Pharmacology of Drugs Used in Parkinson’s Disease Jose Paciano B.T. Reyes, FPNA ASMPH January 27, 2011

Definitions What are Movement Disorders? conditions of abnormal, insufficient, or excessive motor activity clinically, seen as: stiffnessrigidity bradykinesiapaucity of movement tremorsdystonia choreatics myoclonusgait disturbances

What causes movement disorders? specific pathologic and biochemical basis for many movement disorders is not known clinical manifestations often implicate the basal ganglia as the primary site of disturbance

Definitions What is the basal ganglia? group of interconnected subcortical nuclei (caudate, globus pallidus, putamen, subthalamic nucleus, substantia nigra)‏ exert an inhibitory influence in the premotor area of the cortex by way of output from the ventrolateral thalamus

Definitions What is Parkinson’s Disease? a progressive neurodegenerative disorder loss of dopaminergic neurons in the substantia nigra pars compacta more common in the elderly 15% familial

Parkinson’s Disease Types: endogenous/idiopathic arteriosclerotic post-encephalitic post-traumatic toxic tumor related drug induced Clinical Features: tremor at rest rigidity bradykinesia postural impairment autonomic symptoms psychic symptoms

Parkinson’s Disease Histopathologic Features: degeneration of the nigrostriatal pathway dopaminergic neuron degeneration in the substantia nigra Striatum (caudate+putamen)‏ contains the highest levels of dopamine in the mammalian brain has a high level of cholinergic markers

1. Tremor at rest 2. Cogwheel rigidity 3. Bradykinesia/hypokinesia 4. Flexed posture 5. Loss of postural reflexes 6. Freezing phenomenon At least 2 of these features with at least one being either 1 or 3 Parkinson’s Disease

reduced attention span fearful, indecisive, passive lack of motivation depression some cognitive decline slow to respond Parkinson’s Disease

oxidative stress hypothesis environmental neurotoxin - MPTP genetic susceptibility - defects in mitochondrial genome Parkinson’s Disease

Dopamine Acetylcholine

Cell destruction in the substantia nigra Destruction of dopaminergic terminals in the striatum Decreaseddopaminergictransmission Disinhibited cholinergic neurons cholinergic neurons Dominance of cholinergic stimulation rigor, tremor akinesia

Sites of Drug Action 1. action potential in nerve presynaptic nerve fiber 2. synthesis of transmitter 3. storage 4. metabolism 5. release 6. reuptake 7. degradation 8. receptor of transmitter 9. receptor-induced increase or decrease in ionic conductance

Parkinson’s Disease Treatment Approaches: Enhance dopaminergic function a. Increase synthesis of dopamine b. Increase pre-synaptic release of dopamine c. Decrease dopamine synaptic reuptake d. Stimulate post-synaptic dopamine receptors e. Inhibit metabolic enzymes Reduce cholinergic drive anticholinergic medications

Dopamine Synthesis & Metabolism conversion of tyrosine to L- dopa is the rate limiting step action of dopamine is terminated by a reuptake mechanism metabolic degradation of dopamine is facilitated by: 1. monoamine oxidases (MAO-A, MAO-B) 2. catechol-O- methyltransferase (COMT)‏ L-tyrosine L-dopa dopamine dopa decarboxylase tyrosine hydroxylase

Dopaminergic neuronal impulse transmission Tyrosine hydroxylase Decarboxylase dopamine agonists

Dopamine Receptors 5 types of receptors: D 1 type (D 1, D 5 )‏ D 2 type (D 2, D 3, D 4 )‏ all are G-protein coupled transmembrane receptors thus signal transduction is linked to adenylate cyclase D 1, D 2 receptors are most widespread in the CNS motor effects mediated primarily by D 2 receptors and to a lesser extent by D 1 receptors D 3, D 4, D 5 receptors exert less motor effects

Functional pathways: 1. Nigrostriatal (motor control)‏ 2. Mesolimbic & mesocortical (behavioral control)‏ 3. Tuberohypophyseal (endocrine control)‏ Dopamine Receptors

Many antipsychotic drugs are D 2 -receptor antagonists thus have Parkinsonian effects due to block of nigrostriatal D 2 -receptors D 2 -receptors occur near the medullary chemoreceptor trigger zone thus most dopamine agonists cause nausea & vomiting

Approach to Therapy Begin therapy when work performance or activities of daily living living affected. Minimal dose of antiparkinsonian medication to adequately control motor symptoms. Monotherapy with a dopamine agonist. Add levodopa when agonist cannot control symptoms.

Drugs used for Parkinson’s Disease Drugs that enhance dopaminergic function: 1. Levodopa 2. Bromocriptine HCl 3. Amantidine 4. Selegiline 5. Tolcapone 6. Pergolide 7. Apomorphine 8. Entacapone 9. Pramipexole 10. Ropinerole 11. Piribedil Drugs that reduce cholinergic drive: 1. Benztropine 2. Biperiden 3. Trihexyphenidyl 4. Diphenhydramine

Levodopa amino acid precursor of dopamine decarboxylated into dopamine clinical use: –most potent agent for symptomatic treatment –unequivocal response to the drug is used as a diagnostic confirmation –combined with peripheral dopa decarboxylase inhibitors (benzeraside, carbidopa) to increase its bioavailability & reduce its side effects

1. GI effects nausea and vomiting, anorexia 2. CVS effects arrhythmia, postural hypotension hypertension (when combined with MAO inhibitors)‏ 3. Dyskinesias chorea, ballismus, athetosis, dystonia, myoclonus, tics, tremor 4. Behavioral effects depression, anxiety, nsomnia, somnolence Levodopa

Preparations: Carbidopa / Levodopa: 25/100, 25/250 Benserazide / Levodopa: 50/200, 25/ 100 Usual dose 1tab 25/100 bid, tid 1 tab 25/250 bid

Bromocriptine an ergot derivative functions: 1. dopamine agonist at D 2 receptors 2. mild antagonistic activity at D 1 receptors clinically, also used to treat hyperprolactinemia monotherapy/adjunctive therapy

Bromocriptine Preparation: 2.5 mg / tab Usual dose: mg once a day, before bedtime up to 40 mg/day

Synthetic ergot derivative 10x more potent than bromocriptine functions: 1. direct stimulant of post-synaptic dopaminergic receptors in the striatum 2. act mainly as agonist at the D 2 receptors clinically used as an adjunct to levodopa treatment or as monotherapy may cause hypotension Pergolide

Pramipexole Non-ergot dopamine agonist D 2 and D 3 agonist efficacy similar to bromocriptine and pergolide 90% excreted in the urine unchanged monotherapy or adjunct with levodopa

Pramipexole Preparations: mg tabs, 0.25 mg tabs, 1.0 mg tabs, 1.5 mg tabs Usual dose: three times daily 4-6 mg three times daily over weeks

AgonistD 1 D 2 D 3 Plasma-half-life (n)Elimination Bromocriptine-+++6Hepatic Cabergoline Hepatic Dihydroergocryptine +/- +++?15Hepatic Lisuride+/ Hepatic / renal Pergolide Hepatic / renal Pramipexole Renal Ropinirole Renal according to Brecht (1998) and Gerlach et al. (2000)‏ Examples of Dopamine Agonists

an antiviral against influenza A function: releases dopamine from nerve terminals weak dopamine agonist with anticholinergic properties clinically, may induce side effects typical of anticholinergic agents Amantidine HCl

Preparation: 100 mg / tab Usual dose: 100 mg od to bid upper limit is 100 mg qid

functions: 1. selective, irreversible, MAO-B inhibitor 2. prevents the oxidation of dopamine (which produces free radicals and H 2 O 2 ) clinically, the only agent shown to have a possible effect in retarding the progression of Parkinson disease Selegiline

Preparation: 5 mg / tab Usual dose: 5 mg once a day up to twice a day

function: selective, reversible, peripherally and centrally active COMT inhibitor clinically, increases the T 1/2, bioavailability and plasma levels of levodopa used as an adjunct with levodopa Tolcapone

Preparation: 100 mg / tab Usual dose: 50 mg three times a day maximum of 400 mg three times a day

Entacapone Selective reversible peripherally acting COMT inhibitor increases bioavailability and half-life of levodopa extends clinical effect of levodopa by min. adjunct agent for use with levodopa

Entocapone Preparation: 200 mg / tab Usual dose: 200 mg with every dose of levodopa

Acetylcholine-Blocking Drugs centrally acting antimuscarinic preparations clinically: 1. improve tremor 2. first line treatment for patients with mild Parkinson’s disease adverse effects constipation, pupillary dilatation (mydriasis)‏ urinary retention, paralysis of accommodation dry mouth, confusion

Parkinson’s Disease Dopamine Acetylcholine

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