Académique Documents
Professionnel Documents
Culture Documents
Introduction
Pathophysiology
The dopaminergic deficit in PD arises from a loss of the neurons in the substantia nigra pars compacta that provide innervation to the striatum (caudate and putamen)
Dopamine Receptors
At least 5 different types D1 to D5 All G protein coupled receptors D1 D5 Increase CAMP D2D3D4-Decrese CAMP ,Modulate Ca+ K+ current
Neuronal Circuits
Normal Physiology Parkinsons Disease
Classification of Drugs
Dopamine Agonists- Ropinirole , Pramipexole Levodopa carbidopaCOMT Inhibitors-Entacapone, Tolcapone MAO Inhibitors-Selegiline,Rasagiline Anticholinergics- Trihexyphenidyl , Benztropine mesylate, Diphenhydramine hydrochloride Disease Modifying Agents & Potential therapeutic Targets-Rasagiline, CoenzymeQ10
Levodopa
the metabolic precursor of DA, is the single most effective agent in the treatment of PD administered orally, levodopa is absorbed rapidly from the small bowel by the transport system for aromatic amino acids The t1/2 in plasma is short (1-3 hours) ompetition for absorption sites in the small bowel from dietary amino acids also may have a marked effect on the absorption of levodopa . Entry of the drug into the CNS across the blood-brain barrier also is mediated by a membrane transporter for aromatic amino acids In the brain, levodopa is converted to DA by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the stratium. The DA 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
Carbidopa , Benserazide
If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively little unchanged drug reaches the cerebral circulation and probably <1% penetrates the CNS. In addition, DA release into the circulation by peripheral conversion of levodopa produces undesirable effects, particularly nausea. Inhibition of peripheral decarboxylase 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.
Side Effects: Hallucinosis or confusion Nausea and orthostatic hypotension Fatigue and somnolence Sudden attacks of irresistible sleepiness
Apomorphine
A dopaminergic agonist that can be administered by subcutaneous injection It has high affinity for D4 receptors approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy highly emetogenic , QT prolongation, injection-site reactions hypotension and loss of consciousness have occurred when apomorphine was administered with ondansetron; hence, the concomitant use of apomorphine with antiemetic drugs of the 5-HT3 antagonist class is contraindicated appropriate only when other measures, such as oral DA agonists or COMT inhibitors, have failed to control the "off" episodes
COMT Inhibitors
COMT transfers a methyl group from the donor S-adenosyl-Lmethionine, producing the pharmacologically inactive compounds 3O-methyl DOPA (from levodopa) and 3-methoxytyramine The principal therapeutic action of the COMT inhibitors is to block this peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma t1/2 of levodopa as well as the fraction of each dose that reaches the CNS
Two COMT inhibitors presently are available for this use in the United States, tolcapone (TASMAR) and entacapone (COMTAN) both agents significantly reduced the "wearing off" symptoms in patients treated with levodopa/carbidopa The common adverse effects of these agents are similar to those of levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations
Entacapone
Short duration of action Administered with L+C Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (STALEVO)
Tolcapone
tolcapone has a relatively long duration of action, allowing for administration two to three times a day Hepatotoxic
MAO Inhibitors
MAO-A : deaminates 5HT, NA In Adrenergic nerve endings, Intestinal Mucosa,Placenta,Liver inhibited by Clorgyline,Moclobemide MAO-B: deaminates Phenylethylamines Found in Brain ,Platelets,and Liver Inhibited by Selegiline, Rasagiline
Selegiline
generally 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 of levodopa therapy Metabolites of selegiline include amphetamine which may cause anxiety, insomnia, and other adverse symptoms available in an orally disintegrating tablet, transdermal patch
Rasagiline
Does not give rise to undesirable amphetamine metabolites Rasagiline monotherapy was effective in early PD. Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms in advanced PD. Neuroprotective effect of rasagiline
selegiline can lead to the development of stupor, rigidity, agitation, and hyperthermia when administered with the analgesic meperidine selegiline or rasagiline should not be given in combination with meperidine. Adverse effects have been reported from co-administration of MAO-B inhibitors with tricyclic antidepressants or with serotonin-reuptake inhibitors. concomitant administration of selegiline or rasagiline with serotonergic drugs should be done with caution
Amantidine
Amantadine an antiviral agent used for the prophylaxis and treatment of influenza A has antiparkinsonian activity alter DA release in the striatum, has anticholinergic properties, and blocks NMDA glutamate receptors It is used as initial therapy of mild PD. It also may be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as well as nausea and vomiting