PARKINSONS DISEASE PHARMACOLOGY University of Hawaii Hilo Pre - PowerPoint PPT Presentation

PARKINSON’S DISEASE PHARMACOLOGY University of Hawai‘i Hilo Pre -Nursing Program NURS 203 – General Pharmacology Danita Narciso Pharm D 1

 Understand how movement is initiated and attenuated under normal circumstances and what happens in Parkinson’s Disease  Know which drugs belong to which class in the treatment of Parkinson’s Disease  Understand the pharmacologic properties that give each medication used to treat Parkinson’s disease it’s niche in therapy  Know the general pharmacologic characteristics of each class of medications to treat Parkinson’s and the individual characteristics of each drug that make it unique from others in the same class LEARNING OBJECTIVES 2

 What happens with movement under normal circumstances  What is Parkinson’s Disease  What causes movement disorders like PD (Parkinson’s Disease)  Drugs used to treat PD OVERVIEW 3

Dopamine Acetylcholine  Modulates the initiation of  Stimulates the initiation of movement movement UNDER NORMAL CIRCUMSTANCES 4

 A disease that is characterized by tremor due to a loss of dopaminergic neurons in the central nervous system WHAT IS PARKINSON’S DISEASE 5

Movement disorder – Too Movement disorder – Too much Da little Da  https://www.youtube.com/watch?  https://www.youtube.com/watch?v v=7SyTpEdhBLw =QORlwMeWOeU  Too much movement initiation  Difficulty initiating movement 6 WHAT THESE MOVEMENT DISORDERS LOOK LIKE

7 HOW DO WE TREAT PARKINSON’S DISEASE?

INCREASE DOPAMINE 8

 Dopamine replacement  Dopamine sensitizer  COMT inhibitors  MAO – B inhibitors  Dopamine agonists  Anticholinergics DRUG THERAPY OPTIONS 9

 Levodopa  Carbidopa  Precursor of dopamine (L-Dopa)  Inhibits the peripheral breakdown of that is able to cross the blood brain levodopa barrier DOPAMINE REPLACEMENT – 10 LEVODOPA/CARBIDOPA MOA

L-Dopa (alone) Carbidopa + L-Dopa  Carbidopa acts only in the  Is quickly metabolized in the periphery (is a hydrophilic drug) periphery (before it can cross the does not cross the BBB BBB) by DOPA decarboxylase  Is a DOPA decarboxylase inhibitor Only 1-3% makes it to CNS  11 L-DOPA & CARBIDOPA

 Dosage forms  ADRs  Oral – suspension & tablet (ER, IR, & ODT)  Hypotension , edema, hypertension, dizziness, headache, depression, insomnia,  Kinetics anxiety, confusion, nausea , constipation,  Absorption – affected by high dyskinesia fat/calorie/protein meal  Interactions  Distribution – Levodopa (with carbidopa)  Amisulpride, antipsychotics (1 st & 2 nd increased passage through BBB, carbidopa generation) does not cross BBB  CI – MAOI (non-selective) & narrow angled  Metabolism – 2 major & 2 minor pathways, glaucoma carbidopa decreases the decarboxylation (major) of L-Dopa  High protein diets  Bioavailability – Levodopa > carbidopa  Pregnancy category – C  Half-life – 1.5 hours (increased with ER  Breast milk - excreted formulas)  Time to peak – 0.5 hours (IR), 2 hours (ER/CR)  Excretion - urine 12 DOPAMINE REPLACEMENT – LEVODOPA/CARBIDOPA

 MOA – DA & NE agonist, acetylcholine & glutamate (NMDA receptor) antagonist  ADRs  Nigrostriatal pathway – increase DA synthesis, release, & receptor expression &  Livedo reticularis, agitation, anxiety, decrease DA re-uptake insomnia, headache, confusion, hallucination, constipation, nausea, dry  Dosage forms mouth  Oral – capsule, tablet, syrup  Interactions  Kinetics  antipsychotics (1 st & 2 nd generation), drugs that prolong QTc, mifepristone, separate  Onset – can be slow (within 48 hours) from flu vaccine (48 hours before – 2 weeks  Absorption – well absorbed after)  Metabolism – minor  Half-life – dependent of renal function Normal (9-31 hours)  Males > 60 years (20-41 hours)  ESRD (8 days)   Time to peak – 2-4 hours  Excretion – urine (unchanged drug) 13 DOPAMINE SENSITIZER - AMANTADINE

BBB L-Dopa is broken down in • the periphery by COMT The product is 3-OMD • 3-OMD competed for • the sites where L-Dopa crossed the BBB COMT COMT INHIBITORS – ENTACAPONE , TOLCAPONE 14

BBB Inhibiting the COMT • enzyme will decrease the amounts of COMT Increase the • concentrations of L- Dopa crossing the BBB COMT COMT INHIBITORS – ENTACAPONE , TOLCAPONE 15

 MOA – Reversible & selective inhibitor of catechol-O-methyltransferase, increases the concentration of levodopa available  ADRs for transfer through the BBB by inhibiting  Nausea, dizziness, dyskinesia , diarrhea, the conversion of L-Dopa to 3-OMD abdominal pain, urine discoloration (orange brown), hyper & hypokinesia  Dosage forms  Interactions  Oral – tablet  CNS depressants, zolpidem, hydrocodone , Combination - Entacapone+L-  bupenorphine, MAOI Dopa+Carbidopa (Stalevo)  Kinetics  Pregnancy category – C  Breast milk – not known  Onset – rapid  Absorption – rapid  Protein bound – 98% albumin  Metabolism – liver, not CYP  Half-life – phases  Time to peak – 1 hour  Excretion – mostly feces COMT INHIBITORS – ENTACAPONE , TOLCAPONE 16

May alter PK’s disease Most MAO-B is in the CNS progression  It has been shown that the EPI breakdown of DA by MAOB leads A NE to a reactive oxygen species DA Tyramine  Reactive oxygen species can cause the death of dopaminergic DA only neurons B  MAO-B inhibitors decrease this process Non selective MAOI Selective MAO-B inhibitor MAO – B INHIBITOR – SELEGILINE, RASAGILINE 17

 MOA – stimulates dopamine activity  ADRs by binding to dopamine receptors  Hypotension (orthostatic),  Dosage forms drowsiness, EPS, dizziness, hallucinations, nausea,  Oral – tablet (IR/ER) constipation, dyskinesia, weakness  Kinetics  Interactions  Absorption – rapid  Antipsychotic (1 st & 2 nd generation)  Distribution – well, Vd 500L  Pregnancy category – C  Metabolism – less than 10%  Breast milk – not known  Half-life – 8.5 hours, 12 hours (elderly)  Time to peak – 2 hours/6 hours  Excretion – urine, mostly unchanged drug DOPAMINE AGONISTS - PRAMIPEXOLE 18

 MOA – Agonist at the post synaptic  ADRs D2 receptor in the brain  Orthostatic hypotension, dizziness,  Dosage forms drowsiness, fatigue, nausea, vomiting, viral infection, edema, pain,  Oral – tablet (IR/ER) confusion  Kinetics  Interactions  Absorption – rapid  Antipsychotic agents (1 st & 2 nd  Metabolism – high first pass effect, generation), inducers/inhibitors of CYP1A2, inactive metabolites CYP1A2  Half-life – 6 hours  Pregnancy category – C  Time to peak – 1-2 hours (IR), 6-10  Breast milk – not known hours (ER), Tmax extended by ~3 hours when taken with a high fat meal  Excretion – urine, mostly metabolites DOPAMINE AGONISTS - ROPINIROLE 19

ANTICHOLINERGICS 20

 MOA – Anticholinergic &  ADRs antihistaminic  Tachycardia, confusion, depression,  Dosage forms rash, constipation, nausea, urinary retention, blurry vision  Oral  Interactions  Injection  Other agents with anticholinergic  Kinetics actions, tiotropium  Onset – IV & IM, within minutes  Pregnancy category – Not conducted  Metabolism – hepatic  Breast milk – not known  Time to peak – 7 hours ANTICHOLINERGICS - BENZTROPINE 21

 MOA – inhibition of the PNS  ADRs  Dosage forms  Tachycardia, confusion, depression,  Oral rash, constipation, nausea, urinary  Kinetics retention, blurry vision  Metabolism – hydroxylation (liver)  Half-life - 33 hours  Time to peak – 1.3 hours  Excretion – urine & bile ANTICHOLINERGICS - TRIHEXYLPHENIDYL 22

QUESTIONS 23