Drugs for Parkinon’s disease• Parkinson's disease

– progressive tremor– Bradykinesia and rigidity

– degeneration of the dopaminergic nigrostriatal pathway

– decrease in the striatal concentration of dopamine

– presence of Lewy bodies

• Degeneration of the nigrostriatal pathway leads to the depletion of the neurotransmitter dopamine

• therapy involved the administration of its precursor levodopa or agents that mimic the action of dopamine

Drug Therapy• Decrease cholinergic activity within

Basal Ganglia– Activating Dopamine receptors in

Substantia Nigra feeding back to Cholinergic Cells in the striatum

– Antagonize Acetylcholine receptors

Antiparkinsonian Drugs • Symptomatic Therapy

– The traditional approach to treating patients with Parkinson's disease is the administration of drugs to alleviate symptoms.

• Anticholinergic Agents and Amantadine • Levodopa • Synthetic Dopamine Agonists

Anticholinergic Agents

• Act by correcting the balance between dopamine and acetylcholine

• trihexyphenidyl and benztropine• Antagonists at muscarinic receptors• raise the concentration of dopamine in the

synaptic cleft

Anticholinergic Agents

• adverse effects– impairment of memory and hallucinations– impaired ocular accommodation– dryness of the mouth– Constipation– urinary retention– vasodilatation

Amantadine

• resembles the anticholinergic drugs• appears to enhance synthesis, release, or

reuptake of dopamine from the surviving Nigral Neurons

• often results in some improvement in rigidity and bradykinesia.

• induce ankle edema and livedo reticularis

of the legs

Levodopa

• the cornerstone of symptomatic therapy• decarboxylated to dopamine• usually administered with a peripheral

decarboxylase inhibitor

L Dopa- Pharmacokinetics

• L Dopa is readily absorbed from GI Tract• Large amount of L Dopa has to be given due to

First Pass Effect • L Dopa metabolized by dopa decarboxylase in

liver and periphery to dopamine• Secreted in urine unchanged or conjugated with

glucoronyl sulfate• Most of L Dopa converted to NE and EPI

Effects of L Dopa on the Symptoms of Parkinson Disease

• L Dopa fairly effective in eliminating most of the symptoms of Parkinson Disease

• Bradykinesia and rigidity respond quickly• Reduction in tremor effect with continued

therapy• L Dopa less effective in eliminating

postural instability and shuffling gait

Effects of L Dopa on Behavior

• L Dopa partially changes mood by elevating mood

• L Dopa increases patient sense of well being

Effects of L Dopa on Cardiovascular System• cardiac stimulation due to beta adrenergic

effect on heart• Elderly- transient tachycardia, cardiac

arrhythmias and hypertension

Effects of L Dopa on Gastrointestinal System

• Nausea, Vomiting, and Anorexia• Abdominal Pain• Diarrhea and Constipation• May cause activation of Peptic Ulcer

Synthetic Dopamine Agonists

• mimic the effect of dopamine by binding directly with the post-synaptic dopamine receptors

• Bromocriptine, pergolide and lisuride• tetracyclic ergot derivatives• longer plasma half-lives

Synthetic Dopamine Agonists

• The nonergot dopamine agonists ropinirole and pramipexole

• higher doses, they produce similar side effects

Protective Therapy • treat the underlying pathogenesis of

Parkinson's disease so that neurodegeneration is prevented or delayed

• Possible mechanisms of cell damage :– Autoimmunity– excessive excitatory drive– disturbance of trophic factors– increase in the concentration of toxic free

radicals

Protective Therapy

• vitamins• co-enzyme Q10• dopamine agonists• monoamine oxidase type B (MAOB)

inhibitors.

Management of Different Stages of Disease

• Newly Diagnosed Parkinson's Disease – Hoehn-Yahr stage I– the patient has minor symptoms that are not

sufficiently troublesome to affect routine daily activities

– selegiline, levodopa, or a synthetic dopamine agonist or no pharmacotherapy

• National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.

Levodopa

Dopamine Agonist

Monoamine oxidase type B(MAOB) inhibitors

ono

Beta Adrenergic agents

Amantadine

Anticholinergics

Severe Parkinson's Disease

• Management is directed toward decreasing the dose of the drug causing the most troublesome side effects and raising the dose of an alternative drug

Levodopa

Dopamine agonist

MOAB inhibitors

COMT

Amantadine

Management of Adverse Reactions to Therapy

• nausea and hypotension– associated with peak plasma concentrations

of dopaminomimetic agent– minimized by taking the medications after light

meals or snacks.– Domperidone 10 to 20 mg

Management of Adverse Reactions to Therapy

• Hypotension– increased intake of water and salt– fludrocortisone 0.1 mg once or bid– midodrine 2.5 to 20 mg

Management of Adverse Reactions to Therapy• Dyskinesia, fluctuations in mobility

– unpredictable "on-off" reactions– predictable "wearing-off" effects– Avoid high protein meals

Management of Adverse Reactions to Therapy• Psychiatric side effects

– confusion, visual hallucinations, and paranoia– begin as nocturnal phenomena– Neuroleptic drugs in general are

contraindicated

Thank you

Calne D. N Engl J Med 1993;329:1021-1027

Structure of the Dopamine D2A Receptor

Calne D. N Engl J Med 1993;329:1021-1027

Dopamine D1A Receptor Coupled to a G Protein and Linked to Adenylate Cyclase in a Striatal Neuron

Calne D. N Engl J Med 1993;329:1021-1027

Dopamine D1A Receptor Coupled to a G Protein and Linked to Adenylate Cyclase in a Striatal Neuron

Agents that Increase Dopamine functions• Increasing the synthesis of dopamine - l-Dopa• Inhibiting the catabolism of dopamine -

selegiline• Stimulating the dopamine receptor sites

directly - bromocriptine & pramipexole• Blocking the uptake and enhancing the release

of dopamine - amantadine