University:
West Coast University
Course:
PHAR 835 | IPC Neurology/Psychiatry
Academic year:

2024
Views:

314

Pages:

19
Author:

Asal A.

invoweinment parkinson Mi Mo syizophona Dopamine Pharmacology Parkinson Treatment Supplemental Guidance to Handout and Reading Assignment Parto Khansari Ph.D. 8/20/2024 (9:30-12:30) Drugs List Dopamine precursor Dopamine Agonists Parkinson’s Disease Carbidopa/levodopa Sinemet Pramipexole Mirapex Ropinirole Requip Amantadine Symmetrel Bromocriptine Parlodel COMT inhibitor Entacapone Comtan Anticholinergic Benztropine Cogentin Biperiden Akineton Trihexyphenidyl Artane Rasagiline Azilect Selegiline Eldepryl Carbidopa/levodopa/ entacapone Stalevo MAO-B inhibitor Combination Product Major Dopaminergic Pathways if problem delusional substagtafoomoyent •The nigrostriatal pathway. (upward dashed blue arrows) lossofdopey movant reward 2 A •The mesocortico/mesolimbic pathway. (solid blue arrows). parkinson's 3 •The tuberoinfundibular pathway. (red arrows). hydroxyl WIZ swept IBenzerering catecholamine Doponee Epinephir norepinephrine fr Dopamine Structure needtoknowwhich sereodingepinephire andDopamine are Onearecategganie andaminguine monoamineoxidase motivate reward me gsqedm emotioalresporsiaddiatfmessgic.gl nida SN sVTA atypothalomwsapop.me tyrostemon movement raÉep Typist iosstep L Dopants Dopamine Synthesis G tyrosine tyrosine hydrolyse Dopamine (DA) is synthesized in the cytoplasm and transported into secretory vesicles by the action of a nonselective monoamine-proton antiporter (VMAT) that is powered by the electrochemical gradient created by a proton ATPase. Upon nerve cell stimulation, DA is released into the synaptic cleft, where the neurotransmitter can stimulate postsynaptic dopamine receptors and presynaptic dopamine autoreceptors. DA is transported out of the synaptic cleft by the selective, Na+coupled dopamine transporter (DAT). Cytoplasmic DA is re-transported into secretory vesicles by VMAT or degraded by the enzyme monoamine oxidase (MAO). specific It notspecific fate limits AAI Dopamine Receptors gyratory edited inhibitory Stimulation of the D1 family is excitatory, increasing cAMP and intracellular Ca2+ levels and activating protein kinase C (PKC). Stimulation of the D2 family is inhibitory, decreasing cAMP and intracellular Ca2+ levels and hyperpolarizing the cell. The five receptor subtypes exhibit distinctive patterns of distribution in the central nervous system; the major areas of distribution are listed for each subtype. Dopamine Receptor Distribution AM, amygdala; C, caudate; Cx, cerebral cortex; H, hypothalamus; HIPP, hippocampus; nAc, nucleus accumbens; OT, olfactory tubercle; P, putamen; SN, substantia nigra; VTA, ventral tegmental area. Basal Ganglia Pathway to Regulate Movement The basal ganglia do not directly control the individual movements of muscles, instead assist in learning coordinated patterns of movement. Basal ganglia forms a loop by receiving input from the cerebral cortex, processing this information in the context of dopaminergic input from the substantia nigra, and sending information back to the cortex by way of the thalamus Basal Ganglia Pathway to Regulate Movement inparkinsons Dy Da inhibeted activated Voluntary Movement The voluntary movement is a complex function that involve many neurotransmitters and neuromodulators including GABA, Dopamine, Glutamate and Acetylcholine. It also involves multiple structure in basal ganglion and cortex. Two pathways in basal ganglia regulate movement: • direct (stimulatory and involves D1 family) • indirect pathway (inhibitory and involves D2 family) In Direct pathway, dopamine enables movement. It also inhibits the indirect pathways through inhibiting the GABAergic output (recall that GABA has an inhibitory effect). On the contrary indirect pathway inhibits movement. Degradation of dopaminergic neurons in substantia nigra results in under stimulation of the direct pathway and under inhibition of indirect pathway. Dopamine Metabolism ax catamineand monoamine oxidase are degraded by zenare andME It Inotspyid Potential Drug Target PD d LDopa t Dopamine destructions PD Pharmacology Dopamine Precursor WE  Levodopa (L-DOPA) • Oldest and still the most effective medication to treat PD. • Dopamine itself does not cross the blood brain barrier, • L-DOPA is converted to dopamine by Aromatic L-amino acid decarboxylase (AADC) • AADC is also available in GI and accounts for rapid reduction of L-DOPA after an oral administration. • Sinement • Combination of L-DOPA and carbidopa (AADC inhibitor) • Contraindicated in narrow angle glaucoma and interacts with number of antidepressant drugs including bupropion. Co-administration of carbidopa with L-DOPA Is moreEndopominein Gut the getsto it of concentration More breed O not a lot of dopamine if u corbidopamore to protectit Dopamine Receptor Agonist  Pramipexole (Mirapex)  Ropinirole (Requip) • Higher half-life than L-dopa • Do not require enzymatic conversion • Major side effect: sedation, hallucination, edema, nausea and hypotension specially in elderly population. • Contraindicated in patients with recent MI and episodes of psychosis. Inhibitors of Dopamine Degradation •MAO-B Inhibitor •Selegiline (Eldepryl) •selective for MAO-B, at the higher dose it also effects MAO-A resulting in a toxic effect specially in elderly population •Rasagiline (Azilec) •only effect MAO-B and hence have a safer profile •COMT Inhibitor •Degrade both dopamine & L-DOPA •Tolcapone (Tasmar) •Entacapone (Comtan) if Miscellaneous Amantadine: • Adenosine receptor antagonist • Possible effect dopamine autoreceptors on presynaptic neurons. • Antiviral drug with a short-term effect in PD Anticholinergic Drugs  Benztropine mesylate  Trihexyphenidyl • Mostly treats the tremor in the early disease and associated with anticholinergic side effects including sedation PD Pharmacology Summary

Dopamine Pharmacology Parkinson Treatment

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