PHARMACOTHERAPY OF PARKINSONISMDR. JINIA GHOSHMD PGT (PHARMACOLOGY)RGKMCH

INTRODUCTION

Parkinsonism is a generic term that is used to define a syndrome manifest as bradykinesia with rigidity and/or tremor. It has a differential diagnosis that reflects damage to different components of the basal ganglia.

Among the different forms of parkinsonism, idiopathic form is the most common known as Parkinsons Disease (approximately 75% of cases).

PARKINSONS DISEASE

Second commonest neurodegenerative disease, exceeded only by Alzheimer's disease.Affects men and women of all races, all occupations, and all countries.Mean age of onset is about 60 years, but cases can be seen in patients in their 20s, and even younger.Prevalence will dramatically increase in future decades.

CLINICAL FEATURES

ETIOLOGYMost PD cases occur sporadically (~8590%) and are of unknown cause.Environmental factors : Important role in patients >50 years. Increased risk with exposure to pesticides, rural living,and drinking well water. Reduced risk with cigarette smoking, caffeine, anti-inflammatory drug and high serum uric acid levels.

Genetic factors : Important in younger patients. LRRK2 mutation, alpha synuclein, tau, and HLA are risk factors.UCHL1 gene AD parkinsonism.parkin gene early-onset, AR, familial, or sporadic juvenile-onset parkinsonism.Others : Excitotoxicity, mitochondrial dysfunction, oxidative stress, inflammation and apoptosis.

PATHOPHYSIOLOGY

The dopaminergic deficit which arises from a loss of the neurons in the substantia nigra pars compacta that provide innervation to the striatum.

The disorder affects a wide range of other brain structures, including the brainstem, hippocampus, and cerebral cortex. This pathology is likely responsible for the non-motor features of PD.

Basal Ganglia in PD

MOLECULAR ASPECTS

Associated with the development of intracellular protein aggregates known as Lewy bodies. They consist largely of -synuclein, a synaptic protein. -synuclein may act as a prion-like protein and that PD is in fact a prion-like disease. -helical conformation -sheet-rich structure polymerises to form toxic aggregates and amyloid plaques. Misfolding and aggregation renders the protein resistant to degradation within cells pile up in Lewy bodies.

How PD Medications Work

LEVODOPAMetabolic precursor of DA.Single most effective agent in the treatment of PD.About 80% of patients show initial improvement particularly of rigidity and bradykinesia, and about 20% are restored virtually to normal motor function.Does not alter the disease course. Administered orally.Absorbed rapidly from the small bowel. Peak plasma concentration between 0.5 and 2 hours. The plasma t1/2 is 1-3 hours.

The rate and extent of absorption depends on the rate of gastric emptying, the pH of gastric juice, the degradative enzymes of the gastric and intestinal mucosa, competition with dietary amino acids ,co-administration with high-protein meals.

Entry of the drug into the CNS across the blood-brain barrier also is mediated by a membrane transporter for aromatic amino acids.

Molecular structure :

Metabolism of Levodopa

Adverse EffectsA. Gastrointestinal Effects : Anorexia, nausea and vomiting.

B. Cardiovascular Effects : Tachycardia, ventricular extrasystoles and, rarely, atrial fibrillation. Postural hypotension is common, but often asymptomatic.Hypertension may also occur, especially in the presence of nonselective MAO inhibitors or sympathomimetics or massive doses of levodopa.

C. Behavioral Effects :Depression, anxiety, agitation, insomnia, somnolence,confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality.

D. Dyskinesias and Response Fluctuations :Dyskinesias occur in up to 80% of patients receiving levodopa therapy for >10 years.

wearing off phenomenon - Each dose of levodopa effectively improves mobility for a period of time, but rigidity and akinesia return rapidly 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.

on/off phenomenon In the later stages of PD, patients may fluctuate rapidly between being off, having no beneficial effects, and being on but with disabling dyskinesias. Dyskinesias are observed most often when the plasma levodopa concentration is high, rising or falling.

E. Miscellaneous Adverse Effects :Mydriasis may occur and may precipitate an attack of acute glaucoma. Various blood dyscrasias; a positive Coombs testwith evidence of hemolysis, hot flushes.Aggravation or precipitation of gout. Abnormalities of smell or taste. Brownish discoloration of saliva, urine, or vaginal secretions. PriapismMild elevations of blood urea nitrogen, serum transaminases, alkaline phosphatase, and bilirubin.

Drug Interactions

Pyridoxine (vitamin B 6 ) enhance the extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect.

Levodopa should not be given to patients takingMAO-A inhibitors or within 2 weeks of their discontinuance because such a combination can lead to hypertensive crises.

Contraindications

Psychotic patients. Angle-closure glaucoma Should be used cautiously in patients with cardiac disease, active peptic ulcer.Should be used with particular care in patients with a history of melanoma or with suspicious undiagnosed skin lesions.

PERIPHERAL DECARBOXYLASE INHIBITOR

Carbidopa & benserazide.Peripherally acting inhibitor of aromatic L-amino acid decarboxylase.Do not penetrate well into the CNS. Markedly increases the fraction of administered levodopa that remains unmetabolized and available to cross the blood-brain barrier and reduces the incidence of GI side effects.In clinical practice, levodopa is almost always administered in combination with this drug.

Fate of orally administered levodopa with or without carbidopa

Dosage & Formulation

Total daily dose should be increased very slowly.The most commonly prescribed form of carbidopa/levodopa is the 25/100 form, three or more tablets daily.A controlled-release formulation is available.A formulation of carbidopa-levodopa (10/100, 25/100, 25/250) that disintegrates in the mouth is available and is best taken about 1 hour before meals.Finally, therapy by intraduodenal infusion appears to be safe and is superior to a number of oral combination therapies in patients with response fluctuations.

DOPAMINE RECEPTOR AGONISTS

Older dopamine agonists - Bromocriptine and Pergolide are ergot derivatives, and are rarely used to treat parkinsonism. Newer agents Pramipexole, Ropinirole and Rotigotine . Better tolerated.Mechanism of action - Direct agonists of striatal DA receptors. Selective activity at D2 class sites(specifically at the D2 and D3 receptor) and little or no activity at D1 class sites.

Advantages -Do not require enzymatic conversion to an activeMetaboliteHave no potentially toxic metabolitesDo not compete with other substances for active transport into the blood and across the BBB.Selectively affecting certain DA receptors. May have more limited adverse effects.Do not depend on the functional capacities of the nigrostriatal neurons. Longer durations of action.May have the potential to modify the course of PD.

Uses

Lower incidence of the response fluctuations and dyskinesias. May be first-line therapy. Alternatively, a low dose of carbidopa+levodopa is introduced, and a dopamine agonist is then added.May also be given to patients who are becoming resistant to treatment with levodopa. The response is generally disappointing in patients who have never responded to levodopa.

Dose

The dose is built up gradually depending on response and tolerance.Initial dose of pramipexole 0.125 mg orally 3 times dailyInitial dose of ropinirole 0.25 mg orally 3 times dailyBoth are available in once-daily sustained release formulation, which is more convenient and may reduce adverse effects. Rotigotine is delivered daily through a skin patch in early PD.

Adverse effects A. Gastrointestinal Effects -Anorexia and nausea and vomiting.Constipation, dyspepsia, and symptoms of reflux esophagitis.Bleeding from peptic ulceration has been reported.B. Cardiovascular Effects -Postural hypotensionCardiac arrhythmiasPeripheral edema

C. Dyskinesias -Abnormal movements. D. Mental Disturbances -Confusion, hallucinations, delusions, and other psychiatric reactions. More common & severe than with levodopa.Disorders of impulse control.

Contraindications contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration.

APOMORPHINE

Dopaminergic agonist. It has high affinity for D4 receptors, moderate affinity for D2, D3, D5, and adrenergic 1D, 2B, and 2C receptors.Administered by SC injection.rescue therapy for the acute intermittent treatment of off episodes.Highly emetogenic. Oral trimethobenzamide should be started 3 days prior and continued at least during the first 2 months of therapy.

QT prolongation, injection-site reactions, and abuse potential.Used only when other measures, such as oral DA agonists or COMT inhibitors, have failed.Initiated with a 2-mg test dose. If tolerated, it can be titrated slowly up to a maximum dosage of 6 mg three or more injections daily.The concomitant use with 5-HT3 antagonist class is contraindicated.

CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORSTolcapone and EntacaponeSignificantly reduce the wearing off symptoms.Mechanism of action - Addition of carbidopa reduces the formation of DA but increases the fraction of levodopa that is methylated by COMT. COMT inhibitors block this peripheral conversion of levodopa to 3-O-methyl DOPA.Tolcapone -Relatively long duration of action, administered two to three times a day. Both central and peripheral inhibition of COMT.

Entacapone - Short duration of action and administered simultaneously with each dose of levodopa/carbidopa. Peripheral inhibition of COMT.

Adverse effects - Nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An important adverse effect associated with tolcapone is hepatotoxicity. Up to 2% of the patients treated have increased serum ALT and AST. Entacapone has not been associated with hepatotoxicity and requires no special monitoring.

MAO-B INHIBITORSMAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of DA in the brain.Two selective MAO-B inhibitors are used for the treatment of PD: selegiline and rasagiline.Selectively inactivate MAO-B through irreversible inhibition of the enzyme.selective MAO-B inhibitors do not substantiallyinhibit the peripheral metabolism of catecholamines and can be taken safely with levodopa. Do not exhibit the cheese effect

Selegiline Well tolerated in younger patients with early or mild PD. In patients with more advanced PD or underlying cognitive impairment, selegiline may accentuate the adverse motor and cognitive effects.Metabolites of selegiline include amphetamine and methamphetamine anxiety, insomnia, and other adverse symptoms. Available in an orally disintegrating tablet and a transdermal patch reduce hepatic first-pass metabolism decreased formation of the amphetamine metabolites.

Rasagiline -Does not give rise to undesirable metabolites.Monotherapy was effective in early PD. Adjunctive therapy significantly reduced wearing off symptoms in advanced PD.Inhibition of MAO-B in the brain reduction in the overall catabolism of DA reduced formation of potentially toxic free radicals. No conclusive evidence suggesting a neuroprotective effect of rasagiline.

MUSCARINIC RECEPTOR ANTAGONISTSTrihexyphenidyl (2-4 mg 3 times/day), Benztropine mesylate (1-4 mg 2 times/day), and Diphenhydramine hydrochloride (25-50 mg 3 or 4 times/day).Only used in the treatment of early PD or as an adjunct to dopamimetic therapy.May act within the neostriatum which has intrinsic cholinergic innervation arises primarily from cholinergic striatal interneuronsAdverse effects - sedation and mental confusion. Other side effects are constipation, urinary retention, and blurred vision. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma.

AMANTADINE

An antiviral agent. Appears to alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors. The effects are modest. Initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias. Dose - 100 mg twice a day. well tolerated.Adverse effects Mild. Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as well as nausea and vomiting.

MANAGEMENT OF THE NONMOTOR AND NONDOPAMINERGIC FEATURES

Dopaminergic drugs - anxiety, panic attacks, depression, sweating, sensory problems, freezing,and constipation all tend to be worse during off periods and may improve with better dopaminergic control.Antidepressants - Approximately 50% of PD patients suffer depression during the course of the disease. Antidepressants should not be withheld, particularly for patients with major depression. Pramipexole may have antidepressant effects.

Benzodiazepines - Anxiety can be treated with short-acting BZD.Atypical neuroleptics - Psychosis can be a problem. Clozapine is the most effective drug, but it can be associated with agranulocytosis. For this reason, many physicians start with quetiapine. Anticholinesterase may have anti-psychotic effects.Measures for dementia - Dementia is common, affecting as many as 80% of patients. Drugs are usually discontinued in the following sequence: anticholinergicsamantadinedopamine agonists COMT inhibitorsMAO-B inhibitors.Patients should be managed with the lowest dose of levodopa. Rivastigmine and donepezil can be tried.

Sleep Disorders - Modafinil may be considered for daytime hypersomnolence .Autonomic dysfunction - General measures for treating urinary urgency and incontinence. Add peripherally acting anticholinergic drugs.Constipation - Apply general measures for treating constipation. Reduce or discontinue drugs with anticholinergics activity. Add domperidone.

Orthostatic hypotension 1. Non-pharmacological: fluid intake, dietary salt, avoid alcohol / large meals (frequent small meals instead) / excessive warmth, elevate head of bed. Patients should be advised to rise slowly, especially in morning or after sitting/lying for a period of time 2. Discontinue unnecessary medications, e.g., antihypertensives3. Fludrocortisone 4. Domperidone 5. Midodrin6. Consider pyridostigmine

DRUG-INDUCED PARKINSONISMPredictable Neuroleptic Drugs (Both Typical And Atypical) Hidden Neuroleptics Metoclopromide Prochlorperazine Combination With Antidepressants (Fluphenazine ) Calcium Antagonist Idiosyncratic Lithium Sodium Valproate AmiodaroneMainly Tremor But Parkinsonism Reported.

Causative drugs Reserpine and tetrabenazine deplete biogenic monoamines from their storage sites. Haloperidol, metoclopramide, and the phenothiazines block dopamine receptors.These drugs may therefore produce a parkinsonian syndrome, usually within 3 months after introduction.Treatment - It is related to high dosage and clears over several weeks or months after withdrawal. If treatment is necessary, antimuscarinic agents are preferred. Levodopa is of no help and may in fact aggravate the mental disorder.

RECENT ADVANCES

NEUROPROTECTIVE AGENTSMAO inhibitors: selegiline & rasagilineAntiexcitotoxicity drugs: RiluzoleBioenergetic antioxidant agent: coenzyme Q10, creatineGDNFAnti apoptotic kinase inhibitors(eg omigapil,CEP-1347)AntiglutamatergicsCalcium channel blocker : IsradipineVaccine : PD01A (to destroy -synuclein)Deacetylase inhibitors -target the transport system and reverse the defects caused by the faulty LRRK2 within nerve cells.

GENE THERAPY

Adeno-associated virus (AAV) type 2 used as vector. Gene for aromatic L-amino acid decarboxylase (AADC) into putamen to increase metabolism of levodopa.Gene for glutamic acid decarboxylase to STN to facilitate synthesis of GABA.Gene for neurturin to putamen to enhance the survival of dopaminergic neurons.

Intraduodenal gel formation in development is a combination of levodopa and carbidopa, which helps prevent levodopa from being degraded before it reaches the brain. This mechanism of delivery helps prevent levodopa degradation and promotes faster absorp-tion, and maintenance of more constant levels of levodopa.

Adenosine A2A receptor antagonists (eg, istradefylline) : A2A receptor regulates glutamate and dopamine release. Antagonist reduces dyskinesia.Nicotine Intake of nicotine has shown to slow the degeneration of neurons. Acts similar to levodopa.Melatonin Serotonin derivative that helps insomnia. Also shown to cause a reduction in production of neurodegenerative radicals.

STEM CELL THERAPY Transplant strategies are based on the concept of implanting dopaminergic cells into the striatum to replace degenerating SNc dopamine neurons. Fetal nigral mesencephalic cells have been demonstrated to survive implantation, re-innervate the striatum in an organotypic manner, and restore motor function in PD models.

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