Treatment of Parkinsonism.pptx

Treatment of Parkinson Disease, Classification, MOA, Uses and Side Effects

1. Parkinson’s Disease By Dr. Faraza Javaid

2. PARKINSON'S DISEASE? P arkinsonism is a neurodegenerative disorder which affects the basal ganglia and is associated with : a loss of dopaminergic neurons in the substantia nigra and degeneration of nerve terminals in the striatum PARKINSON ´S SYNDROME : I s the adverse effect of antipsychotic agents due to D2-receptor blockade in the basal ganglia . Its acute form is reversible .

3. FEATURES OF PARKINSON'S DISEASE: Parkinson's disease is a progressive disorder of movement that occurs mainly in the elderly. The chief symptom are: Tremors at rest, usually starting in the hands ('pill-rolling' tremor), which tends to diminish during voluntary activity. Muscle rigidity, detectable as an increased resistance in passive limb movement. Suppression of voluntary movements (hypokinesis), due partly to muscle rigidity and partly to an inherent inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate.

4. Hoehn and Yahr Staging of Parkinson's Disease Stage 1: Mild signs and symptoms on one side only, not disabling but friends notice. Stage 2: Symptoms are bilateral, minimal disability, posture and gait affected. Stage 3: Significant slowing, dysfunction that is moderately severe. Stage 4: Severe symptoms, walking limited, rigidity, bradykinesia, unable to live alone. Stage 5: Cachectic, complete invalidism, unable to stand, walk, require nursing care.

5. Aetiology and Pathogenesis: Remain largely unknown Heredity have a limited role Defective gene responsible for a rare condition called autosomal recessive juvenile parkinsonism (teens and 20s) The damage is caused by : EXCITOTOXICITY OXIDATIVE STRESS APOPTOSIS /NECROSIS OF NEURONS

6. Parkinson's disease often occurs with no obvious underlying cause, but it may be the result of cerebral ischemia, viral encephalitis or other types of pathological damage. The symptoms can also be drug-induced, the main drugs involved being those that reduce the amount of dopamine in the brain e.g. reserpine or block dopamine receptors (e.g. antipsychotic drugs such as chlorpromazine. There are rare instances of early-onset PD that runs in families, and several gene mutations have been identified, the most important being synuclein and parkin . Study of these gene mutations has given some clues about the mechanism underlying the neurodegenerative process.

7. In normal conditions : A cetylcholine release from the striatum (cholinergic neurons) is strongly inhibited by dopamine (depleted from the nigrostriatal neurons). Joint GABA-ergic neurons then opposite excitatory function of glutamate neurones connected to the motor cortex.

8. motor cortex glutamate Corpus striatum Substantia nigra dopamine ACH GABA glutamate MOVEMENT GABA

9. In Neurodegeneration : Neurodegeneration of the dopaminergic neurons (Subs.nigra) + loss of dopamine (the striatum) leads to both hyperactivity of these cholinergic striatal neurons + blockade of GABA-ergic cells (Subst.nigra). The result is an increase in excitatory activity of glutamate + the motor cortex muscle rigidity, tremor, hypokinesia

10. Molecular aspects Parkinson's disease, as well as several other neurodegenerative disorders, is associated with the development of intracellular protein aggregates known as Lewy bodies in various parts of the brain. They consist largely of α-synuclein, a synaptic protein present in large amounts in normal brains. Mutations occur in rare types of hereditary PD , and it is believed that such mutations render the protein resistant to degradation within cells, causing it to pile up in Lewy bodies.

11. It is possible that the normal function of α-synuclein is related to synaptic vesicle recycling, and that the mutated form loses this functionality, with the result that vesicular storage of dopamine is impaired. This may lead to an increase in cytosolic dopamine, degradation of which produces reactive oxygen species and hence neurotoxicity. Other gene mutations that have been identified as risk factors for early-onset PD code for proteins involved in mitochondrial function, making cells more susceptible to oxidative stress.

12. TREATMENT OF PARKINSON’S DISEASE How to treat deficit of dopamine? INCREASE IN DOPAMINERGIC ACTIVITY : (1) dopamine precursors (replacement of dopamine) (2) MAO-B blockade (3) Catechol-O-methyltransferase inhibitors ( 4 ) increase in dopamine release ( 5 ) blockade of amine neuronal reuptake ( 6 ) dopamine receptors agonists

13. How to treat excitatory function of cholinergic and glutaminergic neurons? MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS .

14. ( 1) D opamine precursors (replacement of dopamine) : Levodopa: Levodopa is a metabolic precursor of dopamine. It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20 percent of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off .”

15. Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up exogenously administered levodopa and converting it to dopamine for subsequent storage and release. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body.

16. Mechanism of action: Because parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. Dopamine itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to dopamine in the brain . Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension.

17. Carbidopa: Carbidopa, a dopa decarboxylase inhibitor, diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine.

18. Actions: Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. Therapeutic uses: Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson disease. In approximately two-thirds of patients with Parkinson disease, levodopa–carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy.

19. Interactions: The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. Concomitant administration of levodopa and monoamine oxidase inhibitors (MAOIs), such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. Therefore, caution is required when they are used simultaneously. In patients with glaucoma, the drug can cause an increase in intraocular pressure. Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias.

20. (2) MAO-B blockade : Selegiline and rasagiline : Selegiline also called deprenyl , selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin). By, thus, decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain Therefore, it enhances the actions of levodopa when these drugs are administered together. Selegiline substantially reduces the required dose of levodopa . Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises.

21. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than midafternoon. Rasagiline , an irreversible and selective inhibitor of brain monoamine oxidase Type B, has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine like substance.

22. 3. Catechol-O-methyltransferase inhibitors: Entacapone and tolcapone: It inhibits COMT, which converts levodopa to 3OMD in the gut and liver. So it produces a twofold increase oral bioavailability and half-life of levodopa. 3OMD competes with L-dopa for transport across the blood-brain barrier and may contribute to the “wearing off” and“on-off” effects seen in patients taking L-dopa By inhibiting 3OMD formation, it may stabilize dopamine levels in striatum.

23. 4. Dopamine-receptor agonists: This group of anti-Parkinson compounds includes bromocriptine, an ergot derivative, and newer, non ergot drugs, ropinirole, pramipexole, and rotigotine. Bromocriptine, pramipexole, and ropinirole are all effective in patients with advanced Parkinson disease complicated by motor fluctuations and dyskinesias.

24. A. Bromocriptine and pergolide: Both are ergot alkaloids. Bromocriptine, a derivative of the vasoconstrictive alkaloid, ergotamine, is a dopamine-receptor agonist. Bromocriptine is a D 2 receptor agonist and a D 1 receptor antagonist. Pergolide is a D 1 and D 2 receptor agonist. Pergolide is much more potent than bromocriptine, higher affinity to D 2 receptors, longer duration of action.

25. Both are useful adjuncts to levodopa in patients have advanced parkinson and experience wearing off and on-off Side effects are nausea (50%), confusion, dyskinesia, sedation, vivid dreams, hallucinations, orthostatic hypotension, dry mouth, decreased prolactin levels .

26. B. Apomorphine, pramipexole, ropinirole, and rotigotine: These are non-ergot dopamine agonists that have been approved for the treatment of Parkinson disease. Pramipexole and ropinirole are agonists at dopamine receptors. Apomorphine is meant to be used for the acute management of the hypomobility “off” phenomenon. These agents alleviate the motor deficits in both levodopa-naïve patients (patients who have never been treated with levodopa) and patients with advanced Parkinson disease who are taking levodopa.

27. 5. Amantadine: It was accidentally discovered that the antiviral drug amantadine, which is effective in the treatment of influenza , has an anti-parkinsonism action. Amantadine has several effects on a number of neurotransmitters implicated in causing parkinsonism, including increasing the release of dopamine, blockading cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors.

28. Current evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations. The drug may cause restlessness, agitation, confusion, and hallucinations, and, at high doses, it may induce acute toxic psychosis. Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. The drug has little effect on tremor, but it is more effective than the anti-cholinergics against rigidity and bradykinesia.

29. 6. Anti-muscarinic agents: Anticholinergic drugs such as benztropine and trihexyphenedyl are used. They are less effective than dopaminergic drugs. They are more effective in reducing tremor than the other symptoms. They are useful in treatment of early and advanced Parkinson’s disease, they can reduce Parkinson’s symptoms caused by dopamine receptor antagonists e.g. haloperidol.

30. Neuroprotective Therapy: A number of different compounds are currently under investigation as potential neuroprotective agents that may slow disease progression. These include antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, coenzyme Q10, and anti-inflammatory drugs. The role of these agents remains to be established, however, and their use for therapeutic purposes is not indicated at this time.

31. References: www.studentconsult.com Elsvier . Rang et al: pharmacology 6e. Lippincott’s Illustrated Reviews: Pharmacology 5th edition. Goodman & Gilman’ Manual of Pharmacology and Therapeutics 2008. Katzung -basic: clinical pharmacology 10 th edition.