Parkinson s Pharmacology

Transcription

1 PHPP 517 (IT-III) Fall 2011 JACOBS Wed 10/12 8:00 8:50 AM 1

2 Learning objectives 1. Describe the direct and indirect pathways of the extrapyramidal system and its modulation by ACh and DA. 2. Contrast the ACh and DA imbalance of Parkinson s and Huntington s diseases. 3. Name the agents (brand and generic) used to treat Parkinson s Disease, and explain their mechanisms based on dopaminergic or cholinergic balance in the nigrostriatal pathway. 4. Recall the side effects of anti-parkinson s drugs (examples: psychosis, dyskinesia, livedo reticularis, liver toxicity, cardiac fibrosis, valvuopathies, anticholinergic effects) and recall which agents can cause them. 5. Explain how MPTP causes the death of dopaminergic neurons in the CNS and can cause Parkinsonism. 6. Explain the effects of carbidopa, tolcapone, and entacapone on L-DOPA metabolism and how this relates to: side effects, L-DOPA efficacy, and L-DOPA dosage. 7. Explain how MAO-B inhibitors may protect dopaminergic neurons from cell death; and explain why it doesn t cause tyramine sensitivity like other MAOIs 8. Contrast the receptor affinities, bioavailabilities, and metabolism of dopamine agonists. Also contrast their adverse effects vs. L-DOPA. 2

3 Brain Regions in Motor Control Cerebral Cortex Striatum Thalamus Globus Pallidus Substantia Nigra 3

4 Direct Pathway: Striatum (+) Motor Activity GABA GLUTAMATE + Motor Cortex Striatum + - Thalamus - Globus palludus 4

5 Indirect Pathway: Striatum (-) Motor Activity GABA GLUTAMATE + Motor Cortex Striatum + - Thalamus Subthalamic nucleus Globus palludus 5

6 Direct Pathway (i.e. the express route ) Striatum Parkinson s Pharmacology Net effect of striatum on motor control EXCITATORY (motor initiation) Indirect Pathway (i.e. the scenic route ) + Striatum INHIBITORY (motor inhibition) How do you figure this? Add up the number of (-) inhibitory connections Even = no longer inhibitory (i.e. cancel each-other out) Odd = still inhibitory 6

7 What is missing from these diagrams? Effect of Dopamine (DA) Effect of Acetylcholine (ACh) 7

8 DIRECT pathway Parkinson s Pharmacology Substantia Nigra Projection Neurons DA D 1 D 2 INDIRECT pathway Striatum Globus pallidus M 4 ACh Striatal Interneurons M 1 Striatum Globus pallidus Subthalamic nucleus Thalamus Globus pallidus Cortex 8

9 Modulation by DA and ACh DA ACh DIRECT pathway DA STIMULATES movement: DIRECT INDIRECT INDIRECT pathway ACh ATTENUATES movement: DIRECT INDIRECT 9

10 Huntington s Disease Advanced Huntington s Normal Harvard Medical School NEURODEGENERATIVE disorder Characteristic CHOREIFORM movements Sometimes described as the OPPOSITE of Parkinson s Disease Genetically based, DOMINANT mutation gene for Huntingtin protein Normal role is unclear: cell signaling; cell trafficking; transcription Normal gene contains CAG (tri-nucleotide) REPEATS Mutant gene contains >35 CAG REPEATS (CAG = glutamine) POLYGLUTAMINE tract disease Onset: years Life expectancy after symptoms onset: up to 20 years 10

11 Huntington s Disease Normal GABA Motor INITIATION DIRECT Pathway DA Substantia Nigra INDIRECT Pathway Motor INHIBITION Huntington s REDUCTION in GABA signaling GABA Motor INITIATION DIRECT Pathway DA Substantia Nigra INDIRECT Pathway Motor INHIBITION 11

12 Huntington s Disease Chemical Disturbance in Huntington s DIRECT pathway Choreiform movements INVOLUNTARY initiation of motor activity INDIRECT pathway 12

13 Huntington s Disease Treating Huntington s SYMPTOMS DA ACh DA antagonists Restore balance between DA and ACh signaling in the striatum 13

14 Parkinson s Disease Advanced Parkinson s Normal University of Rochester Medical Center LOSS of dopaminergic neurons in the substantia nigra Toxin exposure DA neurons year of life >120 Normal Parkinsons SYMPTOM threshold (20% remaining) 14

15 Parkinson s Disease Chemical Disturbance in Parkinson s DIRECT pathway INDIRECT pathway Parkinsonism: Difficulty initiating motor activity 15

16 APPROACH #1 Parkinson s Pharmacology Parkinson s Disease Treating Parkinson s SYMPTOMS DA precursors, DA agonists DA ACh Restore balance between DA and ACh signaling in the striatum 16

17 Parkinson s Disease Treating Parkinson s SYMPTOMS APPROACH #2 DA ACh Anticholinergics Restore balance between DA and ACh signaling in the striatum 17

18 Parkinsonism in Antipsychotic Therapy VTA too much DA D 2 antagonists Nucleus accumbens Hippocampus Amygdala Tight-binding drugs (slow off-rates) POSITIVE Symptoms SN DA Striatum Parkinsonism 18

19 J Org Chem 12(6): (1947) The MPTP Story Synthetic opioids Meperidine-related compounds MPPP, reverse ester of meperidine Barry Kidston, Graduate Student University of Maryland (1976) San Francisco Area (1982) Accidental self-poisoning. Thought was making pure MPPP. Used too much heat in reaction, made MPTP as major impurity Impure China white, MPPP Six addicts poisoned with contaminant, MPTP William Langston, Stanford Professor Discovers role of MPTP in MPPP toxicity 19

20 Starting materials Parkinson s Pharmacology The MPTP Story Unstable Intermediate opioid MPPP Dopaminergic synaptic cleft DA transporter MPTP MPP + too much heat Monoamine oxidase (MAO-B) DA DOPAC COMT COMT 3-MT HVA MAO-B MPP + Urine Mitochondria 20

21 Anti-Parkinson s Agents Dopamine replacement Levodopa/Carbidopa Dopamine sensitizer Amantadine COMT inhibitors Entacapone Tolcapone MAO-B inhibitor Selegiline Rasagiline Dopamine agonists Bromocriptine Pramipexole Ropinirole Apomorphine Anticholinergics Trihexyphenidyl Benztropine Biperiden Ethopropazine 21

22 Dopamine Replacement Dopamine DOES NOT cross the bbb Dopamine biosynthesis Tyrosine Tyrosine hydroxylase L-DOPA DOPA decarboxylase Dopamine Dopamine β-hydroxylase Epinepherine PNMT Norepinepherine Levodopa (L-DOPA) DOES cross the bbb 22

23 % of L-DOPA dose Parkinson s Pharmacology Dopamine Replacement Fate of ORAL L-DOPA 1-3% CNS Peripheral DOPA decarboxylase 70% Metabolism (gut wall) 27-29% Peripheral tissues (toxicity) 23

24 L-DOPA + Carbidopa (Sinemet ) % of L-DOPA dose Carbidopa Parkinson s Pharmacology Dopamine Replacement Carbidopa DOPA decarboxylase inhibitor (acts only in periphery) IONIZED at physiological ph, DOES NOT cross bbb 10% CNS 40% Metabolism 50% Peripheral SAME CNS levels achieved with about 75% LOWER oral dose 24

25 Dopamine Replacement Adverse effects of PERIPHERAL dopamine L-DOPA Dopamine CTZ (D 2 ) Nausea, vomiting (80%) L-DOPA Carbidopa Dopamine CTZ (D 2 ) Nausea, vomiting (<20%) Benserazide (Serazide ) is also a peripheral DDC inhibitor, used in combination with L-DOPA (Prolopa - Canadian) 25

26 Dopamine Replacement L-DOPA is NOT just a precursor for DA L-DOPA Dopamine NE Other peripheral adverse effects, due to HIGH NE levels: Orthostatic hypotension Reflex tachycardia Syncope (fainting) Cardiac arrhythmias Hypertension 26

27 Dopamine Replacement Adverse effects of LONG-TERM L-DOPA: Dyskinesias Choreiform (involuntary) movements Jerking of arms and neck Psychotic symptoms Caused by HIGH DA in limbic system Can be alleviated with certain (atypical) antipsychotics ON-OFF phenomenon Transient (HOURLY) fluctuations Akinesia --- Dyskinesia 27

28 Dopamine Replacement Potential Drug Interactions MAO inhibitors (e.g. Phenelzine; Procarbazine; Isocarboxazide; Selegiline) Inhibit DA metabolism Combination can cause hypertensive crisis Antipsychotics (esp. typical, e.g.: Haldol; Fluphenazine; Prochlorperazine) Antagonism of dopamine receptors in the striatum can worsen condition Pyridoxine (Vitamin B 6 ) precursor to pyridoxal phosphate (PLP), which is a cofactor for DOPA decarboxylase; Can INCREASE peripheral L-DOPA metabolism 28

29 Dopamine Sensitizer Amantadine (Symmetrel ) Antiviral drug used to treat influenza Mechanism Poorly understood (?) Agonist of DA and NE Antagonist of ACh and Glutamate SEVERAL EFFECTS in nigrostriatal pathway: DA synthesis and release DA receptor expression DA reuptake Efficacy MINOR reduction in rigidity, bradykinesia Effects are QUICKLY lost 29

30 Amantadine Potential Drug Interactions Antipsychotics (esp. typical e.g.: Haldol; Fluphenazine; Prochlorperazine) Pharmacokinetics Parkinson s Pharmacology Dopamine Sensitizer Absorption: WELL absorbed Oral bioavailability: GOOD, 90% Onset of action: < 48 hr Excretion: UNCHANGED in URINE 30

31 Amantadine Parkinson s Pharmacology Dopamine Sensitizer Adverse effects Restlessness; Insomnia; Ankle swelling; Psychoses Livedo reticularis reddish-blue fishnet mottling of skin of lower extremities, caused by local catecholamines that causes vasoconstriction Anticholinergic symptoms: Blurred vision (mydriasis) Dry mouth Urinary retention Constipation 31

32 COMT Inhibitors 3-O-Methyl DOPA (3-OMD): COMPETES with L-DOPA for transport across bbb May contribute to the wearing off and on-off effects blood brain Tolcapone Entacapone COMT L-DOPA L-DOPA Tolcapone 3-OMD 3-OMD Used ALONG WITH L-DOPA/Carbidopa to: 1. Inhibit metabolism of L-DOPA (keeps L-DOPA levels high) 2. Prevent formation of 3-OMD ( L-DOPA import into CNS) 32

33 COMT Inhibitors Tolcapone (Tasmar ) Entacapone (Comtan ) Entacapone + L-DOPA + Carbidopa (Stalevo ) Adverse effects (mostly related to L-DOPA) Nausea Dyskinesia Orthostatic hypotension Psychoses Tolcapone may cause LIVER DAMAGE (Boxed warning!) 33

34 MAO-B Inhibitors Selegiline (deprenyl; Atapryl ; Eldepryl, etc) Rasagiline (Azilect ) DA B DOPAC MAO-B Inhibitor Other use for selegiline: Antidepressant Administration: ORAL, TRANSDERMAL Absorption: Good Onset of action: Rapid 34

35 MAO-B Inhibitors Selegiline, Rasagiline MAY alter the progression of Parkinson s disease by: production of reactive oxygen species (ROS) B DA DOPAC + NH 3 + H 2 O 2 Fe 2+ ; Cu 1+ OH - + HO MAO-B Inhibitor H 2 O 2 is a product of DA metabolism Protein Damage; Aggregates Death of DA neurons 35

36 Selegiline, Rasagiline Normally LOW bioavailability Adverse effects of Selegiline Headache Insomnia Dizziness Parkinson s Pharmacology MAO-B Inhibitors EPI, NE DA Tyramine DA A Tyramine Effect MAOI (nonspecific) B MAO-B Inhibitor NO Tyramine Effect 1. Most MAO-B is in the CNS 2. MAO-B is mostly selective for DA 36

37 MAO-B Inhibitors Selegiline, Rasagiline OFFENDING DRUG Tricyclic Antidepressants Bupropion INTERACTION Potentiation of side effects SSRIs Meperidine Dextromethorphan Serotonin syndrome Stimulants (e.g. methylphenidate) Buspirone Recreational Sympathomimetics e.g. cocaine, amphetamine, MDMA (ecstasy) Hypertensive crisis 37

38 DA Agonists Ergot alkaloid: Bromocriptine (Parlodel ) D 2 Non-Ergoline: Apomorphine (Apokyn ) D 2, D 4 > D 3 (morphine decomposition product; QTc warning) Pramipexole (Mirapex ) D 3 > D 2, D 4 Ropinirole (Requip ) D 3 > D 2, D 4 Pergolide (Permax ) Former ergot alkaloid (withdrawn 2007: cardiac fibrosis, valvulopathies) 38

39 DA Agonists MAY help reduce the on-off phenomenon Adverse effects BAD: MORE incidence of psychosis vs. L-DOPA: (hallucinations, delusions) GOOD: LESS motor side effects (dyskinesia) vs. L-DOPA Sedation Orthostatic hypotension, headache, nausea, vomiting Inhibition of prolactin secretion (i.e. DA = PIF) 39

40 DA Agonists Pharmacokinetics Bioavailability Bromocriptine: 28% (1 st pass) Pramipexole: % Ropinirole: 50% (1 st pass) Administration: ORAL Apomorphone: 100% Administration: Abdominal SQ (acute treatment of off episodes) 40

41 Pharmacokinetics Parkinson s Pharmacology DA Agonists Bromocriptine CYP3A4 FECES + URINE t 1/2 = 15 h Apomorphine? FECES + URINE t 1/2 = 40 min Pramipexole Ropinirole NOT METAB URINE 8-12 h CYP1A2 URINE 6 h Elimination much slower with renal impairment 41

42 ACh Antagonists Trihexyphenidyl (Artane ) Benztropine (Cogentin ) Orphenadrine (Norflex ) skeletal muscle relaxant Biperiden (Akineton ) Mechanism Restore balance to nigrostriatal pathway by inhibiting ACh Adverse Effects (primarily antimuscarinic) Blurred vision (mydriasis) Dry mouth Urinary retention Constipation 42

43 ACh Antagonists Half-lives Trihexyphenidyl: 33 hr Benztropine: not known Orphenadrine: hr Biperiden: 24 hr Disease-related concerns (precautions) CV disease: tachycardia, cardiac arrhythmias GI obstruction: slows GI motility Glaucoma: will worsen narrow angle glaucoma OTC substitute: Has anticholinergic activity 43