics, or nonselective MAO inhibitors are taken.

  •  Dyskinesias:levodopa

    • With long-term treatment -- dyskinesia frequency = 80%

    • dose-related; more common with combination treatment (L-DOPA plus carbidopa)

    •  Dyskinesias include:

      •  chorea, ballismus, athetosis, dystonia, myoclonus, takes, tremor

      •  the particular dyskinesia in a patient tends to remain constant

      • Most common dyskinesia: choreoathetosis

    • Management of dyskinesias:

      •  dosage reduction (reduced antiparkinsonism effect)

      •  drug holidays may be helpful

      • pallidotomy is often very effective in reducing/eliminating L-DOPA dyskinesia

  • Behavioral Effects:levodopa

    • Wide variety of adverse mental effects including:

      •  depression, agitation, insomnia, somnolence, anxiety, confusion, delusions, hallucinations, euphoria, nightmares, mood changes, personality changes

      •  More common in patients taking combination treatment (L-DOPA + carbidopa)

      •  drug holiday may be helpful

  • Response Fluctuations:levodopa

    • sometimes related to L-DOPA intake timing--referred to as:

      • wearing-off

      • end-of-dose akinesia

    • May be unrelated to L-DOPA intake timing:

      • on-off phenomenon

        •  alternating intervals of marked akinesia with intervals of control

        • unknown mechanism

        •  may be managed by use of dopamine agonists (e.g., bromocryptine)

        •  dietary changes may be useful

        •  other routes of levodopa administration may help

  • Miscellaneous Adverse Reactions:levodopa

    •  Mydriasis: leading to acute glaucoma

    • Blood dyscrasias: rare

    • precipitation/worsening: gout

    • many others

  • Drug Holidays:levodopa

    • may help some neurological/behavioral adverse levodopa effects (little advantage in managing the on-off phenomenon

    • levodopa withdrawal: gradually (rapid withdrawal ® akinesia)

    • Duration: 3-21 days

    • Patients benefit by requiring lower doses with reduced adverse mental effects and reduced dyskinesias

    •  Risks associated drug holiday (secondary to reduce mobility associated with worsened Parkinsonism)

      •  aspiration pneumonia, pulmonary embolism, venous thrombosis, depressive illness

  •  Drug Interactions:levodopa

    • pyridoxine (vitamine B₆): increases extracerebral levodopa metabolism unless carbidopa is given

    • levodopa: do not administer to patients taking MAO-A inhibitors or within two weeks after discontinuation of these drugs (risk for hypertensive crisis)

  •   Contraindications:levodopa

    •  Psychotic patients-- exacerbation of mental disturbance

    •  Patients with angle-closure glaucoma

      • patients with well-controlled & monitored chronic open- angle glaucoma may be given levodopa

    •  Careful management required in cases of:

      • cardiac disease (use carbidopa/L-DOPA combination)

      • peptic ulcer disease (bleeding may be precipitated by levodopa)

    • Avoid in patients with a history of melanoma/suspicious undiagnosed skin lesions-- levodopa is a precursor of melanin

Dopamine Agonists

• Overview:dopamine agonists

  • Dopamine agonists directly activate dopamine receptors

    • not requiring enzymatic activation (e.g. levodopa)

    • no toxic metabolites

  • Dopamine agonists include:

    • bromocriptine (Parlodel), pergolide (Permax),  (pramipexole, ropinirole {clinical trials})

• Bromocriptine  (Parlodel):

  • Overview:bromocriptine

    • ergot alkaloid--partial agonist at presynaptic dopamine D₂ receptors

    • Used also to treat hyperprolactinemia (at lower doses)

    • Oral administration; variably absorbed from the GI tract; the plasma levels -- 1-2 hours

    • Excreted in bile & feces

  • Clinical Use:bromocriptine  (Parlodel)

    •  first-line drug in Parkinsonism

    •  compared with levodopa: less likelihood of response fluctuation and dyskinesias

    • Variable clinical use of bromocriptine (sometimes early in treatment; sometimes prescribed to patients becoming refractory to levodopa)

    •  customization of levodopa and bromocriptine required on a patient to patient basis to achieve optimal clinical response

    •  Hypotensive reaction to bromocriptine: ® care required during initial dosing

    •  Stop Treatments If: psychiatric disturbance, ergotism, cardiac arrhythmia, erythromelalgia (painful, swollen feet)

  •  Adverse Effects: bromocriptine (Parlodel):

    • Gastrointestinal:bromocriptine

      •  Common initial side effect: anorexia, nausea, vomiting {reduced when medication is taken with food)

      • Others GI side effects:

        • constipation, dyspepsia, symptoms of reflux esophagitis

        • peptic ulceration with bleeding

    • Cardiovascular:bromocriptine

      •  Common: postural/orthostatic hypotension (early in therapy)

      • digital vasospasm -- occurs with long-term treatment {reversible by decreasing dosage}

      • cardiac arrhythmias: indication for drug discontinuation

    • Dyskinesias:bromocriptine

      •  similar to levodopa dyskinesias; reduction in total dopaminergic agents indicated

    • Mental Disturbances:bromocriptine

      •  More common/severe with bromocriptine than with levodopa. Symptoms include:

        • confusion, hallucinations, delusions, etc.

        • psychiatric effects dissipate with drug discontinuation

    • Miscellaneous Adverse Effect:bromocriptine

      • headache, nasal congestion, pulmonary infiltrates, erythromelalgia (may be associated with arthralgia), increased arousal

  •  Contraindications:bromocriptine  (Parlodel)

    • history/presence of psychosis

    • recent myocardial infarction

    •  relative contraindications: peripheral vascular disease or peptic ulcer

• Pergolide  (Permax): (Removed From Market 3/2007)

  • Activates both D₁ and D₂ receptors

  • prolongs levodopa responsive patients with response fluctuation

  • well tolerated (adverse effect similar to bromocriptine)

Monoamine Oxidase Inhibitors

• Overview:monoamine oxidase inhibitors

  • Monoamine oxidase A (MAO-A):  metabolizes serotonin/norepinephrine

  • Monoamine oxidase B (MAO-B):  metabolizes dopamine

• Selegiline (deprenyl): selective monoamine oxidase B inhibitor

  • prolongs levodopa effect (inhibits metabolism)

    • may allow levodopa dose reduction

    • may reduce mild on-off syndrome

    • may reduce wearing-off phenomenon

  • adjunctive treatment to L-DOPA

  •  Adverse/toxic Effects:selegiline

    • should not be used if patients are taking:

      •  meperidine (Demerol)

      •  tricyclic antidepressants

      •  serotonin specific reuptake inhibitors

      •  levodopa adverse effects:  may be enhanced by selegiline

    •  Combination of levodopa and nonselective MAO inhibitor may cause hypertensive crises

Amantadine  (Symmetrel)

• Overview:amantidine (Symmetrel)

  • Antiviral drug

  • Mechanism of action: unclear;may influence dopamine release /reuptake/synthesis

• Pharmacokinetics:amantadine

  • peak plasma levels: 1-4 hours following oral route of administration

  • half-life: 2-4 hours

  • urinary excretion: mainly unchanged

• Clinical Use:amantadine

  • short-term benefits; less potent levodopa

  • improves rigidity, tremor, bradykinesia

•  Adverse Effect:amantadine

  • adverse CNS effects include:

    • restlessness, agitation, excitement, hallucinations, confusion, irritability, depression

    • overdosage: acute psychosis

  • livedo reticularis: (peripheral vascular condition -- reddish blue skin mottling, affecting extremities) -- resolves with drug discontinuation

  • peripheral edema -- not associated with renal/hepatic/cardiac disease

  • headache, CHF, orthostatic hypotension, gastrointestinal disturbances {anorexia, nausea, dry mouth, constipation}, urinary retention

•   Contraindications:amantidine (Symmetrel)

  •  use with caution: seizure history or congestive heart failure

Anticholinergics

• benztropine (Cogentin)

• biperiden (Akineton)

• orphenadrine (Norflex)

• procyclidine (Kemadrin)

• trihexyphenidyl (Artane)

• Clinical Use:anticholinergics (antimuscarinics)

  • Improvement: rigidity/tremor

  •   Minor effect: bradykinesia

  • A patient unresponsive to one antimuscarinic may be responsive to another choice

•  Adverse Effects:antimuscarinics

  •  CNS:

    • drowsiness, restlessness, vegetation, delusions, hallucinations, mood changes, drowsiness, etc.

    • CNS effects -- occasionally associated with concurrent infection

    • withdrawal from drug -- adverse effects subside

    • Dyskinesias (earlier)

  •  Autonomic:common side effects

    • dry mouth, urinary retention, blurred vision, tachycardia, cardiac arrhythmias

  •  Miscellaneous:

    • nausea, vomiting,increased intraocular pressure, etc.

•  Contraindications:antimuscarinics

  • prostatic hyperplasia

  • obstructive gastrointestinal disease (pyloric stenosis/paralytic ileus)

Surgical Intervention

• Pallidotomy

• Thalamotomy

• Pallidal/Thalamic stimulator implantation

• Subthalamic nucleus (STN) stimulator implantation

"This is an axial MRI image through the basal ganglia. Included in the basal ganglia are the caudate and putamen, globus pallidus externus (GPe), and globus pallidus internus (GPi). These structures are adjacent to the internal capsule, which is composed of myelinated axons traveling from neurons in the cortex to structures deep within the brain, and further down in the brain stem and spinal cord. The thalamus is also shown in this figure inside the internal capsule and lateral to the third ventricle." From the work of Professor Iacono

"Here is a coronal image of the brain, cut from the top of the head to the bottom. This is adapted from a Shaltenbrand atlas image. The axons are stained black, and the neurons are unstained. In this figure you can see the putamen, GPe, and GPi. These structures are lateral to the internal capsule. Directly below the GPi is the optic tract. This bundle of axons carries the visual information from your eyes to the back of your brain, where it is processed". Professor Iacono's Laboratory

• Some Other Movement Disorders

  • Tremor:

    • Physiologic postural tremor (normal)

      • increased by:

        •  thyrotoxicosis

        •  isoproterenol (Isuprel)/epinephrine (IV)

        •  anxiety

        •  fatigue

    • Drug-Induced-- increasing normal physiologic tremor

      •  bronchodilators

      •  tricyclic antidepressants

      •  lithium

    • Tremors induced/enhanced by sympathomimetics: blocked by propranolol (sometimes not blocked by metoprolol -- ß₁ antagonist), suggesting tremor may be due to ß₂ receptor activation.

• Essential Tremor:

  • postural tremor, similar to normal physiologic tremor; maybe familial

  • ß₁ antagonists effective in reducing tremor indicative of possible ß₁receptor mediation

  • Drugs/Drug Classes useful in management of the essential tremor:

    •  Beta adrenergic receptor blockers

    •  Primidone (Mysoline)

    •  Alprazolam (Xanax) (occasionally useful);benzodiazepines/anti--arkinsonian agents not useful

• Intention Tremor:

  • may be caused by toxic reactions to alcohol and other drugs (e.g. phenytoin)

  • withdraw of causative agents alleviates symptoms

• Huntington's Disease

  • dominant, inherited

  • progressive chorea in dementia (typically adult onset)

  • Chorea: dopamine/acetylcholine/GABA basal ganglia imbalance

    • Mechanism: chorea

      •  Dopaminergic nigrostriatal pathway overactivity

      •  Possibilities:

        • postsynaptic dopamine receptor hypersensitivity

        • reduction in dopamine antagonizing neurotransmitter concentration

      •  anti-dopaminergic agents: reduce chorea

        • reserpine

        • phenothiazines and butyrophenones (haloperidol)

      •  dopaminergic drugs (e.g. levodopa): increase chorea

•  Chorea: complication of non-neurological disorder:

  • thyrotoxicosis, hypocalcemia, lupus erythematosus, hepatic cirrhosis, polycythemia vera rubra

    • treat the underlying disease

  •  Drug-Induced:chorea

    • levodopa, antimuscarinics, lithium, phenytoin, oral contraceptives, amphetamine, etc.

    • treatment: withdraw the drug

    •  Antipsychotics: acute or tardive dyskinesia -- more difficult to manage

• Ballismus

  • Treatment: dopamine-blocking drugs, e.g., perphenazine, haloperidol

• Athetosis & Dystonia

  • pharmacological treatments -- not usually satisfactory

  • agents to try:

    • diazepam, high-dose antimuscarinic agents, levodopa, baclofen, phenothiazines, amantadine

• Tics

  • unknown pathophysiology

  • chronic, multiple tics -- Tourette's syndrome

    • Treatment: haloperidol (most effective available)

    • Other treatment options, if haloperidol is not effective:

      • temazepam (Restoril), carbamazepine (Tegretol), clonidine (Catapres), fluphenazine (Prolixin) 

•   Drug-Induced Dyskinesias

  •  Phenothiazines: acute dyskinesia/dystonia

    • Treatment: antimuscarinic agents primarily:

      •  benztropine (Cogentin)(IV)

      •  diphenhydramine (Benadryl) (IV)

      •  biperiden (Akineton) (IV/intramuscular)

      •  diazepam (Valium) (IV)

• Tardive dyskinesia:

  •  Consequence of long-term antipsychotic drug treatment

  • Characteristics:

    •  Dosage reduction: worsens symptoms

    •  Dosage increase: suppresses symptoms

    •  Difficult to treat; in adults may well be irreversible

  •  Newer antipsychotic agents, e.g. olanzapine and risperidone do not appear to cause tardive dyskinesia, thus avoiding the problem

• Wilson's disease:

  • recessive, inherited copper metabolism error

  • reduced serum copper/ceruloplasmin

  • increased copper concentration: brain, viscera

  • Clinical Presentation:Wilson's disease

    • hepatic dysfunction

    • neurologic dysfunction

  • Treatment:Wilson's disease

    • Penicillamine (dimethylcysteine) -- copper chelating agent

    • Trientine, Imdur chelating agent -- for patients not tolerating penicillamine

    • Zinc acetate: increases copper excretion

    • Zinc sulfate: decreases copper absorption