Drug Therapy of Neurodegenerative Disorders PDF

MBBS 52 SDL DRUG THERAPY OF NEURODEGENERATIVE DISORDERS Learning Outcomes 1. Classify drugs used for the treatment of Parkinson’s disease based on their mechanism of action. *** 2. Explain the important adverse effects of L-dopa.*** 3. Explain the drug interaction between L-dopa an...

MBBS 52 SDL DRUG THERAPY OF NEURODEGENERATIVE DISORDERS Learning Outcomes 1. Classify drugs used for the treatment of Parkinson’s disease based on their mechanism of action. *** 2. Explain the important adverse effects of L-dopa.*** 3. Explain the drug interaction between L-dopa and pyridoxine. ** 4. Apply the pharmacokinetic feature of L-dopa and mechanism of action of carbidopa/benserazide to provide benefits and limitations of using them together in Parkinson’s disease. *** 5. Explain the antiparkinsonian action of the following: MAO-B inhibitors, COMT inhibitors, dopamine agonists and amantadine. ** 6. Apply pathogenesis of drug-induced parkinsonism to provide rationale for the use of centrally acting anticholinergics in its treatment. ** 7. List the drugs used in Alzheimer’s disease and Huntington’s chorea. *** Reading materials 1. List the drugs used in Alzheimer’s disease. Anticholinesterases – donepezil, rivastigmine, galantamine NMDA receptor antagonist – memantine 2. List the drugs used in Huntington’s chorea. Chlorpromazine, haloperidol, olanzapine, tetrabenazine 3. Classify drugs used for the treatment of Parkinson’s disease based on their mechanism of action. a. Drugs which increase brain dopamine level: Dopamine precursor - Levodopa Decarboxylase inhibitors – Carbidopa, Benserazide COMT inhibitors – Tolcapone, Entacapone Dopamine releasing agent – Amantadine b. Drugs which prevent dopamine degradation: MAO-B inhibitor – Selegiline, Rasagiline c. Dopamine receptor agonists: Bromocriptine, Cabergoline, Ropinirole, Pramipexole d. Drugs which restore DA-ACh balance: Centrally acting anticholinergic drugs - Benztropine, Benzhexol 1 MBBS 52 SDL 4. Explain the important adverse effects of L-dopa (levodopa). Levodopa gets converted into dopamine (DA) by dopa decarboxylase enzyme both in peripherally as well as in the brain. The formed dopamine stimulates dopamine receptor and causes adverse effects. Peripheral adverse effects: Due to the agonistic action of dopamine on DA receptor on chemoreceptor trigger zone (CTZ), nausea and vomiting occurs. Cardiovascular effect –Arrhythmia is due to the agonistic action on the beta receptor of heart. Exacerbation of angina in patients with preexisting heart disease. Postural hypotension in some patients, but tolerance develops upon continued treatment. Others – alteration of taste and smell. CNS adverse effects of levodopa: Fluctuations in response - Wearing-off effect (duration of benefit is shortened from each dose of levodopa) and on-off phenomenon (during on state, the patient is free from symptoms and during off state, the patient develops rigidity and other symptoms) due to rapid fluctuation in plasma level of levodopa. Dyskinesias: abnormal movements of limb, trunk, face and tongue. Eg: tics, tremor, choreoathetoid Hallucination, delusion, vivid dreams, confusion, insomnia, precipitation of schizophrenia- like syndrome 5. Apply pharmacokinetics/pharmacodynamic properties of L-dopa and pyridoxine to provide rationale for the drug interaction between them. Levodopa is converted to dopamine by peripheral decarboxylase enzyme. Pyridoxine (Vit. B6) is the co-factor for decarboxylase enzyme. Increased decarboxylase enzyme activity in the presence of pyridoxine leads to enhanced extracerebral metabolism of levodopa --> less levodopa crosses BBB --> Thus, there is a decrease in therapeutic effects of levodopa. 2  MBBS 52 SDL 6. Apply the pharmacokinetic feature of L-dopa and mechanism of action of carbidopa/benserazide to provide benefits and limitations of using them together in Parkinson’s disease. Only 3% of levodopa crosses BBB as it is peripherally converted into dopamine by the enzyme dopa decarboxylase. Dopamine so formed cannot cross the BBB and causes peripheral adverse effects. Carbidopa/benserazide inhibits peripheral dopa decarboxylase enzyme, thus no conversion of levodopa to dopamine in the periphery. It favours maximum availability of levodopa in the brain, which is converted to dopamine by central dopa decarboxylase. This relieves symptoms of parkinsonism. Advantages of carbidopa + levodopa combination: Plasma half-life of levodopa is prolonged ↑ Bioavailability of dopamine in brain Levodopa dose is reduced by 75% Systemic concentration of DA is reduced --> reduced peripheral adverse effects ‘Pyridoxine reversal of levodopa' effect does not occur ‘On-off’ effect is minimized since sustained level of brain dopamine is maintained Limitations of carbidopa + levodopa combination: Postural hypotension effect is not resolved Involuntary movements may be accentuated Behavioural abnormalities may be pronounced 3  MBBS 52 SDL 7. Explain the antiparkinsonian action of COMT inhibitors. Inhibition of decarboxylase enzyme by carbidopa/benserazide leads to the diversion of levodopa towards catechol-O-methyl transferase (COMT) mediated degradation, in which 3-O- Methyldopa (3O MD) is the end product. 3OMD competes with levodopa in crossing BBB. COMT inhibitors prevent the degradation of levodopa in the periphery and divert it into the brain. Tolcapone crosses BBB, inhibits COMT enzyme in basal ganglia and prevents degradation of dopamine. Availability of dopamine for long duration can afford clinical improvement. 8. Explain the antiparkinsonian action of MAO-B inhibitors. Selegiline inhibits mono amine oxidase – B (MAO-B) enzyme in basal ganglia, thus increases the dopamine level. Availability of dopamine for long duration can afford clinical improvement. Selegiline also possesses antioxidant, neuroprotective, antiapoptotic effect and also retards disease progression. 9. Explain the antiparkinsonian action of amantadine. Amantadine is an anti-influenza drug. It facilitates presynaptic DA release and prevents DA reuptake from the synaptic cleft. Availability of dopamine for long duration can afford clinical improvement. It has additional weak antimuscarinic action and glutamate NMDA receptor blockade activity. These properties also help in symptomatic relief of parkinsonism 10. Explain the antiparkinsonian action of dopamine agonists. Dopamine receptor agonists (bromocriptine, cabergoline, ropinirole, pramipexole) directly stimulate DA receptors in post synaptic nigrostriatal pathway. These drugs are useful in advanced patients who have lost the capacity to synthesise DA. They have longer duration of action than levodopa with lesser dyskinesias and on-off phenomenon. 4 MBBS 52 SDL FIGURE 28–2 Pharmacologic strategies for dopaminergic therapy of Parkinson’s disease. The actions of the drugs are described in the text. MAO, monoamine oxidase; COMT, catechol- O- methyltransferase; DOPAC, dihydroxyphenylacetic acid; l-DOPA,levodopa; 3- OMD, 3-O- methyldopa. (Adapted from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 28–5.) 5  MBBS 52 SDL 11. Apply pathogenesis of drug-induced parkinsonism to provide rationale for the use of centrally acting anticholinergics in its treatment. Certain drugs (Eg: Metoclopramide) by blocking DA receptor in basal ganglia produce extrapyramidal symptoms. This condition is called as drug-induced Parkinsonism. Due to the blockade of DA receptor, there will be an imbalance in the DA: ACh level in CNS. In such cases, the aim is to balance the cholinergic activity in basal ganglia by administering centrally acting anticholinergics such as benztropine, benzhexol. They block muscarinic receptors in basal ganglia and reduce striatal cholinergic activity. These drugs correct tremor and rigidity more efficiently than controlling other symptoms. Sialorrhoea is controlled by their peripheral action. Since the dopamine receptors of basal ganglia are blocked in the drug- induced parkinsonism, only centrally acting anticholinergic are useful for its treatment. All other anti-parkinsonian drugs are not useful – because they act through dopamine/ its receptors. 6 MBBS 52 SDL MODEL QUESTIONS 1. List the drugs used in Alzheimer’s disease and Huntington’s chorea. 2. List different groups of drugs with an example for each used in the treatment of parkinsonism. 3. Explain peripheral adverse effects of levodopa. 4. Explain specific adverse effects of levodopa in central nervous system. 5. Explain the consequence of co-administering both levodopa and pyridoxine. 6. Mr. Nagesh, a 57 years old policeman developed Parkinson’s disease and was prescribed levodopa + carbidopa combination. Except some central nervous system symptoms, most of the other symptoms are improved a lot. Q. Explain the pharmacological basis for combining levodopa and carbidopa in the treatment of parkinsonism. 7. List the advantages of combining levodopa and carbidopa. 8. Explain the antiparkinsonian action of the following: a. Selegiline b. Tolcapone c. Amantadine d. Cabergoline 9. Explain the role of benztropine in the treatment of drug induced parkinsonism. 7