Parkinsonism treatment

Drug treatment of Parkinsonism

1. Antiparkinsonian drugs Dr Naser Tadvi

2. Parkinsonism Slowly progressive neurodegenerative disease characterized by Akinesia Muscular rigidity Tremors With secondary symptoms like Postural instability, mask like face, sialorrhoea , seborrhoea

3. 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.

4. Parkinsonism Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia ↓ DA ↑ ACH

5. CLINICAL FEATURES OF PD cont.. P ill rolling tremors A kathesia R igidity I nstable posture N o arm swinging In rhythm with legs S ialorrhea O culogyric crisis N ervous depression I nvoluntary tremors

6. M asked like face expression S eborrhea (scalp) Cont…

7. classification of antiparkinsonian drugs

8. 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

9. Drugs ↓ central cholinergic activity Centrally acting anticholinergics : Trihexyphenidyl , benztropine , biperidene , procyclidine Antihistaminics : (having anticholinergic action) Diphenhydramine, promethazine, prphenadrine

10. LEVO- DOPA: Universal antiparkinson drug Metabolic precursor of dopamine: Prodrug Single most important drug Manages all major manifestations but not progression of disease

11. Pharmacological actions CNS: Marked improvement in symptoms, Akinesia first, then rigidity & tremors Other symptoms improve gradually General alerting response; ↑ excitability, sexual activity, psychosis

12. Pharmacological actions: contd CVS: ↓BP (Postural hypotension) tachycardia Large doses: ↑ BP CTZ: stimulation Endocrine: Pitutary mammotrophs – inhibit prolactin release & increase GH release

13. pharmacokinetics: T1/2: 1-3 hrs 95% peripheral decarboxylaton (GIT, liver, other tissues) Less than 1 % reaches CNS

14. Administered l- dopa Fate of administered l- dopa DA Metabolised in peripheral tissue Metabolised in GIT Anorexia, nausea, vomiting, tachycardia, hypotension. > 95%

15. Adverse effects GIT: Nausea, vomiting, alteration of taste Cardiovascular postural hypotension, palpitations Sinus tachycardia cardiac arrhythmias, exacerbation of angina Early adverse effects

16. 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

17. Drug interactions Pyridoxine Phenothiazines , metoclopramide : block DA receptors Non selective MAO inhibitors: hypertensive crisis Antihypertensives: postural hypotension is accenuated

18. 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

19. 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

20. Disadvantages of this combination More chances of dyskinesia Behavioural abnormalities are more common Postural hypotension is not resolved

21. 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

22. 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

23. MAO – B inhibitor: Selegiline Protects DA from intraneuronal degradation Arrests progression, neuroprotective Dose : 5 mg BD, Breakfast &lunch

24. Inhibition of peripheral COMT by entacapone increases the amount of L-DOPA and dopamine in the brain and improves the alleviation of P D symptoms.

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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