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Parkinsons Disease
A neurodegenerative disorder characterized by progressive motor dysfunction which includes:
Tremor Rigidity Bradykinesia (slow movement) disturbance of posture
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
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
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
L-Dopa
Adverse effects (cont.)
Long term effects
severity correlates with the degree of clinical improvement, duration of therapy and dose. No tolerance develops
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
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
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
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
Amantadine
effective quickly but for short time (6-8 weeks) Adjunct used early in treatment
Useful adjunct early and advanced PD also useful to reduce parkinson symptoms caused by DA receptor antagonists such as haloperidol
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)
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