Anti Parkinsons Drugs

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

Location D1D2- Striatum D3- Nucleus Accumbence, Olfactory Tuberclw D4D5-Extrastriatal

Neuronal Circuits
Normal Physiology Parkinsons Disease

Effect of Loss of Dopaminergic Neurons

Decreased activity of D1 dependent direct pathway Increased activity of D2 Dependant Indirect pathway Effective increase in inhibitory impulses to Thalamus Leading to Decesed excitation of cortex trough thalamus Ultimate loss of Upper motor neuron inhibition

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

Inhibitors of aromatic L-amino acid decarboxylase

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.

Dopamine Receptor Agonists

Ropinirole,Pramipexoe(selectiv D2D3 noD1) Pergolide(Cardiac Valve fibrosis), Bromocriptine Advantages: Activity do not depend on the functional capacities of the nigrostriatal neurons. Longer duration of action(8-24 ) Less motor fluctuation Might retard progression Ropinirole is also available in a once-daily sustained release formulation

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

Apomorphine therapy should be initiated with a 2-mg test dose

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

Nonspescific: phenelzine, tranylcypromine, and isocarboxazid

Selective MAO-B Inhibitors

Selegiline, Rasagiline Selectively inactivate MAO-B through irreversible inhibition of the enzyme Inhibition of breakdown of DA in the striatum do not substantially inhibit the peripheral metabolism of catecholamines and can be taken safely with levodopa do not exhibit the "cheese effect"

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

Drug Interactions Of MAO-B Inhibitors

Muscarinic Receptor Antagonists

The biological basis for the therapeutic actions of anticholinergics is not completely understood. Trihexyphenidyl , Benztropine mesylate, Diphenhydramine hydrochloride modest antiparkinsonian activity and are only used in the treatment of early PD or as an adjunct to dopamimetic therapy sedation and mental confusion. Other side effects are constipation, urinary retention, and blurred vision through cycloplegia. All anticholinergic drugs must be used with caution in patients with narrow-angle glaucoma

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

Neuroprotective Treatments for Parkinson Disease

Rasagiline Coenzyme Q10