Pharmacotherapies for neurodegenerative disorders
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This seminar was presented to 2nd year pharmacy students enrolled in a pharmacology & toxicology course and accompanies Goodman & Gilman's (12e) chapter 22.
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Pharmacotherapies for neurodegenerative disorders
- 1. Pharmacotherapies of Neurodegenerative Disease: Alzheimer’s, Huntington’s, & ALS Brian J. Piper, Ph.D., M.S.
- 2. Goals • Describe mechanism & efficacy of pharmacotherapies for AD. • List drug therapies used for symptomatic management of HD & ALS.
- 3. Alzheimer’s Prevalence Dementia cases in U.S. Year Patients (millions) 2010 5.8 2020 6.8 2030 8.7 2040 11.8 2050 14.3 Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128.
- 4. Aloysius ”Alois” Alzheimer • German psychiatrist • Described symptoms + pathology – Neuronal loss 1864-1913 – Plaques – Tangles • Presentation to SW German Psychiatrist meeting ignored but Emil Kraeplin Cipriani et al. (2011) Neurological Sciences, 32(2), 275-279. Auguste Deter, 1851-1906
- 5. 1st, but possibly, atypical case
- 6. Healthy Alzheimer’s Disease
- 8. AD, coronal cross section
- 9. Genetic Risk Factors • Apolipoprotein E: Isoform 112 158 – Chromosome 19 E2 Cysteine Cysteine – 299 amino acids – E3 > E2 > E4 E3 Cysteine Arginine E4 Agrinine Agrinine
- 10. Apolipoprotein E & Alzheimer’s Disease • ε4 – 1 copy: 2.5x – 2 copies: 7x Corder et al. (1993). Science, 261, 921-3.
- 11. Test of Neurocognitive Function • Mini-Mental State Exam (MMSE) – Where are we in? – Count backwards by 7 starting with 100 – Remember 3 words – Copy drawing • Executive function Folstein, Folstein, & McHugh (1975). J Psychiatric Research, 12, 189-198.
- 12. Executive Function Test: Trail Making Test: Part A
- 13. Trail Making Test: Part B
- 14. Amyloid Plaque • Amyloid Beta Peptide: 40/42 amino acids • Amyloid Plaque: clusters of Beta amyloid +
- 15. Alzheimer’s Vaccine? • Immunization against AB42 peptide produced antibodies • MMSE – 30: maximum – 21-24: mild – 10-20: moderate – <9: severe • Brain versus behavior Holmes et al. (2008). Lancet, 372, 216-223.
- 16. Alzheimer’s Vaccine? • Immunization against synthetic AB42 produced antibodies • MMSE – 30: maximum – 21-24: mild – 10-20: moderate – <9: severe • Brain versus behavior Holmes et al. (2008). Lancet, 372, 216-223.
- 17. Pharmacotherapies for AD Donepezil Galantamine Rivastigmine Memantine (Aricept) (Razadyne) (Exelon) (Namenda) FDA Approved mild mild mild for: moderate moderate moderate moderate severe severe Mechanism cholinesterase cholinesterase cholinesterase NMDA inhibitor inhibitor Inhibitor antagonist Adverse effects nausea nausea nausea headache vomiting vomiting vomiting constipation ↓ appetite ↓ appetite ↓ appetite confusion ↑ bm ↑ bm ↑ bm dizziness http://wps.prenhall.com/wps/media/objects/3775/3866436/proto/donepezil.wav
- 18. Acetylcholine Breakdown AChE: actylcholinesterase – brain (neurons) BuChE: butyrylcholinesterase (pseudo) – plasma – liver – gut – brain (glia) Stahl (2008). Essential Psychopharmacology, p. 915.
- 19. Mechanism of Donepezil Stahl (2008). Essential Psychopharmacology, p. 925.
- 20. Mechanism of Rivastigmine Stahl (2008). Essential Psychopharmacology, p. 926-929, http://www.youtube.com/watch?v=Pk89_b3FI5E
- 21. Mechanism of Galantamine • Found in several plants including daffodil • AChE inhibitor & nACh Positive Allosteric Modulator Stahl (2008). Essential Psychopharmacology, p. 919.
- 22. Galantamine Stahl (2008). Essential Psychopharmacology, p. 929-31.
- 23. Response to Cholinesterase Inhibitor AChE BuChE nACh Inhib Inhib PAM Donepezil yes no no Rivastigmine yes yes no Galantamine yes no yes Stahl (2008). Essential Psychopharmacology, p. 924.
- 24. Glutamateric Transmission in Health • Excitatory amino acid • Important for cognition Stahl (2008). Essential Psychopharmacology, p. 302, 933.
- 25. Glutamateric Transmission & Neurotoxicity • Free radicals – superoxide (O2-) – hydrogen peroxide (H2O2) – hydroxyl (OH) Stahl (2008). Essential Psychopharmacology, p. 933.
- 26. Low affinity NMDA binding
- 27. Efficacy & Great Tolerability of Memantine • Double-blind randomized controlled trial of memantine (20 mg/day). • Participant age >50 with MMSE 3-14 • Dependent measures include Activities of Daily Living scale (Max = 78) completed by the caregiver Reisburg et al. (2003). New England J Medicine, 348(14), 1333-1341.
- 28. Huntington’s Chorea • Autosomal dominant (Huntingtin) 1912 - 1967 • # CAG repeats predicts onset • motor -> personality/dementia H h h Hh hh h Hh hh Example patient (1 min): http://www.youtube.com/watch?v=JzAPh2v-SCQ Woody Guthrie (1 min): http://www.youtube.com/watch?v=wxiMrvDbq3s
- 29. Thompson et al. (2012). Journal of Neuropsychiatry & Clinical Neuroscience, 24(1), 53-60.
- 30. Fluoxetine • depression & anxiety • Not selective – SERT – 5-HT2C – NET – Sigma (σ) Stahl (2008). Essential Psychopharmacology, p. 533.
- 31. Tetrabenazine • Tx: chorea • MOA: reversible VMAT2 inhibitor • Adverse Effects: depression/suicidal ideation Joseph Janovik, MD
- 32. Clinically Significant Reduction in Chorea • Participants were randomized to placebo (N=30) or individualized dose of tetrabenazine (N=51) for 12 weeks. • Unified Huntington’s Disease Rating Scale interview was conducted blind. Huntington’s Study Group (2006). Neurology, 66, 366-372.
- 33. Amyotrophic Lateral Sclerosis • Symptoms: weakness, muscle atrophy, dysarthria, dysphagia, respiratory compromise • Pathophysiology: glutamate excitotoxity in upper (motor cortex) & lower (ventral horn) motor neurons 1903-1941 1942 -
- 34. Riluzole • Tx: disease progression (?) • MOA: ↓ glutamate release & ↑ uptake; • Adverse Effects: nausea & asthenia • Cost: $10K/year Cifra et al. (2012-in press). Neuroscientist, 1-8. http://www.howjsay.com/index.php?word=riluzole&submit=Submit
- 35. Slight, but Significant, Benefits • Meta-analysis of 4 studies (N Riluzole = 974, N Placebo = 503) • Likelihood of surviving one year was ↑10% • Overall survival was – Placebo 11.8 months – Riluzole 14.8 months Miller et al (2012). Cochrane Database Systematic Reviews.
- 36. Baclofen • Tx: ALS spasticity • MOA: GABAB agonist • Adverse Effects: – drowsiness & fatigue (oral) – somnolence, dizziness (intrathecal) Pump 2:05 to 4:10 min: http://www.youtube.com/watch?v=NDys_6lPa5U
- 37. Terminology • dysarthria (p. 624): disorders of articulation, as stammering or stuttering • dysphagia (p. 624): pronounced dis-fey-juh; difficulty swallowing http://dictionary.reference.com/browse/dysphagia?s=t
Editor's Notes
- Image by Texas photographer Tom Hussey in campaign for Exelon.
- The global prevalence of dementia is 24 million, and is predicted to double every 20 years until at least 2040. Alzheimer disease is the leading cause of dementia.
- 93, 86, 79, …
- AN1792, Elan Pharmaceuticals vaccine. Antibody production was quite variable.
- Note disconnect between amyloid and cognitive levels.
- The gi side effects of donepezil are mostly transient.Rivastigmine is available as capsules or via a patch.bm: bowel movements; pronunciation of memantine (ma man TINe, long I) donepezil (dawn ep ah zil)
- AChE & BuChE convert ACh into choline where it can be transported into the axon. AChE is found in gut, skeletal muscle, red blood cells, platelets, and at high levels in areas that receive cholinergic input. BuChE may also be present in amyloid plaques.
- Donepezil is made by a Japanese (Eisai) and American (Pfizer) companies and is a selective & reversible AChE inhibitor. The gi side effects (nausea, diarhea, abdominal pain) of donepezil are typically temporary.
- Rivastigmine is made by Novartis, a Swiss company based in Basel, Switzerland.Rivastigmine is apseudoirreversible (reverses itself over hours) nonselective cholinesterase inhibitor. The patch is useful for this population as they may forget to take their meds and gi upset is an appreciable source of medicine nonadherance for AChE inhibitors.
- Galantamine is found in the bulbs and flowers of daffodil (left),Caucasian snowdrop (middle), snowflake, andRed Spider Lily. Galantamine causes the channel to open more frequently.
- LTP: Long-Term Potentiation; Calcium is the ion whole levels must be very carefully controlled.
- LTP: Long-Term Potentiation; There are a wide variety of pro-oxidant enzymes (hydroxylases, oxidases, oxygenases, peroxidases and synthases) that may be activated by Ca to form free radicals. Low levels of free radical formation may cause dendritic pruning but higher levels result in neuron death.
- The low affinity of Memantine to the magnesium binding site on the NMDA receptor results in binding and removal from the channel.
- Mean MMSE at baseline was 7.9; Age = 76. ADL includes bathing, using bathroom, dressing, kitchen, & tv. More patients receiving placebo than memantine discontinued the study prematurely because of adverse events (17 versus 10 %)!
- Chorea (pronounced kor EE ah or like nation Korea) is abnormal writhing movements. The medium spiny neurons of the striatum are most severely affected.
- Genetically verified HD patients (N = 111, Age = 48, mean illness duration = 5.5) completed annual interviews over 4 years. Interestingly, these patients were attending a clinic and rates may have been higher without psychiatric meds. 99% of patients endorsed at least one item.
- Non-selectivity includes 5-HT2C antagonist and binding to several liver enzymes. Effects on NET may only occur at high doses.
- FDA: orphan disease effects less than 200K; Janovik from Texas spent 3 decades getting tetrabenazine FDA approved. It is the only currently approved drug for HD. VMAT2 inhibition results in larger effects on dopamine than norepinephrine.
- SAE included 1 suicide by drowning, 1 fall, & 1 suicidal ideation requiring hospital visit. Study drugs were withdrawn after week 12. Other research has noted that as many as 2% of HD patients attempt suicide.
- Right image is of theoretical physicist Stephen Hawking on the “Vomit Comet” in 2007. Hawking has a disease related to ALS. Most patients die of pneumonia after 2 years!dysarthria: disorder of articulation, as stammering or stutteringdysphagia: pronounced dis-fey-juh; difficulty swallowing
- Pronounced RIL yoozol. Riluzole is the only currently approved drug for ALS. In vitro studies indicate that Riluzole increases activity of the Glutamate Transporters and decreases presynaptic release. Adverse effects result in 10% of patients stopping treatment.Pronounced as-thee-nee-uh and defined as lack of strength and weakness.
- About half of ALS patients die within 3 years of developing symptoms. Bottom two lines are from a separate study with much older and more severely effected at study onset (not included in Pooled mean). All shown studies used oral 100 mg/day.
- Spasticity refers to an increased muscle tone. Baclofen may be administered orally (5 mg upto 200 mg/day) or intrathecally.