Parkinsonism_2.pptx
Download as PPTX, PDF0 likes88 views
Parkinsonism is a progressive neurological disorder characterized by bradykinesia, muscular rigidity, resting tremor, and impaired balance. It is caused by the loss of dopamine-producing neurons in the substantia nigra. Treatment aims to enhance the dopaminergic pathway and inhibit the cholinergic pathway. Levodopa is the most effective drug as it is converted to dopamine in the brain, but it causes side effects when taken alone. Co-administering it with carbidopa limits peripheral conversion and side effects. Other treatment options include dopamine agonists, MAO-B inhibitors like selegiline, COMT inhibitors, amantadine, and antimuscarinic drugs, each with their own
Parkinsonism_2.pptx
- 5. Definition : Parkinsonism is a progressive neurological disorder of muscle movement as a clinical syndrome consisting of 4 cardinal features: 1) bradykinesia (slowness of movement) and, in extreme cases, a loss of physical movement (akinesia) 2) muscular rigidity 3) resting tremor (which usually disappears during voluntary movement) 4) impairment of postural balance leading to disturbances of gait and falling
- 6. Causes of parkinsonism: 1) - Due to loss of dopaminergic neurons of the substantia nigra -Progressive loss of dopamine-containing neurons is a feature of normal aging; however, most people do not lose the 70% to 80% of dopaminergic neurons - Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism 2) Secondary : e.g., following stroke, and intoxication with dopamine- receptor antagonists as antipsychotics and antiemetics, manganese toxicity and CO.
- 7. Role of substantia nigra in Parkinson's disease
- 9. Treatment of parkinsonism Aim of treatment is to enhance dopaminergic pathway inhibit cholinergic pathway in the brain
- 10. Classification Increased Dopamine Synthesis Entacapone Entacapone / L-Dopa / Carbidopa L-Dopa / Carbidopa Monoamine Oxidase B Inhibitor Selegline Dopamine Receptor Agonist Apomorphine, Bromocriptine, Pergolide Dopamine Releasing Drugs Amantadine Antimuscarinic Drugs Benztropine, Orphendrine
- 11. levodopa Levodopa is (the most effective drug used in the treatment of parkinsonism) Chemistry: • It is the metabolic precursor of dopamine Mechanism of action: • In the brain, levodopa is converted to dopamine by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the striatum (by action of L-aromatic amino acid decarboxylase). The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT) .
- 12. If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the peripheral sites so that little unchanged drug reaches the cerebral circulation. In addition, dopamine release into the circulation by peripheral conversion of levodopa produces undesirable effects,
- 13. PERIPHERAL DOPAMINE DECARBOXYLASE INHIBITORS (PDI) • In practice, levodopa is administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the CNS. • Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa that crosses the blood-brain barrier and reduces the incidence of peripheral side effects. • The most commonly prescribed form of carbidopa/levodopa is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa.
- 14. Carbidopa, Does not penetrate the BBB Reduce the peripheral metabolism & increase plasma levels of levodopa Prolongs the plasma half life of levodopa Increase available amounts of dopa for entry into the brain Reduce the daily requirement of levodopa by 75%
- 16. Adverse effects: A) Central: 1) long-term therapy leads to "wearing off" phenomenon: each dose of levodopa improves mobility for 1 to 2 hours ( shortening of duration of action) rigidity and akinesia return at the end of the dosing interval. Increasing the dose and frequency of administration can improve this situation, but this often is limited by the development of dyskinesias (excessive and abnormal involuntary movements). Patients may fluctuate between being "off," having no beneficial effects from their medications, and being "on" but with dyskinesias, a situation called the on/off phenomenon.
- 17. 2) Mental effects Depression, anxiety, agitation, insomnia, delusions, hallucinations, euphoria 3) Dyskinesias (excessive and abnormal involuntary movements) as chorea and tremor
- 18. B) Peripheral Due to formation of dopamine peripherally 1. The most common peripheral side effects are anorexia, nausea, and vomiting (likely due to dopamine’s stimulation of the chemoreceptor trigger zone in the medulla oblongata). 2. Cardiovascular side effects in the form of orthostatic hypotension and cardiac arrhythmias 3. Stimulation of gastric dopamine receptors delay stomach emptying can be antagonized by domperidone
- 19. Drug Interactions: 1. Pharmacologic doses of pyridoxine (vitamin B6) enhance the extra cerebral metabolism of levodopa and prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken. 2. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance, because such a combination can lead to hypertensive crises.
- 20. Contraindications 1. Psychotic patients 2. Angle-closure glaucoma 3. Cardiac disease 4. Peptic ulcer 5. Melanoma (skin cancer)
- 21. DOPAMINE AGONISTS Do not require enzymatic conversion for an active metabolite No potential toxic metabolites Do not compete with other substances for an active transport First line in parkinsonism End of dose akinesia to levodopa On & off phenomenon refractory to levodopa
- 22. Four orally administered dopamine-receptor agonists are available for treatment of PD: 1) Ergot derivatives: as bromocriptine or pergolide 2) Non ergot derivatives as ropinirole and pramipexole
- 23. Adverse effects: I. Central: • Dyskinesias , mental Disturbances II. Peripheral: A) Gastrointestinal Effects: •Anorexia and nausea and vomiting B) Cardiovascular effects: 1. postural hypotension 2. cardiac arrhythmias
- 24. MONOAMINE OXIDASE INHIBITORS MAO – A: metabolizes NE & serotonin MAO – B: metabolizes dopamine
- 25. SELEGILINE (Deprenyl) Selective irreversible inhibitor of MAO-B (normal doses) Inhibits MAO-A (higher doses) Retards breakdown of dopamine Prolongs & enhances the effect of levodopa Adjunct in fluctuating response to levodopa
- 26. Not to be taken with meperidine, TCAs, SSRIs METABOLITES: amphetamine & metamphetamine
- 27. 3- Catechol O methyl transferase inhibitors Tolcapone 1. Inhibit catechol O methyl transferase (COMT) which is responsible for the conversion of dopa into methyl dopa. Elevated levels of methyldopa decreases the response to levodopa, because methyldopa competes with levodopa for an active carrier mechanism that governs its transport across the blood-brain barrier. 2. prolong the action of levodopa by diminishing its peripheral metabolism. These agents may be helpful in patients receiving levodopa to reduce dose and decrease fluctuations in response • Side effects are similar to levodopa
- 28. 4- Amantadine Amantadine, an antiviral agent. Its mode of action in parkinsonism is to enhance the release of dopamine from its stores Clinical Use • Amantadine is less potent than levodopa and its effects disappear after only a few weeks of treatment Adverse Effects 1. Central nervous system effects 2. Peripheral edema 3. headache 4. Heart failure 5. postural hypotension 6. urinary retention
- 29. ACETYLCHOLINE BLOCKING AGENTS Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia Benztropine mesylate, Biperiden, Orphenadrine, Procyclidine
- 30. ACETYLCHOLINE BLOCKING AGENTS Adverse Effects 1) Central nervous system effects, including drowsiness, restlessness, confusion, agitation, hallucinations, and mood changes. Dyskinesias occur in rare cases 2) Atropine – like actions: dryness of the mouth, blurring of vision, urinary retention, nausea and vomiting, constipation, tachycardia, palpitations, and cardiac arrhythmias. withdrawal should be gradual in order to prevent acute exacerbation of parkinsonism.