Drugs used in Parkinson’s disease

Understand the epidemiology, basic pathophysiology and impact of Parkinson’s Disease (PD). Identify the clinical features of Parkinson’s Disease Recognize and list the various treatments \ drugs available to treat PD Learning Objectives

"Parkinson's disease" (Parkinsonism, PD) is a progressive neurodegenerative brain disorder that was first described by Dr. James Parkinson in The disease occurs mainly in the elderly (above the age of 65) and affects the "extrapyramidal system" at the level of the "corpus striatum" & "substantia nigra" (parts of the brain "basal ganglia").

In the basal ganglia, the 2 neurotransmitters "dopamine" & "acetylcholine" co-exist in a normal balance, where dopaminergic neurons exert an inhibitory effect on excitatory cholinergic neurons. In Parkinson’s disease, the "nigrostriatal dopaminergic neurons" are degenerated (damaged) while cholinergic neurons are intact, resulting in a marked decrease in dopamine content (dopamine deficiency syndrome) and a relative predominance of cholinergic activity. DA ACh Therefore, the strategy for treatment of Parkinsonism is to restore the normal balance between dopaminergic & cholinergic tones in the basal ganglia.

Corpus striatum Caudate nucleus Putamen Globus pallidus Loss of dopaminergic input to striatum Degeneration of neurons in substantia nigra pars compacta Disrupted signaling between basal ganglia, cortex, and thalamus Midbrain Thalamus Cortex Pathophysiology of PD Disease

Symptoms of Parkinsonism The symptoms of Parkinsonism appear only when dopamine depletion exceeds 80%. It is characterized by: Tremors at rest (especially in hands) which diminish during voluntary movements. Muscle rigidity and resistance to passive movements. Bradykinesia (i.e. slowness of movements) where the motor activity is difficult to be initiated or stopped. Diagnosis requires 2 of 3 symptoms: - bradykinesia, - rigidity, - resting tremor Abnormalities of posture and gait (shuffling gait). Mask-like facial expressions, impaired speech & skilled acts such as writing and eating.

Levodopa preparations : –Carbidopa/levodopa –Sinemet® –Sinemet CR® –Parcopa™ –Stalevo® Dopamine agonists –Apomorphine (Apokyn®) –Pramipexole (Mirapex®) –Ropinirole (Requip®) –Rotigitine (Neupro®) –Bromocriptine (Parlodel ®)* –Pergolide (Permax®)* Pharmacotherapy of PD

NMDA Antagonists –Amantadine (Symmetryl®) MAO-B Inhibitors –Selegeline (Eldepryl® or Deprenyl) –Zydis Selegeline (Zelapar®) –Rasagiline (Azilect®) –Carbidopa Anticholinergic agents –Benztropine (Cogentin®) –Trihexyphenidyl (Artane®) COMT Inhibitors –Entacapone (Comtan®) –Tolcapone (Tasmar®) Pharmacotherapy of PD

Treatment of Parkinsonism TyrosineDOPADA MAO-B Dopaminergic Nerve terminal D2D2 D2D2 D2D2 D2D2 Postsynaptic receptors

Drugs used to treat Parkinsonism do not stop the progression of the disease but they can only ameliorate the symptoms. Parkinsonism could be managed by: A. Enhancing dopaminergic activity using: 1.drugs that replace dopamine (levodopa) 2.drugs that release dopamine from its stores (amantadine) 3.drugs that prolong the action of dopamine by preventing its metabolism (seligiline) 4.drugs that mimic the action of dopamine (dopaminergic agonists) B.Reducing cholinergic activity by the use of anticholinergic drugs (benzatropine) C.Neurotransplantation (which is still in experimental phase). D.Physical therapy & regular exercise.

Levodopa "Levodopa" is the first line treatment of Parkinsonism. Dopamine itself has no therapeutic effect in Parkinsonism as it is not lipid soluble and therefore is not absorbed from the GIT and cannot cross the blood brain barrier. However, "levodopa" (which is the immediate precursor of dopamine) is well absorbed from the GIT and can cross the blood brain barrier, where it is taken up by dopaminergic neurons and converted to dopamine by the action of the enzyme "dopa decarboxylase".

In patients with early Parkinsonism, the number of residual dopaminergic neurons in the substantia nigra (about 20% of normal) is still enough to convert levodopa to dopamine. However, when the disease progresses, a fewer number of neurons are capable to take up levodopa and convert it to dopamine resulting in a “declined effectiveness” of levodopa. This indicates that the effect of levodopa depends on the presence of "functional dopaminergic neurons".

Major disadvantage of levodopa: Only 5% of an oral dose of levodopa can reach the brain because 95% of the dose undergoes decarboxylation to dopamine in the gut & peripheral tissues producing peripheral side effects. Peripheral sites CNS BBB L-dopa 5% decarboxylation

This problem was solved by the concomitant administration of levodopa with an inhibitor of dopa decarboxylase that does not cross the BBB (peripheral dopa decarboxylase inhibitor). Example of peripheral dopa decarboxylase inhibitors: carbidopa or benzerazide. Carbidopa or benzerazide inhibit the peripheral decarboxylation of levodopa allowing it to reach its desired site of action (i.e. the nigrostriatal system) in a greater proportion.

SINEMET (CARBIDOPA-LEVODOPA) DESCRIPTION SINEMET * (Carbidopa-Levodopa) is a combination of carbidopa and levodopa for the treatment of Parkinson's disease and syndrome.

Combing levodopa with the peripheral dopa decarboxylase inhibitors "carbidopa" or "benzerazide" has the following advantages: 1.The dose of levodopa can be reduced by about 75%. 2.The peripheral side effects of levodopa are greatly reduced. 3.If levodopa is administered alone (i.e. without carbidopa), it can interact with pyridoxine (vitamin B 6 ) in multivitamin preparations which enhances its peripheral metabolism (dopa decarboxylase is a pyridoxine-dependent enzyme). On the other hand, if levodopa is combined with carbidopa, pyridoxine cannot reduce the therapeutic effectiveness of levodopa since the peripheral decarboxylation of levodopa is already inhibited with carbidopa.

Levodopa restores "dopamine" content in the basal ganglia. Dopamine then acts on dopaminergic D 2 receptors in the nigrostriatal pathway to ameliorate the symptoms of Parkinsonism and improve the overall functional ability of Parkinsonian patients. Dopamine can also act on the limbic system, tuberohypophyseal system and CTZ producing side effects. Pharmacological actions of levodopa:

Side effects of levodopa: 1. " On-Off" effect: This effect results from fluctuations of the level of levodopa in the plasma because of its very short t½ (1-2 hours). The "off" effect can be very sudden so that patients stop while walking or are unable to rise from a chair in which they have sat down normally a few moments earlier. This effect is counteracted by the combination of levodopa with an inhibitor of COMT (e.g. entacapone) to inhibit the degradation of dopamine. 2."Dyskinesia" and induction of abnormal voluntary movements. 3."Nausea & vomiting" due to stimulation of dopamine receptors in the chemoreceptor trigger zone (CTZ) in the medulla oblongata. This effect is counteracted by the co-administration of "food" and peripheral (but not central) dopaminergic antagonists (e.g. domperidone) with levodopa. 4.Tachycardia resulting from dopamine action on the heart. 5.Psychological effects: levodopa may lead to an over activity of dopamine in the limbic system leading to "schizophrenia-like syndrome". 6.Endocrine effects: inhibition of prolactin secretion due to the effect of DA on the tuberohypophyseal system.

Drug interactions of levodopa: 1."Pyridoxine" (vitamin B 6 ) increases the peripheral break down of levodopa and reduces its effectiveness. 2.Concomitant administration of levodopa with "MAO inhibitors" leads to hypertensive crisis due to increased catecholamines (dopamine is a substrate for MAO and is also converted to noradrenaline). 3."Antipsychotic drugs" block central dopaminergic receptors and can induce parkinsonism-like syndrome themselves. Therefore they are contraindicated during Parkinsonism or levodopa therapy since they can reverse the benefits of levodopa.

Pramipexole (Mirapex®) Ropinirole (Requip®) Rotigitine (Neupro™) Apomorphine (Apokyn®) (cabergoline, lisuride) Dopamine Agonists

May be used as initial therapy for patients with mild disease or as “add on” therapy for patients with more severe disease May delay need for levodopa therapy in early patients Later stage patients may be able to decrease levodopa dosing if DA added Neuroprotective effect? Dopamine Agonists

Directly stimulate dopamine receptors No metabolic conversion required Longer half-life than levodopa (exception: apomorphine) May delay onset of dykinesias or motor fluctuations Dopamine Agonists

Advantages over levodopa: no need for biotransformation; no competition with other substances across intestine Absorption rate decreased in when patient has full stomach Side effects: hallucinations, peripheral edema, somnolence, compulsive behavior Ergot alkaloid DA no longer used Dopamine agonists

Structurally similar to dopamine First synthesized in 1869 from acidic treatment of morphine (but retains no opiate properties) Requires parenteral delivery Apomorphine

Indications –Acute, intermittent treatment of hypomobility, off episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) associated with advanced PD –As an adjunct to other medications Contraindicated –In patients who have demonstrated hypersensitivity to the drug or its ingredients, such as its preservative metabisulfite Apomorphine

Monoamine Oxidase Inhibitors (MAOIs) As shown above, monoamine oxidase is an enzyme that catalyzes the destruction of primary amines (such as dopamine,norepinephrine, seritonin) and secondary amines. The type B isoform of MAO (MAO-B) is primarily responsible for metabolism of dopamine.

Metabolism of Dopamine via Monoamine Oxidase (MAO)

MAO-B breaks down dopamine within the CNS Inhibition of MAO-B increases dopamine levels and function Because of increase in dopamine activity within CNS, potential for increased dopamine side effects MAO Inhibitors - General

Inhibitor of MAO-B Selegiline (l-deprenyl, Eldepryl® or Anipryl® veterinary) is a drug used for the treatment of early-stage Parkinson's disease and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor.

In late stage Parkinson’s Disease, Selegiline is usually added to levodopa to prolong and enhance its effect

Selegeline –At low doses, remains selective for MAO-B –At doses >10 mg, becomes non-selective –Active amphetamine-like metabolite MAO Inhibitors

Rasagaline –Precise mechanism of action is unknown – thought to contribute to increased dopamine levels within CNS due to inhibition of MAO –Although thought to be MAO-B selective, packaged with non-selective dietary and drug restrictions MAO Inhibitors

Metabolism of Dopamine via Catachol-O-Methyl Transferase (COMT)

Inhibitors of COMT EntacaponeTolcapone

Inhibitors of COMT Entacapone is marketed by Novartis as Comtan in the US Stalevo is a combination of Levodopa, Carbidopa, and Entacapone

In presence of a decarboxylase inhibitor (carbidopa), COMT is major metabolizing enzyme of levodopa Effect of medication thought to be due to increased/sustained plasma levels of levodopa Entacapone and Tolcapone COMT Inhibitors

General precautions: should not be given with non-selective MAO inhibitors May decrease metabolism of epinephrine, isoproterenol, norepinephrine, dobutamine, alpha-methyldopa Will potentiate side effects of levodopa Tolcapone: Black box warning; liver monitoring required COMT Inhibitors

Antiviral agent; anti-PD effect found accidentally Effective for tremor, rigidity and dyskinesias Actual mechanism of action poorly understood: – perhaps facilitates release of dopamine from striatal neurons, inhibits presynaptic reuptake of catacholamines, or creates an NMDA receptor blockade. Does have weak DA properties Decreases glutamatergic output from STN (may account for anti-dyskinetic effect) Amantadine

T1/2 is 2-4 hours Medication is excreted mostly unchanged in the urine Side effects may include hypotension, hallucinations, sedation, dry mouth Rare side effect unique to amantadine is livido reticularis – patchy discoloration of the skin (although unsightly, harmless to patient; resolves with discontinuation of med) Amantadine

Livido reticularis

Trihexiphenidyl (Artane) Benztropine mesylate (Cogentin) Diphenhydramine (Benadryl) ALL: –Potential benefit for tremor, little or no effect on rigidity or bradykinesia –Prominent side effects: dry mouth, sedation, mood changes, “mental slowness”, blurred vision, increased intraocular pressure –Contraindicated in patient with prostatic enlargement, narrow-angle glaucoma, obstructive GI disease Anticholinergic agents

Anticholinergic drugs are less effective than levodopa and can diminish mainly the tremors and to a lesser extent the rigidity and bradykinesia. Therefore, they are used as supplemental treatment with levodopa. Anticholinergic drugs are used "instead of levodopa" in: 1.Parkinsonian patients who cannot tolerate levodopa because of its side effects or contraindications. 2.Parkinsonian patients who cannot benefit from levodopa because of non-functional dopaminergic neurons. 3.Parkinsonian patients receiving central dopaminergic antagonists (antipsychotic drugs) which can nullify the effect of levodopa.

Side effects of anticholinergic drugs: Dry mouth Blurred vision Constipation Urine retention Glaucoma

Summary of the Treatment of Parkinson’s Disease

Formally described in 1872 by George Huntington Occurs in 5 to 10 per 100,000 people Inherited as an autosomal dominant disorder Caused by trinucletoide repeats in gene IT15 Disease usually starts in mid-thirties to mid-forties Personality change and adventitious movement develops into chorea, cognitive dysfunction and memory loss Death usually occurs as a result of secondary factors within 10 to 30 years Huntington’s Disease