Parkinson's Disease Pharmacotherapy Study PDF

PHARMACOTHERAPY OF PARKINSON’S DISEASE Dr. Isaac Tabiri Henneh Department of Pharmacotherapeutics and pharmacy practice School of Pharmacy and Pharmaceutical Sciences Epidemiology Prevalence is 1 million in the United States. Onset is usually at 40–70 years of age, with peak onset in sixth decade....

PHARMACOTHERAPY OF PARKINSON’S DISEASE Dr. Isaac Tabiri Henneh Department of Pharmacotherapeutics and pharmacy practice School of Pharmacy and Pharmaceutical Sciences Epidemiology Prevalence is 1 million in the United States. Onset is usually at 40–70 years of age, with peak onset in sixth decade. Slightly more common in men Observed in all countries, ethnic groups, and socioeconomic classes Signs and Symptoms Cardinal signs Akinesia or hypokinesia Rigidity Tremor Posture or gait abnormalities Tremors Bradykinesia Postural instability Signs and Symptoms b. Secondary a. Cognitive Autonomic signs dysfunction dysfunction c. Speech d. e. Masked disturbance Micrographi facies s a General No treatment has unequivocally been shown to prevent the progression of Parkinson disease; therefore, treatment treatmentis based on symptoms. principlesIn patients who need the initiation of dopaminergic treatment, either levodopa or a dopamine agonist may be used. Choice depends on the relative impact of improving motor disability (better with levodopa) compared with the lessening of motor complications (better with dopamine agonists) for each patient. Treatment may be initiated with rasagiline as well, but the effects are not robust. Treatment with several different classes of medications simultaneously is common MEDICATIONS Levodopa and Carbidopa Levodopa inhalation powder (Inbrija) Treats off-episodes Dose: 2 capsules (84 mg) inhaled as needed, up to five times daily Adverse effects: Cough, nausea, discolored sputum Carbidopa Combined in fixed ratios with levodopa Prevents some of the peripheral conversion of levodopa to dopamine by inhibiting peripheral dopamine decarboxylase; therefore, levodopa is available to cross the blood-brain barrier 75 mg/day is usually needed to inhibit peripheral decarboxylase activity. Levodopa and Carbidopa Carbidopa/levodopa (Parcopa, Sinemet, Duopa, Rytary) Pharmacokinetic considerations High-protein diets decrease absorption. Immediate-release half-life 60–90 minutes Orally disintegrating tablet available; not absorbed sublingually Slow-release considerations: Fewer daily doses; less plasma fluctuations; delay to effect; cannot crush; can divide. No measurable effect on “freezing” Acute adverse effects: Nausea and vomiting, orthostatic hypotension, cardiac arrhythmias, confusion, agitation, hallucinations  Levodopa and Carbidopa Long-term adverse effects: Wearing-off and on-off phenomena, involuntary movements (dyskinesias) Wearing-off phenomenon is the return of Parkinson disease symptoms before the next dose. Treatment of wearing-off includes adding a dopamine agonist, adding a MAO-B inhibitor, adding a catechol-O-methyl transferase inhibitor, or increasing the frequency or dose of levodopa. On-off phenomenon is a profound, unpredictable return of Parkinson disease symptoms without respect to the dosing interval. Treatment of on-off includes adding entacapone, rasagiline, pramipexole, ropinirole, apomorphine, or selegiline or redistributing dietary protein. Dyskinesias are drug-induced involuntary movements including chorea and dystonia. Treatment of dyskinesias includes decreasing the levodopa dose or adding amantadine as an antidyskinetic drug. Levodopa and Carbidopa Therapy initiation a. Standard formulation: 25 mg/100 mg 1 tablet orally three times daily; also available as orally disintegrating tablet b. Controlled-release formulation: 1 tablet orally two or three times daily c. Titration always necessary d. A combination of formulations may be needed (e.g., ½ tablet of Sinemet 25 mg/100 mg on awakening and 1 tablet of Sinemet CR 25/100 three times daily). Levodopa may improve disability and mortality. Greatest benefit for rigidity and bradykinesia, less benefit for tremor and postural instability Monoamine oxidase type B (MAO-B) inhibitors Selegili Loses selectivity for MAO-B at doses greater than 10 mg/day Contraindicated with meperidine because of serotonin ne syndrome risk (Eldepr They may slow the progression of PD, but it does not directly treat Parkinson symptoms. Dose: 5 mg orally twice daily (tablets; usually morning and yl, noon); 1.25–2.5 mg/day (orally disintegrating tablets) Zelapar ) Adverse effects: Nausea, hallucinations, orthostatic hypotension, insomnia (metabolized to amphetamine) Dosage forms: Tablets, orally dissolving tablets, and patches. The patches are FDA indicated for depression; they should not usually be used for Parkinson disease.  Monoamine oxidase type B (MAO-B) inhibitors Rasagiline (Azilect) Selectivity for MAO-B has not been definitively established. Contraindicated with meperidine because of serotonin syndrome risk Do not administer with tramadol, methadone, dextromethorphan, sympathomimetics, fluoxetine, or fluvoxamine because of serotonin syndrome risk. Ciprofloxacin can double the concentration of rasagiline (through CYP1A2 inhibition). Dose: 0.5–1 mg/day orally Safinamide (Xadago) Highly selective MAO-B inhibitor Dose 50–100 mg daily Reduce dose in hepatic failure (Child-Pugh class C) Adverse effects and drug interactions similar to other MAO-B inhibitors  Istradefylline (Nourianz) Adenosine receptor antagonist Adjunct to carbidopa/levodopa Treats off-episodes Dose: 20 mg daily; may increase to maximum of 40 mg daily Adverse effects: Dyskinesia, dizziness, constipation, nausea, hallucinations, insomnia Drug interactions: CYP3A4 substrate; avoid use with CYP3A4 inducers; maximum dose 20mg daily with CYP3A4 inhibitors Direct Dopamine agonists Drugs: Apomorphine (Apokyn), bromocriptine (Parlodel), pramipexole (Mirapex), ropinirole (Requip), rotigotine (Neupro) Bromocriptine is an ergot-derived product: Very rarely, adverse effects such as retroperitoneal, pleuropulmonary, or cardiac fibrosis have been attributed to it; regular ECG monitoring is recommended. Rotigotine is a transdermal system. With the initial formulation, problems occurred with crystallization of the medication. The product was withdrawn from the market and has since been reformulated. Rotigotine is currently available  Direct Dopamine agonists Adverse effects: Nausea, vomiting, postural hypotension, hallucinations, impulsive behaviors (e.g., hypersexuality, gambling, shopping, eating), falling asleep during activities of daily living Pramipexole and ropinirole also have FDA indications for restless legs syndrome. Ropinirole and pramipexole are available as extended-release formulations. Ropinirole is usually preferred for initial treatment in individuals younger than 65 or as add-on therapy to carbidopa/levodopa in older patients. Apomorphine: Short-acting dopamine receptor agonist Indication: Acute, intermittent treatment of “off” episodes associated with advanced Parkinson disease Contraindications: Its use with 5-hydroxytryptamine-3 antagonists (ondansetron, granisetron, dolasetron, palonosetron, and alosetron) causes profound hypotension, sulfite sensitivity, or allergy. Pharmacokinetics: When given orally, poorly bioavailable and extensive first-pass metabolism; used as subcutaneous injection in a pen self-injector Apomorphine Adverse effects (1) Severe nausea and vomiting Treat with trimethobenzamide 300 mg three times daily for 3 days before initiating treatment and for at least 6 weeks during treatment. About 50% of patients can discontinue trimethobenzamide after 2 months. Thirty-one percent of patients had nausea and 11% had vomiting with trimethobenzamide. (2) Hypotension (3) Hallucinations (4) Injection site reactions (5) Dyskinesias Apomorphine Dosing Must be titrated in a setting where blood pressure can be monitored In the “off” state, the patient should be given a 0.2-mL (2 mg) test dose. Supine and standing blood pressure taken before dose; 20, 40, and 60 minutes after dose If tolerated, begin with a 0.2-mL dose as needed; increase by 0.1 mL, if necessary. Doses greater than 0.6 mL, more than five times daily, or greater than 20 mg/day have limited experience. If first dose is ineffective, do not re-dose. If patients do not dose for more than 1 week, reinitiate at a 0.2-mL dose. Anticholinergics Drugs: Trihexyphenidyl (Artane), benztropine (Cogentin) Useful only for tremor Initial dosing (a) Trihexyphenidyl 0.5 mg 1 tablet orally twice daily (b) Benztropine 0.5 mg 1 tablet orally twice daily Adverse effects: Dry mouth, urinary retention, dry eyes, constipation, confusion  Catechol-O-methyl transferase inhibitors Prevent breakdown of dopamine, more levodopa available to cross blood- brain barrier Tolcapone (Tasmar): Severely restricted because of hepatotoxicity; must sign consent form Entacapone (Comtan) Increased area under the curve, increased half-life; no change in Cmax or Tmax of levodopa Dosing: 1 tablet with each carbidopa/levodopa dose; maximum of eight times daily; one dosage form (Stalevo) includes carbidopa, levodopa, and entacapone 200 mg Must use with carbidopa/levodopa Adverse effects: Dyskinesias, nausea, diarrhea (may be delayed for up to 2 weeks after initiation or dose increase), urine discoloration (orange), hallucinations or vivid dreams Opicapone (Ongentys) Dosing: 50 mg daily at bedtime Take doses 1 hour before or after eating. Reduce dose by 50% with moderate hepatic failure. Avoid use in severe hepatic failure.  Surgery: Several types of surgery are done for Parkinson disease. a. Thalamotomy: Ablation of portions of the thalamus to control tremor b. Pallidotomy: Ablation of structures in the globus pallidus for the treatment of Parkinson disease c. Fetal transplants: Transplantation of dopaminergic tissue into the striatum; considered experimental d. Trophic factors: Glial-derived nerve growth factor and neurturin have been delivered directly to the striatum or substantia nigra; considered experimental Surgery e. Deep brain stimulation i. Most common surgery for Parkinson disease ii. Thought to stimulate areas of the basal ganglia to reversibly block the neuronal activity in the area iii. Patient selection focuses on patients with (a) Motor fluctuations or dyskinesias that are not adequately controlled with optimized medical therapy (b) Medication-refractory tremor (c) Intolerance of medical therapy (d) Some centers will not do the surgery in patients older than 70.  Two areas are targeted. (a) Globus pallidum (1) Reduces off-time (2) Reduces dyskinesias Surger (3) Thought to have fewer cognitive adverse effects than subthalamic nucleus y: DBS stimulation (b) Subthalamic nucleus (1) Reduces off-time (2) Reduces dyskinesias (3) Thought to be more effective than globus pallidum stimulation  4. Special situations a. Hallucinations or psychosis may be caused by either Parkinson disease or treatment. i. Discontinue or reduce Parkinson disease medications as tolerated. ii. If an antipsychotic is needed, use quetiapine or clozapine as the first choice. Surge iii. Pimavanserin (Nuplazid) FDA approved for Parkinson disease psychotic disorder ry: iv. Avoid typical antipsychotics, risperidone, and olanzapine because they may worsen Parkinson symptoms. DBS b. Cognitive disorders i. Discontinue or reduce Parkinson disease medications as tolerated. ii. Rivastigmine (Exelon) has an FDA indication for treatment; other cholinesterase inhibitors may have efficacy. c. Sleep disorders, depression, agitation, anxiety, constipation, orthostatic hypotension, seborrhea, blepharitis, and restless legs syndrome can occur in Parkinson disease; treat as usual.