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: Structure of the Dopamine D2A Receptor

Calne D. N Engl J Med 1993;329: 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: 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