Antiparkinson Agents

Parkinsons Disease
A neurodegenerative disorder characterized by progressive motor dysfunction which includes:
Tremor Rigidity Bradykinesia (slow movement) disturbance of posture

Affects ~ 1% of over age 65

Anti Parkinsonian Drugs

These are the specific drugs used to treat the ExtraPyramidal Side effects of antipsychotic agents. EPS: includes
Parkinsonism Akathisia Acute Dystonia Tardive Dyskinesia

CLASSIFICATION
Anticholinergic Drugs: - Benzotropine (0.5-0.6 mg/day) - Trihexyphenidyl Hydrochloride (THP) {2-12 mg/day} - Procyclidine hydrochloride (5-20 mg/day)

Contd
Antihistamines - Diphenhydramine Benadryl 75-100 mg/day Capsule and syrup

Contd..
Dopamine Drugs -Levadopa Larodapa 2-3 gms/day Tablet -Carbidopa & L.dopa Sinemet 10-100mg/day Tablet

Contd
-Selegline Deprenyl 5-10 mg/day Tablet -Amantidine Hydrochloride Symmetrel 10-100mg/day Tablet

Drugs Used in the Treatment of Parkinsonism

Levodopa single most effective agent
immediate precursor of dopamine crosses the blood brain barrier by means of transporter 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)

Levodopa
Pharmacological properties
No change in muscle tone or movement in normal individuals Bradykinesia and rigidity are reversed quickly 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
Pharmacokinetics
Well absorbed orally via aromatic amino acid transporter but can be altered by Rate of gastric emptying pH of gastric fluids (acidity interferes with absorption) Degradation by enzymes in intestinal mucosa Dietary protein (amino acids compete for transport)

L-Dopa
Pharmacokinetics (cont.)
~ 95% of l-dopa is metabolized in the periphery to dopamine; metabolism may be increased with prolonged therapy Passes from gut lumen through liver Only a small portion enters the brain Metabolites are 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 of therapy

Early side effects

Dose dependent; tolerance may develop
GI nausea, vomiting (80%) CVS orthostatic hypotension (30%), cardiac arrhythmias

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 arms and/or head Reduction in dosage required

Psychiatric and behavioral disturbances (15%)

Depression, anxiety,agitatio, insomnia, delusions Hallucinations, euphoria ,nightmares

L-dopa
Long term adverse effects
On-Off syndrome oscillations in performance involving rapid changes from akinesia to dyskinesia
different from end of dose or wearing off effect Mechanism of On-Off syndrome unclear

L-Dopa
Drug interactions
Pyridoxine (vitamin B6) increases peripheral conversion of dopa to dopamine (co-factor for LAAD) Antipsychotic drugs are dopaminergic antagonists and thus counteract the effects of dopa MAO inhibitors increase the effects of dopa, may lead to hypertensive crises Anticholinergic drugs may slow gastric emptying time and decrease absorption of l-dopa Tricyclic antidepressants may aggravate hypotensive symptoms

Drugs Used in the Treatment of Parkinsonism

Carbidopa
L-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 peripheral decarboxylase and allows greater amounts of dopa to enter the CNS (carbidopa doesnt cross BBB)
Only available in combination with l-dopa (Sinemet) Highly effective in first 2 5 years

Carbidopa
Advantages
Allows reduction in dopa dose Nausea and vomiting are decreased Cardiac side effects decreased Pyridoxine (vitamin B6) antagonism of levodopa prevented

Carbidopa
Adverse effects increased central side effects of dopa
Earlier development of long term side effects possible

Slow release form (SINEMET CR) is available which 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 often have trouble swallowing tablets

Dopamine agonists used in the Treatment of Parkinsonism

Ergot derivatives
Bromocryptine (Parlodel) is the prototype but now rarely used.
Pergolide (Permax) no longer available because of valular heart disease.

directly stimulate dopamine receptor (D2)

Not dependent on uptake into DA neurons

Rapidly absorbed, effective levels reached quickly and persists 3-4 times longer than ldopa

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 that progression of disease appears to be slowed somewhat Effective as monotherapy in mild PD also helpful in pts with advanced disease

Dopamine agonists
Kinetics
Pramipexole -Largely eliminated unchanged by kidneys Ropinirol metabolized by CYP1A2 and other drugs may slow its elimination

Non-ergot Dopamine agonists

Adverse effects
Anorexia, nausea, vomiting Confusion, hallucinations, delusions and other psychiatric 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
Contraindications
DA agonists are contraindicated in pts with a history 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 other adjuncts Used as initial therapy (without l-dopa) that may delay need for levodopa Rx adjunctive therapy with l-dopa (lower the dose requirement of levodopa) May be effective in restless leg syndrome

Other drugs Used in the Treatment of Parkinsonism

Amantadine (Symmetrel)
antiviral agent found to be effective against parkinsonism Apparently acts by increasing dopamine release from intact dopaminergic neurons
Also blocks NMDA glutamate receptors Some anticholinergic effects Block reuptake of DA into presynaptic terminal

Amantadine
effective quickly but for short time (6-8 weeks) Adjunct used early in treatment

Adverse effects are mild and reversible and include:

Hallucinations, confusion, and nightmares Insomnia, dizziness, lethargy, slurred speech

Other drugs used in the Treatment of Parkinsonism

Some other drugs are used as adjunct to l-dopa therapy and generally less effective than dopaminergic drugs
Central acting agents block the unopposed cholinergic effects in the basal ganglia of parkinsonism patients

Other drugs for PD

trihexyphenidyl (Artane) and benztropine (Cogentin)
Decrease tremor less effect on rigidity and bradykinesia Generally have little peripheral effect, but may reduce some autonomic symptoms

Useful adjunct early and advanced PD also useful to reduce parkinson symptoms caused by DA receptor antagonists such as haloperidol

Antimuscarinic drugs for PD

Adverse reactions
CNS confusion, delirium, somnolence, hallucinations Peripheral may produce cycloplegia, constipation, and urinary retention in certain patients

MAO inhibitors used in the Treatment of Parkinsonism

Selegiline (Eldepryl)
selegiline selectively and irreversibly inhibits MAOB to decrease catabolism of DA (mostly MAOB in striatum)
Prolongs and enhances the effects of levodopa (allows dosage reduction) Does not inhibit peripheral catabolism of catecholamines

Selegiline
Used in early or mild PD alone or as an adjunct in advanced disease Reduces levodopa dose requirement and may improve 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 adverse effects 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 adverse reactions 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 normal lifespan.

Some Anesthetic implications

Abrupt withdrawal of levodopa can lead to skeletal muscle rigidity which can interfere with adequate ventilation
Continue levodopa therapy during perioperative period including usual morning dose

Consider possibility of orthostatic hypotension, cardiac dysrhythmias, and maybe hypertension in pts Rx with levodopa

Bibliography
Stuart and Laria Principles and practice of Psychiatric Nursing 8th edition Mosby Publishers Pp 604-606 Kapoor Bimla; Psychiatric Nursing; first edition; Kumar Publishing Home, New Delhi; Pp 112-129 .Varcarolis Elizabeth M Foundation of Psychiatric Nursing; second edition; W.B.Saunders Company. Philadelphia; Pp 451-453 Malik Santosh Textbook of Psychiatric Nursing; first edition; Lotus Publishers, Jalandhar; Pp 285-293 Kaplans & Sadocks Synopsis Of Psychiatry; tenth edition; lippincott William & Wilkins. Philadelphia; Pp 1115-1121 INTERNET REFERANCES http://jama.ama-assn.org/content/291/9/1065.3.sh