Pharmacologic Management of Parkinson disease (PD) Chapter 28 Pharmacologic Management of Parkinson disease (PD)

Overview of Parkinson's Disease PD is a progressive neurological disorder of muscle movement, characterized by combination of rigidity, bradykinesia, resting tremor, and postural instability It generally affects the elderly and is estimated to afflict more than 1% of individuals over the age of 65 PD is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum-parts of the brain's basal ganglia system that are involved in motor control

Overview of Parkinson's Disease Thus, the normal modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative over-activity of acetylcholine by the stimulatory neurons This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements

+ _ _ NEOSTRIATUM SUBSTANTIA NIGRA STIMULATORY Ach NEURONE Connection to muscle through motor cortex and spinal cord STIMULATORY Ach NEURONE + _ NEOSTRIATUM Cell death results in less dopamine release in the neostriatum SUBSTANTIA NIGRA _

Strategy of treatment Since there is no cure for PD, the aim of pharmacological therapy is to provide symptomatic relief This is obtained re-establishing the correct dopamine/acetylcholine balance through the use of drugs that either increase dopaminergic actions or antagonizing the excitatory effect of cholinergic neurons

Drugs Used in Parkinson's Disease Drugs used in Parkinson’s disease include: Levodopa Dopamine agonists Monoamine oxidase (MAO) inhibitors Cathechol-O-methyl transferase (COMT( inhibitors Anticholinergic agents Amantadine

Levodopa Levodopa is the single most effective agent in the treatment of PD It is immediate metabolic precursor of DA Levodopa is itself largely inert levodopa, as an a.a, is transported into the brain by a.a transport systems Therapeutic and adverse effects of levodopa result from its decarboxylation to dopamine Oral levodopa is absorbed rapidly from the small intestine by the transport system for aromatic amino acids

Aromatic Amino Acid Decarboxylase Na+ DOPA Aromatic Amino Acid Decarboxylase Tyrosine Hydroxylase Dopamine Tyrosine MAO H+ DA DOPAC COMT Uptake 1 HVA HVA DA Uptake 2 Dopamine receptor HVA DA MAO COMT 3MT

Levodopa Certain a.as from ingested food can compete with levodopa for absorption from gut & for transport from blood to brain About 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the BBB It is combined with a peripheral dopa decarboxylase inhibitor (e.g .carbidopa)

Carbidopa A dopa decarboxylase inhibitor that does not cross the BBB Carbidopa diminishes the metabolism of levodopa in the GIT and peripheral tissues: Increases the availability of levodopa to the CNS Lowers the dose of levodopa needed by about 10-fold Decreases the severity of the side effects arising from peripherally formed dopamine

Levodopa Clinical use Levodopa is widely used for treatment of all types of PD except those associated with antipsychotic drug therapy Levodopa substantially reduces the severity of all the signs and symptoms of PD in the first few years of treatment Patients then typically experience a decline in response during the third to fifth year of therapy (progression of the disease and the loss of striatal dopamine nerve terminals)

Levodopa ADRs Gastrointestinal tract (GIT) Anorexia, nausea, and vomiting (likely due to dopamine’s stimulation of the CTZ) Minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly When levodopa is given in combination with carbidopa, adverse GIT effects are much less frequent & patients can tolerate proportionately higher doses

Levodopa ADRs Cardiovascular effects Cardiac arrhythmias: caused by increased catecholamine formation peripherally Postural hypotension as a result of the peripheral decarboxylation of levodopa and release of dopamine into the circulation Incidence can be reduced if levodopa is taken in combination with Carbidopa

Levodopa ADRs Dyskinesias Occur in up to 80% of patients receiving levodopa within 2 years of starting levodopa therapy Are excessive and abnormal choreiform/ involuntary movements of the limbs, hands, trunk, and tongue The development of dyskinesias is dose-related that occur most often when the plasma levodopa concentration is high There is considerable individual variation in the dose required to produce them

Levodopa ADRs Fluctuations in Response Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues Wearing-off phenomenon/ end-of-dose akinesia: Related to the timing of levodopa intake Each dose of levodopa effectively improves mobility for a period of time (1–2 hrs), but rigidity and akinesia return rapidly at the end of the dosing interval Increasing the dose and frequency of administration can improve this situation

Levodopa ADRs Fluctuations in Response On-off phenomenon Fluctuations in response are unrelated to timing of doses Patients fluctuate rapidly between being “off,” having no beneficial effects from their medications, and being “on” but with disabling dyskinesias Can be reduced by: using a sustained-release formulation, division of the total daily dose into more frequently administered portions, coadministration of COMT inhibitors or selegline, and regulation of dietary protein intake

Levodopa ADRs Behavioral Effects Depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality More common in patients taking levodopa in combination with carbidopa The use the “atypical” antipsychotic agents (e.g., clozapine), which are effective in the treatment of psychosis but do not cause or worsen parkinsonism

Levodopa Careful management in patients with: Contraindications Psychotic patients Angle-closure glaucoma1 Careful management in patients with: History of cardiac arrhythmias or recent cardiac infarction Active peptic ulcer must be managed carefully History of melanoma or with suspicious undiagnosed skin lesions2 1 Levodopa can cause severe mydriasis that would markedly aggravate the glaucoma 2 Levodopa is precursor of skin melanin

Monoamine Oxidase Inhibitors Two types of monoamine oxidase have been distinguished in the nervous system (MAO-A and MAO-B) The isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors Selective MAO-B Inhibitors: Selegiline & Rasagiline

Monoamine Oxidase Inhibitors Neither selegiline nor rasagiline should be taken by patients receiving meperidine (stupor, rigidity, agitation, and hyperthermia) They should be used with care in patients receiving TCAs or SSRIs b/c of the theoretical risk of acute toxic interactions of the serotonin syndrome type ADEs: Most related to the increased levels of dopamine Anxiety, insomnia (selegline) Metabolites of selegiline include amphetamine and methamphetamine

Catechol-O-Methyltransferase Inhibitors Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS Selective COMT inhibitors: tolcapone & entacapone

Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT = catechol-O-methyltransferase

Catechol-O-Methyltransferase Inhibitors Entacapone is generally preferred: tolcapone has both central & peripheral effects, whereas effect of entacapone is peripheral ADRs: Increased levodopa exposure Orange discoloration of urine Hepatoxicity (tolcapone)

Dopamine Receptor Agonists Dopamine agonists may delay the need to employ levodopa therapy in early PD and may decrease the dose of levodopa in advanced Parkinson's disease Dopamine receptor agonists: Ergot derivatives e.g. bromocriptine Non-ergot derivatives e.g. apomorphine, pramipexole, ropinirole, and rotigotine The differences between the ergot derivatives and the newer/ non-ergot agents reside primarily in their adverse effects, tolerability, and speed of titration

Dopamine Receptor Agonists ADRs Gastrointestinal tract effects: Anorexia, N & V: can be minimized by taking the medication with meals Constipation, dyspepsia, and symptoms of reflux Bleeding from peptic ulceration

Dopamine Receptor Agonists ADRs Cardiovascular effects: Postural hypotension common at the initiation of therapy especially with the ergot derivatives Dose-related painless digital vasospasm with the ergot derivatives Cardiac arrhythmias (discontinuation) Peripheral edema

Dopamine Receptor Agonists ADRs Dyskinesias: reversed by reducing the total dose of dopaminergic drugs Mental Disturbances Include confusion, hallucinations, delusions, and other psychiatric reactions which are more common and severe with dopamine receptor agonists than with levodopa Disappear on withdrawal

Dopamine Receptor Agonists Contraindications History of psychotic illness Recent myocardial infarction Active peptic ulceration Peripheral vascular disease (ergot derivatives)

Acetylcholine-Blocking Drugs Centrally acting antimuscarinic drugs include: benzotropine mesylate, biperiden, orphenadrine, procyclidine, & trihexphenidyl Their efficacy in PD is likely due to the ability to block muscarinic receptors in the striatum Are much less efficacious than levodopa and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy

Acetylcholine-Blocking Drugs ADRs The adverse effects of these drugs are a result of their anticholinergic properties (CNS & peripheral effects) CNS: mental confusion, delirium, and hallucinations Peripheral: constipation, urinary retention, and blurred vision through cycloplegia, sinus tachycardia, & dry mouth Are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis