Anti Parkinson Drugs PDF

# Anti Parkinson Drugs Parkinson disease is a progressive neurodegenerative disease, a neurological disorder of muscle movement characterized by tremors, muscular rigidity, bradykinesia and postural and gait abnormalities. Bradykinesia should be present before the diagnosis of Parkinson disease (P...

# Anti Parkinson Drugs Parkinson disease is a progressive neurodegenerative disease, a neurological disorder of muscle movement characterized by tremors, muscular rigidity, bradykinesia and postural and gait abnormalities. Bradykinesia should be present before the diagnosis of Parkinson disease (Paralysis agitans) is made. Focal dystonic features may be present. Cognitive decline occurs in many patients as the disease progresses. Non-motor symptoms include affective disorders (anxiety or depression), confusion, personality changes, apathy, fatigue, abnormalities of autonomic function of sphincter or sexual dysfunction, dysphagia and choking, sweating abnormalities sialorrhea or disturbances of BP, sleep disorders and sensory complaints/pain. The cause of Parkinson disease is unknown but some risk factors exists: hereditary basis, exposure to some toxins eg manganese dust, carbon disulfide, carbon monoxide. May develop after multiple subcortical white matter infarcts or recurrent head injury (as in boxers), or in association with other neurological disorders. The disease is correlated with destruction of doperminergic neurons in the substantia nigra *with a consequent reduction of dopamine actions in the corpus striatum*, part of the basal ganglia that are involved in motor control. The substantia nigra is the source of dopaminergic neurons that terminate in the neostriatum. Each dopaminergic neuron makes many synaptic contacts within the neostriatum and therefore modulates the activity of a large number of cells. These dopaminergic projections from the substantia nigra fire tonically, thus, the dopaminergic system appears to serve as a tonic, sustaining influence on motor activity, rather than participating in specific movements. Neostriatum is connected to the substantia nigra by neurons that secrete the inhibitory transmitter dopamine GABA @ their termini. In turn, cells of the substantia nigra send neurons back to the neostriatum, secreting the inhibiting transmitter, dopamine @ termini. This mutual inhibitory pathway normally maintains a degree of inhibition of both areas. In Parkinson disease, destruction of cells of the substantia nigra results in the degeneration of the nerve terminals that secrete dopamine in the neostriatum. Hence, the normal inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly reduced, resulting in overproduction or relative over activity of acetylcholine by the stimulatory neurons. This triggers a chain of abnormal signalling resulting in the loss of control of muscle movement. Secondary parkinsonism can result from the use of drugs like Haloperidol and phenothiazines, whose major action is blockade of dopamine receptors in the brain leading to Parkinsonian symptoms (pseudoparkinsonism), these drugs should be avoided in patients with Parkinson disease. ## Therapeutic Strategy Many of the symptoms of Parkinson disease reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. The therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons, thus re-establishing the correct dopamine/acetylcholine balance. The drugs used in this condition aim to maintain CNS dopamine levels/signalling, as much steady as possible. They offer temporary relief of the symptoms but cannot arrest or reverse the neuronal degeneration caused by the disease. ### 1) Levodopa and Carbidopa Dopamine alone, don't cross the blood-brain barrier and if given into the peripheral circulation, has no effect in Parkinson disease. Levodopa, the immediate precursor of dopamine, do enter the brain, where it is decarboxylated to dopamine. Levodopa restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. A diagram showing the percentage of levodopa and carbidopa being absorbed at different places in the body ### **MOA** Levodopa is actively transported into the CNS and converted to dopamine. Dopamine *does not cross the blood-brain barrier* but its immediate precursor, levodopa does cross via BBB by active transport. Levodopa is usually given with carbidopa because without carbidopa most of the drug is decaboxylated to dopamine in the periphery, resulting in diminished effect. Carbidopa, a dopamine decarboxylase inhibitor, reduces the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by 4 - 5x, subsquently decreases the severity of adverse effects arising from the peripherally formed dopamine. ## Pharmacokinetics The drug is rapidly absorbed from the small intestine especially on empty stomach. Absorption depends on the pH of the gastric contents. Certain amino acids (proteins) from ingested food competes with the drug for absorption from the gut and for transportation from the blood to the brain. It can be taken 30mins before a meal. * Peak Plasma concentration – 1-2 hours * Half life – 1 -3 hours ## Therapeutic Uses * Bradykinesia especially in Parkinson disease and other motor symptoms. ## Formulation * 25mg Carbidopa, 250mg Levodopa 3 – 4x/d. * Better kept at carbidopa: Levodopa 25/100mg 3-4x/d * **+ Dopamine agonist** to reduce response fluctuations development. * **Extended release formulation** (Rytary) - *capsules 1:4 ratio of cabidopa: levodopa*. * **A formation that disintegrates in the mouth and swallowed with saliva:** 10/100; 25/100 and 25/250mg combination (Parcopa) * **(Stalevo):** a combination of levodpa, carbidopa and a COMT inhibitor, entacapone is also used. * **Infusion therapy of Levodopa -carbidopa into the duodenum & upper jejunum** is available - safe and superior to oral preparations in advance stage of the disease with response fluctuations. An access tube is inserted via a percutaneous endoscopic gastrostomy. * There is gel formulation delivered by a nasoduodenal tube and also that delivered by portable infusion pumps. * Withdrawal is gradual. ## Adverse Effects ### Peripheral * Anorexia, nausea and vomiting from stimulation of the chemoreceptor trigger zone. * Tachycardia and ventricular extrasystole from dopaminergic action on the heart. (Rare – Atrial fibrillation.) * Hypotension * Mydraisis from adrenergic action on the iris. * Blood Dyscrazias (positive Coomb’s test) * Brownish urine/saliva because of melanin pigment produced from catecholamine oxidation. ### CNS * Visual and auditory hallucinations * Dyskinesia (abnormal involuntary movements). * Mood changes * Depression * Psychosis * Anxiety * On-off phenomenon ## Drug Holiday * **3-21/7** temporarily improve responsiveness, with little help in the on-off phenomenon. * There is risk of aspiratory pneumonitis, venous thrombosis, pulmonary embolism and depression from immobility in severe parkinsonism. ## Drug Interactions * **Pyridoxine (Vit B6)** increases the peripheral breakdown of levodopa and reduces its effectiveness unless the decarboxylase inhibitor is used along. * **Concomitant administration of Levodopa and MAOI such as phenelzine can produce a hypertensive crisis caused by ↑ catecholamine production** * **Antipsychotic drugs are generally contraindicated in Parkinson patients** ## Contraindications * Psychotic patients (quetiapine or clozapine in low dose sometimes can be used) * Arrhythmias. * Closed – angle glaucoma * Active PUD (GIT bleeding with levodopa) * Melanoma or Suspicious skin lesion (Levodopa is a precursor of skin melanin) ### 2) Dopamine Receptor Agonists This group of antiparkinsonism drugs include Bromocryptine, pergolide, pramipexole, rotigotine & ropinirole. They have a longer duration of action than levodopa and are effective in patients exhibiting fluctuations in response to levodopa. They do not require enzymatic conversion to active metabolite, they act directly on the postsynaptic dopamine receptors. * No potentially toxic metabolites * Do not compete with other substances for active transport into the blood and across the blood-brain barrier. #### a. Bromocriptine Bromocriptine has similar actions like levodopa except that hallucinations, confusion, delirium, nausea and orthostatic hypotension are more common and dyskinesia is less prominent. Because its an ergot derivative, it has the potential to cause pulmonary *and retroperitoneal fibrosis*. Its use have been superseded by newer agents. #### b. Pramipexole This is not an ergot derivative just like ropinirole but it has a preferential affinity for D3 receptors. It is effective as monotherapy for mild parkinsonism, helpful in advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. May ameliorate affective symptoms. It scavenges for H2O2 which enhances some neuroprotective effect. * Rapidly absorbed orally with peak plasma concentration of ↑ 2hrs * Excreted largely unchanged in the urine * Dosage – starting 0.125mg 3x/d, doubled after 1 week and again after another week. * Extended release preparation is now available more convenient and avoid swings in blood levels. #### c. Ropinirole This is another non-ergot derivative also used in treatment of restless legs syndrome. A D₂ receptor agonist that is effective as monotherapy in mild Parkinson disease and as a means of smoothing the response to Levodopa in advanced stage of *the disease and response fluctuations*. * Dosage – 0.25mg 3x/d. Then can get to 0.75mg/d @ weekly intervals. * Extended release is also available. #### d. Rotigotine * Another dopamine agonist * Delivered through a skin patch * For treatment of early Parkinson Disease * Provides more continuous dopaminergic stimulation than oral medication in early Parkinson disease #### e) Apormorphine Used in acute hypomobility "off" phenomenon in advanced Parkinson disease – transdermal patch once daily dosing. ## Adverse Effects of Dopamine Receptor Agonists * **GIT** – Anorexia, nausea, vomiting, constipation, Dyspepsia, reflux esophagitis, Bleeding peptic ulcer. * **CVS** – Postural hypotension - Painless Digital vasospasm - Cardiac Arrythmias - Peripheral edema – Cardiac valvulopathy (pergolide). * **CNS** – Dyskinesias - Mental disturbances – Confusion - Hallucination - Delusions - Impulse control disorder – compulsive disorder - Withdrawal syndrome * **Miscellaneous** – Headache - Hallucination - Nasal Congestion - Increased arousal - Pulmonary infiltrates - Pleural & Retroperitoneal fibrosis (Ergot - derived Dopamine Agonists mainly) - Erythromelalgia – Red, tender, swollen) - Painful feet + Arthralgia * **Rarely** – Uncontrollable tendency to fall asleep at inappropriate times) esp. with pramipexole & Ripinirole – discontinuation. ## Contraindications * Psychotic illness * Recent myocardial infarction * Active peptic ulcer * Ergot – derivatives agonist best avoided in peripheral vascular disease. ### 3) Monoamine Oxidase Inhibitors There are *two types of monoamine oxidase enzyme in the nervous system*. * **MAO A** – Metabolizes – Norepinephrine, serotonin and Dopamine * **MAO B** – Metabolizes Dopamine alone (selectively) #### Selegiline (Deprenyl) Selegiline (Deprenyl) selectively inhibits MAO type B, that metabolizes dopamine. It doesn’t inhibit type A except @ higher doses where it loses its selectivity. By decreasing the metabolism of dopamine, it increases the dopamine levels in the brain. When given with levodopa, it enhances the actions of levodopa and reduces the required dose of levodopa. Unlike the non selective MAOIs, selegiline at the recommended *dose, has little potential for causing hypertensive crisis*. When it loses selectivity @ higher doses, there is risk of severe hypertension. It is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia. It is used as an adjunct Rx with declining or fluctuating response to levodopa. * **Dosage** – 5mg with breakfast and 5mg with launch. Can cause insomnia if taken after mid-afternoon. #### a) Rasagiline Rasagiline – an irreversible and selective inhibitor of brain MAO type B has 5x, the potency of selegiline. It is not metabolished to an amphetamine-like substance. It is more potent than selegiline in preventing MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)(a.k.a-Tetrahydropyridine) – induced Parkinsonism. MPTP *causes permanent symptoms of Parkinson disease by destroying Dopaminergic neurons in substantia nigra.* Rasagiline is used for early treatment in patients with mild symptoms. * **Dosage** - 1mg/d Adjunctive Rx @ a dosage of 0.5mg - 1mg/d to prolong the effect of levodopa - carbidopa in patients with advanced disease and response fluctuation. #### b) Safinamide Safinamide is also a selective MAO – Type B inhibitor, used as an adjunct to levodopa - carbidopa Px. Not effective as a single therapy for Parkinson disease. Starting dose is 50mg PO, OD, increased after 2 weeks to 100mg OD. ## Precautions: * **MAO – B – inhibitors should not be taken by patients receiving:** - Meperidine - Tramadol - Methadone - Propoxyphene - Cyclobenzapine - Antitussive (Dextromethorphan) (over the counter cold preparations) * **MAO – B – inhibitors should not be taken along with other MAOI** * **Avoid in patients receiving TCAD, or SSRIs because of acute toxic interactions of the serotonin syndrome (rare).** * **MAO B – inhibitors may increase the adverse effect of levodopa such as dyskinesia, mental changes, nausea + sleep disorders. The use of levodopa and a non-selective MAOI should be avoided because of hypertensive crises as a result of peripheral accumulation of NE.** ### 4) Catechol – O – Methyltransferase Inhibitors Usually, the methylation of levodopa by COMT to 3.0 – methyldopa (3-O-MD) is a minor pathway for levodopa metabolism. When peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant level of 3-O-MD is formed, which competes with levodopa for active transport into the CNS (BBB) and across the intestinal lining. These agents in this group – Entacapone and Tolcapone selectively and reversibly inhibit COMT. This leads to decreased plasma level 3-O-MD and increased uptake of levodopa with greater concentration of brain dopamine. * **Tolcapone** has both central and peripheral effects. Half life is about 2 hours, more potent and ha a longer duration of action, taken 100mg/tds. * **Entacapone** has only peripheral effects with half life of 2hours. It's less potent and has shorter duration of action with regards to tolcapone. Entacapone 200mg needs to be taken with each dose of levodopa upto 6x/d. ## Adverse Effects of COMT Inhibitors * Diarrhea * Postural hypotension * Nausea * Anorexia * Dyskinesias * Hallucinations * Sleep disorders * **Most serious** – fulminating hepatic necrosis – Tolcapone, thus it's used with appropriate LFTs monitoring. Entacapone doesn’t exhibit this hence has largely replaced tolcapone. * **Stalevo** is a *combination of levodopa, carbidopa and entacapone as a single tablet*. * **Early occurrence and increased frequency of dyskinesia is present**. * **Opicapone** a new long acting, peripherally selective COMT inhibitor that is taken OD @ bedtime. It reduces "off" period and increases "on" time in patients with fluctuating response to levodopa. ### 5) Others: #### Apomorphine This is a non-ergot derivative dopamine agonist, used for acute management of the hypomobility "off" phenomenon in advanced Parkinson disease. It is given substaneously and interacts with post -synaptic D₂ receptors. #### Amantadine This was accidentally discovered antiviral drug that has some anti-parkinsonism action potentiating dopaminergic function by increasing the synthesis and release of dopamine and blocking cholinergic receptors, inhibiting the N-methyl – D – Aspartate (NMDA) type of glutamate receptors. * Less efficacious than levodopa. * There is immediate release and extended release formulations. ### Acetylcholine – Blocking Agents Antimuscarinic preparations of this agents may improve tremor and rigidity of parkinsonism but have little effect on bradykinesia. Other drug with antimuscrainic properties used in Parkinsonism include Benztropine, Biperiden, Orphenadine, Procyclidine and Trihexyphenidyl. ### Istradefylline A caffeine analog and selective antagonist of Adenosine A2A receptor. It helps to reduce off-periods and improve motor function in patients taking carbidopa-levodopa. ## Other Treatment Modalities of Parkinsonism * Surgical Procedure * Neuroprotective therapy * antioxidants, glutamate antagonist, intraparenchymally administered glial – derived neurotrophic factor and antiinflamatory drugs. * Gene therapy * therapy for non-motor manifestations – rivastigmine in cognitive decline in parkinsonism. ## Drug - Induced Parkinsonism * Depletion of monoaminestores – Riserpine, tetrabenazine * Dopamine receptor blockade – Haloperidol, metoclopromide & phenothiazines. ## Atypical Parkinsonism Syndrome Atypical in the sense that they differ from classical parkinsonism. ## Other Movement Disorders * Tremor * Huntington Disease - Chorea, Ballismus, Athetosis, Dystonia, Tics * Drug-induced Dyskinesia – dose related * Restless legs syndrome * Wilson - disease