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Parkinsonism treatment

Parkinson's disease is a progressive neurodegenerative disorder characterized by tremors, rigidity, akinesia, and postural instability. It results from the loss of dopamine-producing neurons in the substantia nigra. Drug therapy aims to increase dopamine levels through L-Dopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, or dopamine reuptake inhibitors. Anticholinergics may also be used. L-Dopa is very effective but side effects include dyskinesia and fluctuations. Later stages may require additional drugs or surgical interventions like deep brain stimulation. Management involves both drug therapy and non-pharmacological measures tailored to each patient's age, symptoms, and disease progression

Health & Medicine◦
Antiparkinsonian drugs Dr Naser Tadvi
Parkinsonism • Slowly progressive neurodegenerative disease characterized by – Akinesia – Muscular rigidity – Tremors • With secondary symptoms like – Postural instability, mask like face, sialorrhoea, seborrhoea
Pathophysiology  Most consistent lesion in parkinsons disease is Loss of pigmented dopaminergic neurons in the substantia nigra pars compacta and niagrostriatal dopaminergic tract .  Approximately 60-80% of dopaminergic neurons are lost before the motor signs of PD emerge.
Parkinsonism Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia ↓DA ↑ACH
CLINICAL FEATURES OF PD cont.. Pill rolling tremors Akathesia Rigidity Instable posture No arm swinging In rhythm with legs Sialorrhea Oculogyric crisis Nervous depression Involuntary tremors
Masked like face expression Seborrhea (scalp) Cont…
CLASSIFICATION OF ANTIPARKINSONIAN DRUGS
Drugs ↑ dopaminergic activity in brain • Pro-drug of dopamine : l-Dopa • Dopaminergic agonists: – Ergot derivatives: Bromocriptine, pergolide, lisuride – Non-ergot derivatives: Pramipexole, ropinirole • Dopamine releasing drugs: Amantidine • Drugs which inhibit degradation of dopamine: – MAO-B inhibitor: Selegiline – COMT inhibitor: Tolcapone, entacapone
Drugs ↓central cholinergic activity • Centrally acting anticholinergics: – Trihexyphenidyl , benztropine, biperidene, procyclidine • Antihistaminics: (having anticholinergic action) – Diphenhydramine, promethazine, prphenadrine
LEVO-DOPA:Universal antiparkinson drug • Metabolic precursor of dopamine: Prodrug • Single most important drug • Manages all major manifestations but not progression of disease
Pharmacological actions • CNS: – Marked improvement in symptoms, Akinesia first, then rigidity & tremors – Other symptoms improve gradually – General alerting response; ↑ excitability, sexual activity, psychosis
Pharmacological actions: contd • CVS: – ↓BP (Postural hypotension) – tachycardia – Large doses: ↑ BP • CTZ: stimulation • Endocrine: – Pitutary mammotrophs – inhibit prolactin release & increase GH release
pharmacokinetics: • T1/2: 1-3 hrs • 95% peripheral decarboxylaton (GIT, liver, other tissues) • Less than 1 % reaches CNS
Administered l-dopa Fate of administered l-dopa DA Metabolised in peripheral tissue Metabolised in GIT Anorexia, nausea, vomiting, tachycardia, hypotension. >95%
Adverse effects • GIT: – Nausea, vomiting, alteration of taste • Cardiovascular – postural hypotension, – palpitations – Sinus tachycardia – cardiac arrhythmias, – exacerbation of angina Early adverse effects
• Behavioural effect: – Anxiety, nightmares, severe depression, mania, hallucinations, mental confusion , psychosis • CNS – Abnormal movements; facial tics, grimacing, tongue thursting etc • Fluctuation in motor performance: – On and off effect Adverse effects Late ADR`s
Drug interactions • Pyridoxine • Phenothiazines, metoclopramide : block DA receptors • Non selective MAO inhibitors: hypertensive crisis • Antihypertensives: postural hypotension is accenuated
Peripheral Decarboxylase inhibitors • Extra cerebral dopa decarboxylase inhibitors inhibit conversion of l dopa to dopamine in periphery • Do not inhibit conversion of L dopa to dopamine in the brain as they do not cross BBB Carbidopa , Benserazide
Advantages of L-dopa + carbidopa • Dose of l dopa ↓ to ¼ , plasma t ½ ↑ • Less side effects: nausea, vomiting, tachycardia • Effect of this combination not antagonised by pyridoxine • On & off effect is minimized since cerebral dopamine levels more sustained • Enhanced efficacy e.g of potentiation
Disadvantages of this combination • More chances of dyskinesia • Behavioural abnormalities are more common • Postural hypotension is not resolved
Preparation and dose • 10 mg carbidopa + 100 mg L Dopa • 25 mg carbidopa + 250 mg L dopa • 25 mg benserazide + 100 mg L dopa • Dose : L dopa initially 100 mg 3-4 times daily • Maintainence : 200 mg 3-4 times daily
Dopaminergic agonists • Bromocriptine Ropinirole & pramipexole – Supplementary drugs to L dopa in advanced cases , better tolerated fewer GIT side effects • Adverse events : – Fatigue, somnolence, nausea, peripheral edema, dyskinesia, confusion , postural hypotension
• MAO – B inhibitor: Selegiline • Protects DA from intraneuronal degradation • Arrests progression, neuroprotective • Dose : 5 mg BD, Breakfast &lunch
Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of PD symptoms.
Dopamine releasing drugs: Amantidine • Rapid but lower efficacy, tolerance develops • Increases synthesis & release by decreasing reuptake, slight antimuscarinic • Dose 100 mg BD, Adjuvant to L dopa in acute exacerbation • Well tolerated by young
Anticholinergic drugs: • Higher central : peripheral anticholinergic action • Block Ach receptors in CNS, partially redressing imbalance created by decreased dopaminergic activity • 10 -25 % improvement in symptoms • DOC FOR drug induced extrapyramidal toxicity • Control, rigidity, tremors, sialorrhoea, less effect on bradykinesia
•Adverse effects: Dryness of mouth, blurring of vision, photophobia, IOT increased, constipation, urinary retension , palpitation ,confusion , delirium, delusion C/I : BPH, fever, narrow angle glaucoma, urinary & GIT retention Drugs Doses Trihexyphenidyl 6 – 20 mg Benztropine 1-6 mg Biperidene 2- 12 mg Procyclidine 7.5 – 30 mg Diphenhydramine 75 – 400 mg Orphenadrine 150 – 400 mg
Limitations of drug therapy • Drugs do not cure disease, nor effect its course • Tolerance develops • Anticholinergics: Glaucoma, BEP • L dopa therapy expensive, has many adverse events & needs regular supervision
Plan of management • Start therapy when disease interfering day to day activities • General measures are important include- regular physical activity, physiotherapy, speech therapy , occupational therapy • Mild disease: Anticholinergic drug, MAO inhibitor , Non ergot DA agonist, even amantidine may be tried in younger patient
Plan of management; contd • < 50 yrs age: start with DA agonist or anticholinergic • < 50 yrs severe disease L DOPA + Carbidopa with anticholinergic or amantidine in exacerbation • > 70 yrs of age: L dopa + carbidopa • If fluctuations add DA agonist/ MAO –I/ Amantidine
Plan of management: contd • If untolerable dyskinesia; use only L dopa • Unilateral thalamotomy or post ventral pallidotomy is indicated if drug therapy fails • Surgical implantation of adrenal medullary or fetal substantia nigra in caudate nucleus • HIGH gamma thalamic stimulation; resting tremors • Chronic B/L stimulation of subthalamic nuclei & GP internus