Clinical Psychopharmacology

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1 Clinical Psychopharmacology Antiparkinsonian drugs Department of Pharmacy, GGZ WNB Chair on Pharmacotherapy in Psychiatric Patients/Anton Loonen

2 May Basal ganglia diseases Parkinson s disease and other forms of parkinsonism Multisystem Atrophy (MSA) MSA-p type (Parkinsonism) MSA-c type (Cerebellar) Many autonomic signs and symptoms Drug-unresponsive Parkinson s disease Chorea Chorea minor (Sydenham) Chorea major (Huntington) Restless legs syndrome (RLS) & Periodic Limb Movement Disorder (PLMD)

3 May Clinical presentations of Parkinson s disease Slowness of movement Bradykinesia Slow monotonous speach Reduced swallowing (dribbling) Bradyphrenia Rigidity Postural instability Tremors Resting tremor (pill-rolling tremor) Postural tremor (increased)

4 Neuropathology of Parkinson s disease Neurodegeneration Dopaminergic neurons SNc (area A9) > 50-60%. Motor symptoms Adrenergic neurons Autonomic nuclei (NTS) Hypotension Serotonergic neurons Raphe nuclei Mood and anxiety symptoms Cholinergic neurons Nucleus basalis [Meynert] Dementia

5 May Regulation of motor activity Cerebral cortex Pyramidal tract activity (glu) Spasms Cerebellar adjustment Mutual adjustment of movements (GABA) Ataxia Extrapyramidal system Mutual adjustment of muscle agonists/antagonists (Glu/GABA) Parkinsonism

6 May Schedule extrapyramidal regulation Cerebral cortex à Spinal cord (MPG) à muscle Striatum (MSN) à thalamus Spinal cord à Brain stem à cerebellum Thalamus Thalamus à Cortex

7 May Inhibition/augmentation of pyramidal activity Pyramidal pathway Activate MPG in spinal cord Direct EP pathway Carry excitatory DRD1 Augment cortical activity DA increases cortical activity Indirect EP pathway Carry inhibitory DRD2 Inhibit cortical activity DA increases cortical activity

8 May Stratal medium sized GABA-ergic neurons Glutamatergic neurons Corticostriatal synapses Thalamostriatal synapses Cholinergic interneurons Medium spiny neurons Glutamatergic terminals Dopaminergic neurons Medium spiny neurons Serotonergic neurons Medium spiny neurons Dopaminergic terminals GABA-ergic interneurons

9 May Neurobiology of Parkinson Degeneration of DA neurons Oxidative metabolism of DA Free radicals and H 2 O 2 Oxidative stress Genetics of Parkinson s disease Familial Parkinson s disease Large kindreds with PD Mitochondrial inheritance Susceptibility genes

10 Treatment of Parkinson s disease Increase dopaminergic influence Levodopa MAO and COMT inhibitors Dopamine-receptor agonists Adjust sensitivity of MSN Inhibit cholinergic interneurons (anti-muscarinic) Inhibit serotonergic influence (5-HT 2 antagonist) Adapt glutamatergic influence (NMDA antagonists)

11 Levodopa Levodopa alone (obsolete) Levodopa with decarboxylase inhibitor Benserazide Immediate release capsules, tablets Slow release capsules (beginning wearing off) Carbidopa Immediate release tablets Slow release tablets Intestinal gel Carbidopa and entacapon (COMT-inhibitor) Immediate release tablets (less wearing off)

12 Enzyme inhibitors MAO inhibitors Selegeline and rasagiline Selective for MAO-B Blocks oxidative metabolism COMT inhibitors Entacapone and tolcapon (hepatotoxic) Also increases penetration into brain

13 Amantadine Complex mechanism of action N-methyl-D-aspartate (NMDA) antagonism Dopamine reuptake inhibition Dopamine release Anticholinergic activity Indications for use Starting PD Drug-induced parkinsonism Peak-dose dyskinesia

14 Dopamine D2 receptor agonists Halflife (hrs) Ergot-structure Bioavailability (%) Remarks Bromocriptine Weak D1-antagonist Pergolide Weak D1-agonist Pramipexol Preferential D3 Ropinerol 6-50 Preferential D3 Rotigotine transdermal Apomorfine subcuteneously Weak D1-agonist Potent D1-agonist

15 Complications of treatment with levodopa Predictable off phases: wearing off Gradual decrease off effect End of dose bradykinesia Dyskinesia during on phase Abnormal involuntary movements Peak dose hyperkinesia Unpredictable on/off phases Freezing switching suddenly to hyperkinesia Slow decrease of effectivity due to disease progression

16 Drug treatment of Parkinson s disease Phase V Phase IV + amandadine Phase III SR levodopa (+) DRD2 agonist sc apomorphine Intra-intestinal gel Phase II IR levodopa Wearing off Phase I MAO inhibitor Amantadine (DRD2 agonist) Levodopa-induced dyskinesia Refractory hypokinesia Training activities of daily living (ADL) support nursing home

17 New developments Etilevidopam and melevodopa Oromucosal tablets of selegiline Transdermal patches of lisuride Racemide (NMDA antagonist) Adenosine A2 antagonists

18 Extrapiramidal side effects of antipsychotics Acute: akathisia, dystonia, parkinsonism Tardive: dyskinesia, dystonia

19 Akathisia Adversity to standing or sitting still; increased frequency of regular movements; primarily, but not exclusively affects the legs. Treatment with b-blocking drugs, sedatives and anticholinergics

20 Parkinsonism Akinetic syndrome & akinetic hypertonic syndrome Reduction and/or slowing of all movement; equable plastic resistance to passive movement; hypersalivation and shiny skin; slow tremors that appear during rest and decrease during activity Anticholinergics

21 Dystonia Slow, irregular, continuous contractions (spasms); contractions result in slow movements or abnormal postures; contractions continue for more than 2 seconds Acute: anticholinergics Tardive: clozapine, anticholinergics

22 Dyskinesia BLM-syndrome, peripheral syndrome & respiratory syndrome Rapid, irregular, repetitive contractions; motionless intervals between contractions; increases during activity and anxiety Clozapine

23 Other common movement disorders Tremor Postural tremor: beta-blocking drug Nocturnal movement disorders Myoclonus: clonazepam Restless legs syndrome (RLS)/Periodic Limb Movement Disorder (PLMD): DRD2 agonist

24 Thank you for your attention

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