antiparkinson drugs09

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Antiparkinson Agents Art Hupka, Ph.D.

2009



A neurodegenerative disordercharacterized by progressive motordysfunction which includes:Tremor

Rigidity

Bradykinesia (slow movement )

disturbance of posture

Affects ~ 1% of over age 65

Parkinson’s Disease




Signs and symptoms of parkinsonism aredue to the degeneration of dopaminergic neurons projecting from the substantia

nigra to the striatum• Individuals with parkinsonism have a deficiency of

dopamine




there are many hypotheses, the causes ofthe neuronal degeneration in Parkinson‟s

disease remain largely unknown

Oxidative stress theory• Oxidation of DA yields highly reactive free radicals that are

toxic to DA neurons and lead to degeneration

• Agents that prevent DA oxidation may be neuroprotective(selegiline)

Environmental toxins theory• MPTP -- MPP+ interacts with mitochondria cell death

• Selegiline neuroprotective



D1

D2



Parkinsonism

SymptomsTremor

• pill rolling contractions – Often present at rest but disappear during purposeful

movement

Bradykinesia• decreased spontaneous movement, loss of normal

associated movement, slow initiation of movement

Rigidity• due to increased muscle tone

• Cog-wheel like movements



Parkinsonism

Symptoms (cont.)Posture

• progressive stooped position

Psychological changes such as depressionand dementia

Others• Masked facies

• Hallucinations (~ ¼ of patients)

• Oily skin urinary incontinence constipation

• Loss of smell neuropathic pain dizziness



Parkinsonism

Neurochemical defectNormal voluntary movement is controlled by a

balance of dopaminergic and cholinergic nervousactivity

In parkinsonism, there is a deficiency of dopamine,allowing relative cholinergic dominance



Parkinsonism

Parkinson variants

It has become apparent that what has beencalled Parkinson‟s Disease is not a single

disorder

Consequently, symptoms and response todrugs will vary



Pharmacological Intervention

Pharmacological approaches

1. Decrease functional cholinergic component

2. Increase function of nigrostriataldopaminergic component (major approach )



Drugs Used in the Treatment ofParkinsonism

Levodopa – single most effective agent

immediate precursor of dopamine

crosses the blood brain barrier by means oftransporter for aromatic amino acids

Pharmacological properties

• Levodopa itself is fairly inert

• activity is due to conversion to dopamine in CNS,thus increasing dopamine in the basal ganglia(replacement therapy )



AADC or LAAD= aromatic aminoacid decarboxylaseCOMT = catechol-O-methyltransferaseMAO = monoamine oxidasteBBB = blood brain barrier

Metabolism of levodopa



l- dopa kinetics and drug targets



Levodopa

Pharmacological properties• No change in muscle tone or movement innormal individuals

• Bradykinesia and rigidity are reversed

quickly• reversal of tremor requires continued

therapy

• Changes in mood associated with

parkinsonism are reversed – patients more alert and interested in

environment

– dementia may not reverse



LDopa

Pharmacological properties (cont.)Cardiovascular

– Asymptomatic (usually ) orthostatic hypotension – Dopamine stimulates both alpha and beta

receptors – Cardiac stimulation



LDopa

Endocrine• Dopamine important in physiological regulationof anterior pituitary function

• Prolactin secretion inhibited



LDopa

Disposition

• Well absorbed orally via aromatic aminoacid transporter but can be altered by

–Rate of gastric emptying

–pH of gastric fluids (acidity interferes with

absorption )

–Degradation by enzymes in intestinalmucosa

–Dietary protein (aa compete for transport )



L-Dopa

Pharmacokinetics (cont.)

~ 95% of l-dopa is metabolized in theperiphery to dopamine; metabolism may be

increased with prolonged therapyExtensive first pass effect as passes from gut

lumen through liver

Only a small portion entering the brain

Metabolites excreted in urine



ORAL DISPOSITION OF LEVODOPA



L-Dopa

Adverse effects (caused mostly by DA)Most patients treated with l-dopa develop side

effects.

Intensity and type vary at different stages oftherapy

Early side effects

• Dose dependent; tolerance may develop – GI – nausea, vomiting (80%)

– CVS – orthostatic hypotension (30%), cardiacarrhythmias



L-Dopa

Adverse effects (cont.)Long term effects

• severity correlates with the degree of clinical improvement,duration of therapy and dose. No tolerance develops

• Abnormal involuntary movements

– Levodopa-induced dyskinesia (80% after 1 year)

– Most commonly jerky, dance-like movements of armsand/or head

– Reduction in dosage required

• Psychiatric and behavioral disturbances (15%) – Depression anxiety agitation insomnia delusions

– Hallucinations euphoria nightmares



L-dopa

Long term adverse effects

On-Off” syndrome – oscillations inperformance involving rapid changes from

akinesia to dyskinesia• different from „end of dose‟ or „wearing off effect‟

• Mechanism of On-Off syndrome unclear



Wearing off effect

„end of dose‟ or „wearing off effect‟ – Early in PD, still some intact DA neurons

– Treatment elevates levels in striatum and some takeninto DA neurons

– As end of levodopa dose interval, levels of DA fall instriatum but some DA in neuron buffers and keepsneurons functional

– Late in PD, DA neurons are gone and so is bufferingeffect resulting in loss of effectiveness near end of dose

– Can increase dose or frequency of dosing but run risk ofdyskinesias



L-Dopa

Drug interactionsPyridoxine (vitamin B6) increases peripheral

conversion of dopa to dopamine (co-factor for LAAD)

Antipsychotic drugs are dopaminergic antagonists

and thus counteract the effects of dopaMAO inhibitors increase the effects of dopa, may

lead to hypertensive crises

Anticholinergic drugs may slow gastric emptying

time and decrease absorption of l-dopaTricyclic antidepressants – may aggravate

hypotensive symptoms



Drugs Used in the Treatment ofParkinsonism

CarbidopaL-aromatic amino acid decarboxylase (LAAD) is

responsible for the conversion of dopa to dopamine

LAAD activity causes 95% of a dose of dopa to be

converted to dopamine before entering the CNS.

Carbidopa is an inhibitor of this peripheraldecarboxylase and allows greater amounts ofdopa to enter the CNS (carbidopa doesn’t cross

BBB ) – Only available in combination with l-dopa (Sinemet )

– Highly effective in first 2 – 5 years



Carbidopainhibits

peripheralLAAD topreventconversion oflevodopa toDA



Carbidopa

Advantages

• Allows reduction in dopa dose

• Nausea and vomiting are decreased

• Cardiac side effects decreased

• Pyridoxine (vitamin B6) antagonism oflevodopa prevented



Adverse effects – increased central side effectsof dopa

Earlier development of long term side effects possible

Slow release form (SINEMET CR) is availablewhich may help manage „wearing off‟ effect

New on the market is a formulation (Parcopa)which dissolves on the tongue

This may be useful since Parkinsons patients oftenhave trouble swallowing tablets

Carbidopa



Other Drugs Used in theTreatment of Parkinsonism

COMT Inhibitors

Tolcapone (Tasmar)

Entacapone (Comtan)

(Remember Al Capone and Chicago Organized Mob )



tolcapone

COMT inhibitors



COMT Inhibitors

Pharmacological properties – drugsinhibit COMT, thereby increasing theduration of action of l-dopa and dopamine

(remember COMT inactivates l-dopa and dopamine ).

There is a kinetic difference in these drugs in

that tolcapone is highly lipid soluble andreaches CNS. Entacapone does not.



COMT Inhibitors

Adverse reactions – diarrhea, brightorange discoloration of urine, increased l-dopa side effects (dyskinesias, nausea, confusion )

Increased amino-transferase activity(indication of hepatotoxicity ) with tolcaponewhich may require discontinuation

• Apparently not a problem with entacapone.



COMT Inhibitors

Clinical uses – adjunct to l-dopa inpatients with stable PD and in patientswith end of dose (“wearing off”) problems

with l-dopa/carbidopa therapy.A combination of carbidopa + l-dopa +

entacapone is available (Stalevo)

• Simplifies regimen• Less tablets consumed

• Costs less than individual drugs

• Especially useful for pts with wearing off problems



Dopamine agonists used in theTreatment of Parkinsonism

Ergot derivativesBromocryptine (Parlodel) is the prototype

but now rarely used.

• Pergolide (Permax) no longer available because of valularheart disease.

directly stimulate dopamine receptor (D2)

• Not dependent on uptake into DA neurons

Rapidly absorbed, effective levels reachedquickly and persists 3-4 times longer than l-dopa



Non-ergot DA Agonists

ropinirole (Requip) and pramipexole(Mirapex) – non-ergot DA agonists

• Ropinirole relatively pure D2 agonist

• Pramipexole prefers D3

They also alter cellular metabolism so thatprogression of disease appears to beslowed somewhat

Effective as monotherapy in mild PD alsohelpful in pts with advanced disease



Dopamine agonists

Kinetics

Pramipexole -Largely eliminated unchangedby kidneys

Ropinirol – metabolized by CYP1A2 andother drugs may slow its elimination



Non-ergot DA agonists

Adverse effects• Anorexia, nausea, vomiting

• Confusion, hallucinations, delusions and otherpsychiatric reactions are more common and

severe than with levodopa• Orthostatic hypotension can occur early in

treatment. Occasional cardiac arrhythmias

• Pramipexole and ropinirole may cause sudden onset of sleep with no warning



Dopamine agonists

ContraindicationsDA agonists are contraindicated in pts with ahistory of:

• Psychotic illness

• Recent myocardial infarct

• Active peptic ulceration



Dopamine agonists

Clinical use• Useful doses usually established within week or

two

• Often used as initial PD treatment rather than otheradjuncts

• Used as initial therapy (without l-dopa ) that maydelay need for levodopa Rx

• adjunctive therapy with l-dopa (lower the dose

requirement of levodopa )• May be effective in restless leg syndrome

h d d h



Other drugs Used in theTreatment of Parkinsonism

Amantadine (Symmetrel)antiviral agent found to be effective against

parkinsonism

Apparently acts by increasing dopaminerelease from intact dopaminergic neurons• Also blocks NMDA glutamate receptors

• Some anticholinergic effects

• Block reuptake of DA into presynaptic terminal



Amantadineeffective quickly but for short time (6-8 weeks)

Adjunct used early in treatment

Adverse effects – are mild and reversibleand include:

Hallucinations, confusion, and nightmares

Insomnia, dizziness, lethargy, slurred speech

Long term use may result in livido reticularis

O h d d i h



Other drugs used in theTreatment of Parkinsonism

Antimuscarinic drugs – used as adjunctto l-dopa therapy and generally lesseffective than dopaminergic drugs

Central acting agents block the unopposedcholinergic effects in the basal ganglia ofparkinsonism patients



Antimuscarinic drugs for PD

trihexyphenidyl (Artane) and benztropine (Cogentin)• Decrease tremor

• less effect on rigidity and bradykinesia

• Generally have little peripheral effect, but mayreduce some autonomic symptoms

Useful adjunct early and advanced PD alsouseful to reduce parkinson symptoms causedby DA receptor antagonists such ashaloperidol



Antimuscarinic drugs for PD

Adverse reactions

CNS – confusion, delirium, somnolence,hallucinations

Peripheral – may produce cycloplegia,constipation, and urinary retention in certainpatients

MAO inhibitors



MAO inhibitors

MAO i hibit d i th



MAO inhibitors used in theTreatment of Parkinsonism

Selegiline (Eldepryl)selegiline selectively and irreversibly inhibits

MAOB to decrease catabolism of DA (mostly

MAO B in striatum )• Prolongs and enhances the effects of levodopa(allows dosage reduction )

• Does not inhibit peripheral catabolism ofcatecholamines



Selegiline

Used in early or mild PD alone or as anadjunct in advanced disease

Reduces levodopa dose requirement and mayimprove motor function in pts who experience„wearing off‟ or „on-off‟ difficulties with ldopa



Selegiline

Adverse effects• Some metabolites are methamphetamine and

amphetamine which produce some of the adverseeffects

• Nausea (10%), dizziness (7%), hallucinations,confusion, depression

• Insomnia if taken late in the day

• Dose must be kept at 10 mg/day or less to

selectively inhibit MAOB, otherwise adversereactions associated with non-specific MAOs occur – Hypertension with tyramine

– Potential serotonin syndrome (e.g. SSRIs, meperidine)



Therapy for Parkinsonism

Goal

No cure of underlying pathology (although gene

therapy is being tested )

Drug + physiotherapy + exercise +psychological support → provide maximal

symptomatic relief and permits a near normallifespan.



Some Anesthetic implications

Abrupt withdrawal of levodopa can lead toskeletal muscle rigidity which can interferewith adequate ventilation

Continue levodopa therapy duringperioperative period including usual morningdose

Consider possibility of orthostatichypotension, cardiac dysrhythmias, andmaybe hypertension in pts Rx withlevodopa

antiparkinson drugs09

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