Drugs used in Parkinson’s disease

"Parkinson's disease" (Parkinsonism, PD) is a progressive neurodegenerative brain disorder that was first described by Dr. James Parkinson in 1817. 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. DA ACh 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. Therefore, the strategy for treatment of Parkinsonism is to restore the normal balance between dopaminergic & cholinergic tones in the basal ganglia.

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

Symptoms of Parkinsonism The symptoms of Parkinsonism appear only when dopamine depletion exceeds 80%. It is characterized by: Abnormalities of posture and gait (shuffling gait). Mask-like facial expressions, impaired speech & skilled acts such as writing and eating. 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

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

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

Treatment of Parkinsonism • • D2 • • • • • D2 • • • Tyrosine DOPA DA • • • • • • • D2 • • • MAO-B • • D2 • Dopaminergic Nerve terminal 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: Reducing cholinergic activity by the use of anticholinergic drugs (benzatropine) Neurotransplantation (which is still in experimental phase). Physical therapy & regular exercise. drugs that replace dopamine (levodopa) drugs that release dopamine from its stores (amantadine) drugs that prolong the action of dopamine by preventing its metabolism (seligiline) drugs that mimic the action of dopamine (dopaminergic agonists)

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".

L-dopa CNS Peripheral sites 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. decarboxylation L-dopa 5% CNS Peripheral sites BBB

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 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: If levodopa is administered alone (i.e. without carbidopa), it can interact with pyridoxine (vitamin B6) 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. The dose of levodopa can be reduced by about 75%. The peripheral side effects of levodopa are greatly reduced.

Pharmacological actions of levodopa: Levodopa restores "dopamine" content in the basal ganglia. Dopamine then acts on dopaminergic D2 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.

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. Tachycardia resulting from dopamine action on the heart. Psychological effects: levodopa may lead to an over activity of dopamine in the limbic system leading to "schizophrenia-like syndrome". Endocrine effects: inhibition of prolactin secretion due to the effect of DA on the tuberohypophyseal system. "Dyskinesia" and induction of abnormal voluntary movements. "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.

Drug interactions of levodopa: "Pyridoxine" (vitamin B6) increases the peripheral break down of levodopa and reduces its effectiveness. 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). "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.

Dopamine Agonists 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

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

Apomorphine Indications Contraindicated 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

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 Inhibitors - General 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

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

MAO Inhibitors 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

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

Inhibitors of COMT Entacapone Tolcapone

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

COMT Inhibitors 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

Amantadine 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)

Livido reticularis

Anticholinergic agents 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 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: Parkinsonian patients who cannot benefit from levodopa because of non-functional dopaminergic neurons. Parkinsonian patients receiving central dopaminergic antagonists (antipsychotic drugs) which can nullify the effect of levodopa. Parkinsonian patients who cannot tolerate levodopa because of its side effects or contraindications.

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

Summary of the Treatment of Parkinson’s Disease

Huntington’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