AntiParkinsonia drugs: - Normally there is balance between dopamine & acetylcholine in CNS but in Parkinson disease this balance

distorted toward acetylcholine (acetylcholine hyperactivity) - Strategy of treatment is restore balance to normal position, this done by: o Increase dopaminergic activity o Antagonizing the cholinergic activity - Currently available drugs cannot cure PD, they only symptomatic release - We cannot give dopamine because: o Dopamine cannot cross the BBB o Dopamine cannot be given orally Classification: 1) Drug affecting brain dopaminergic system Dopamine precursor e.g., L-Dopa or levodopa L-Dopa combined with peripheral decarboxylase inhibitors Carbidopa or Benserazied Dopaminergic agonists Bromocriptine, Robinirole, Pramipexole Monoamine oxidase inhibitor MOA-B selegiline COMT inhibitors Entacapone & Tolecapone Dopamine facilitator Amantidine 2) Drug affecting brain cholinergic system Central anticholinergic Benzhexol & procyclidine Centrally acting antihistaminic Orphenadrine & Promethazine LEVODOPA: - Or L-dopa - Dopamine precursors - Orally absorbed from GI small intestine - Short half-life - Easily pass BBB & reach basal ganglia to dopaminergic neuron - We have to give the patient very large dose; because L-dopa will decarboxylated to dopamine peripherally before reaching CNS, so only small amount will be available to pass BBB o Large dose of L-dopa will leads to: Sever nausea These effects can be produced by L-dopa & dopamine Vomiting formed after decarboxylation Arrhythmia Hypotension - We can prevent side effect of large dose of L-dopa by: o Select drug which can inhibit peripheral decarboxylation of L-dopa o Select drug which can inhibit the peripheral decarboxylation of L-dopa but cannot cross the BBB - Benserazide or Carbidopa is the drug which can inhibit peripheral decarboxylation of L-dopa, so it will lead to: 1) Decrease L-dopa dose to 25% of initial dose, leading to decrease incidence of side effects to 15% or less 2) Increase brain concentration of dopamine to double or triple - If L-dopa taking with food rich in protein & amino acids it will inhibit both GIT absorption & passage of L-dopa to CNS o Better to give L-dopa at least 45 minute before rich protein & amino acid rich meal - Side effects of L-Dopa: o Acute: experienced by most patients first & disappear after few weeks: Nausea, anorexia & vomiting, which relieved by anti-emetic called Domperidone Domperidone could antagonize the dopamine in CTZ But domperidone cannot antagonize the dopamine effect on basal ganglia Postural hypotension

Tachycardia & arrhythmia Mydriasis, lead to increase intra-ocular pressure (IOP) Psychiatric symptoms, like schizophrenia because of increase in DAergic activity in CNS Saliva & urine turned into brown color o Slowly developing: In form of involuntary writhing movements (Dyskinesia) Writhing movement mainly in face & in upper limb Occur in majority of patients Occur later on course of therapy (usually 2 years) Affecting face & upper limb Can be severe Severity of writhing movement can be decreased by dose reduction Schizophrenia is the opposite of Parkinsonism o Drug antagonize mono amine produce Parkinson o Drug elevate dopamine leads to Schizophrenic manifestations

Drug interactions: - Pyridoxine or vitamine B6 decrease L-dopa o Pyridoxine is a co-factor in decarboxylation of L-dopa accerlate it - MAOI (Mono amine oxidase inhibitor): o Unselective phenelzine leads to hypertensive crisis o Selective toward B type of MAOI useful therapeutically will increase effect of L-Dopa as selegiline - Tricyclic antidepressants useful drug L-Dopa contraindication: Psychiatric patient do not receives L-Dopa or L-Dopa combination with carbidopa; because of emergence of Hallucination, delusions Glaucoma patient L-Dopa will increase IOP Active peptic ulcer patients leads to peptic ulcer Dopaminergic agonists drugs: Ergot derivatives Bromocriptine Non-ergot derivatives Ropinirole & Pramipexole Only effective in patient who are responding to L-DOPA Should be used in patient with PVD Bromocriptine, Ropinriole & Pramipexole o act on dopamine receptors even in patient who have lost capacity to synthesize, store & secrete dopamine from L-Dopa in Parkinsons disease o Longer duration of action than L-Dopa, which will leads to: Less fluctuation response less wear off effect Less risk of dyskinesia o Effective in patients with advanced PD who have fluctuation in response to L-Dopa & who have dyskinesia due to Dopa therapy o Not effective in patient who have shown no response to L-DOPA o Dose should be increased gradually over 2-3 months o Side-effects: Sedation, confusion, hallucination, nauseas & postural hypotension Dyskinesia difficulty in movements is less common than L-Dopa Cardiac problem in patient with MI

Worsening of vasospasm in PVD peripheral vascular disease due to vasoconstrictive effect of ergot alkaloids Aggrevate peptic ulcer Produce pulmonary & retroperitoneal fibrosis; specifically with Bromocriptine

Pramipexole, Ropinirole & Apomorphine alleviate the motor deficits in: 1) L-Dopa nave patient who dosent have been exposed to L-DOPA 2) Patient with advanced PD taking L-Dopa

Dopamine agonists: Delay use of L-Dopa in early PD Decrease of L-Dopa in advanced PD Side effects: - Similar to bromocriptine excepts: o No vasopasm o Cant produce fibrosis MAO-B inhibitors: - Selegiline & Rasagiline selective o Selegiline will: Increase dopamine level in the brain Increase action of L-Dopa Reduce the dose of L-Dopa - MAO-B inhibitor is responsible for metabolism of dopamine - Low dose of MAO-BI are selective, but if the dose increased the selectivity will be lost (higher dose inhibit A & B) - Little potential for hypertensive crisis (but in higher dose may be hypersensitivity crisis) Note: - Selegiline is metabolized to Meth-amphetamine & Amphetamine CNS stimulants o Might lead to insomnia better to given early in morning - Rasagiline: o Irreversible & selective MAO-BI o More potent than selegiline o Cannot be metabolized to Methamphetamine & Amphetamine so no insomnia COMT inhibitors: - Entacapone & Tolecapone o Reduce symptoms of wearing off phenomina in patient with L-DOPA + Carbidopa o Both selectively & reversible inhibit COMT o Entacapone has replaced Tolecapone; because Tolecapone has serious necrotic effect - L-dopa is metabolized by COMT to 3-O-methyldopa o After carbidopa therapy the 3-O-mtehyldopa will increase & compete with L-DOPA transfer to CNS o If inhibit 3-O-methyldopa, then central L-Dopa uptake will be increased & brain concentration of dopamine will incrase - Side effects: o Diarrhea o Postural hypotension o Nausea o Anorexia o Dyskinesia

o Sleep disorder Dopamine facilitator: - Amantidine o Antiviral drug, used for influenza treatment o Have anti-parkinsonian effect improve o Increase dopamine release in basal ganglia clinical effects o Have anti-cholinergic effect o Inhibit N-methy-D-aspartate (NMDA) type of glutamate receptors o Less effective than L-DOPA or Bromocriptine o Action decline with time o Less effective against tremor but better effect against rigidity & bradykinesia Central-anticholinergic drug & antihistamine drugs: - Minor improvement in tremor - Better effect on rigidity & bradykinesia - Side effects: o Blurred vision o Confusion o Mydriasis o Constipation o Urinary retention