antiparkinson drugs09 (1)

7/31/2019 Antiparkinson Drugs09 (1)

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Antiparkinson AgentsAntiparkinson Agents


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A neurodegenerative disordercharacterized by progressive motordysfunction which includes:Tremor

Rigidity

Bradykinesia (slow movement)

disturbance of posture

Affects ~ 1% of over age 65

Parkinsons Disease


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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


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CLASSIFICATION

Anticholinergic Drugs:

- Benzotropine (0.5-0.6 mg/day)

- Trihexyphenidyl Hydrochloride (THP){2-12 mg/day}

- Procyclidine hydrochloride (5-20 mg/day)


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Contd

Antihistamines

- Diphenhydramine

Benadryl

75-100 mg/day

Capsule and syrup


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Contd..

Dopamine Drugs-Levadopa

Larodapa

2-3 gms/day Tablet

-Carbidopa & L.dopa

Sinemet

10-100mg/day

Tablet


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Contd

-Selegline

Deprenyl

5-10 mg/day

Tablet

-Amantidine Hydrochloride

Symmetrel 10-100mg/day

Tablet


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Drugs Used in the Treatment ofParkinsonism

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)


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Levodopa

Pharmacological properties No change in muscle tone or movement innormal 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


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LDopa

Pharmacological properties (cont.)Cardiovascular

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

receptors Cardiac stimulation


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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 intestinalmucosa

Dietary protein (amino acids compete for

transport)


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L-Dopa

Pharmacokinetics (cont.)

~ 95% of l-dopa is metabolized in the

periphery to dopamine; metabolism may be

increased with prolonged therapyPasses from gut lumen through liver

Only a small portion enters the brain

Metabolites are excreted in urine


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ORAL DISPOSITION OF LEVODOPA


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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%), cardiac

arrhythmias


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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


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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


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L-Dopa

Drug interactionsPyridoxine (vitamin B6) increases peripheral

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

Antipsychotic drugs are dopaminergic antagonistsand thus counteract the effects of dopa

MAO inhibitors increase the effects of dopa, may leadto hypertensive crises

Anticholinergic drugs may slow gastric emptying

time and decrease absorption of l-dopaTricyclic antidepressants may aggravate

hypotensive symptoms


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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 doesnt cross

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

Highly effective in first 2 5 years


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Carbidopa

Advantages

Allows reduction in dopa dose

Nausea and vomiting are decreased

Cardiac side effects decreased

Pyridoxine (vitamin B6) antagonism of

levodopa prevented


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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 reached

quickly and persists 3-4 times longer than l-

dopa


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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 somewhatEffective as monotherapy in mild PD also

helpful in pts with advanced disease


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Dopamine agonists

Kinetics

Pramipexole -Largely eliminated unchanged

by kidneys

Ropinirol metabolized by CYP1A2 and

other drugs may slow its elimination


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Non-ergot Dopamine 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


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Dopamine agonists

ContraindicationsDA agonists are contraindicated in pts with ahistory of:

Psychotic illness

Recent myocardial infarct

Active peptic ulceration


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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 may delayneed for levodopa Rx

adjunctive therapy with l-dopa (lower the doserequirement of levodopa)

May be effective in restless leg syndrome


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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


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Amantadineeffective 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


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Other drugs used in theTreatment of Parkinsonism

Some other drugs are used as adjunct tol-dopa therapy and generally less effectivethan dopaminergic drugs

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


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Other 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


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Antimuscarinic drugs for PD

Adverse reactions

CNS confusion, delirium, somnolence,

hallucinations

Peripheral may produce cycloplegia,constipation, and urinary retention in certain

patients


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MAO inhibitors used in theTreatment of Parkinsonism

Selegiline (Eldepryl)selegiline selectively and irreversibly inhibits

MAOBto 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


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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 experiencewearing off or on-off difficulties with ldopa


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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)


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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.


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Some Anesthetic implications

Abrupt withdrawal of levodopa can lead toskeletal muscle rigidity which can interfere

with adequate ventilation

Continue levodopa therapy duringperioperative period including usual morning

dose

Consider possibility of orthostatic

hypotension, cardiac dysrhythmias, and

maybe hypertension in pts Rx with

levodopa


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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; secondedition; 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 1115-1121INTERNET REFERANCES

http://jama.ama-assn.org/content/291/9/1065.3.sh


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