Alzheimer s Pharmacology

Size: px

Start display at page:

Download "Alzheimer s Pharmacology"

Charity Lindsey
5 years ago
Views:

1 PHPP 517 (IT-III) Fall 2011 JACOBS Mon 10/17/11 8:00 8:50 AM 1

2 Learning objectives 1. Describe the roles of amyloid beta 42 (Aβ 42 ), tau (τ) phosphorylation, cholinergic deficits, glutamate toxicity, and metal ions in Alzheimer s Disease (AD), emphasizing opportunities for drug-based disease intervention 2. Contrast pharmacokinetic attributes of the acetylcholinesterase (AChE) inhibitors used for AD: Tacrine; Donepezil; Rivastigmine; and Galantamine 3. Describe the principal side effects caused by cholinesterase inhibitors used to treat AD, and how this differs from a potent AChE inhibitor such as physostigmine 4. Explain why antipsychotics can exacerbate the extrapyramidal symptoms of cholinesterase inhibitors 2

3 Learning objectives 5. Recall the mechanism of action of memantine, the incidence of side effects in comparison to AChE inhibitors, and its pharmacokinetic attributes 6. Recall the types of investigational drugs in advanced clinical trials and the pathways they target in the etiology of AD 3

4 Neurodegeneration Normal Advanced Alzheimer s Atrophy associated with Alzheimer s Cortical shrinkage Enlarged ventricles Atrophy of Broca s area Atrophy of hippocampus and other limbic areas 4

5 Neurodegeneration Hallmarks of AAAAAlzheimer s Amnesia (Impaired memory) Agnosia (Impaired recognition of people, objects or stimuli) Aphasia (Impaired speech and writing skills) Apraxia (Impaired motor skills) Aggression (Moody behavior, depression) 5

6 Nissl Alzheimer s Pharmacology What causes AD how can we treat? Alzheimer Kraepelin Nissl stain Auguste D. (d. 1906) Senile plaques and Neurofibrilary tangles First to use term (1910) Alzheimer s disease 6

7 What causes AD how can we treat? Hypothesis 1: Amyloid plaques α-secretase N-terminus sapp APP Neuron growth Neuron survival Synaptic plasticity α extracellular intracellular C-terminus 7

8 What causes AD how can we treat? Hypothesis 1: Amyloid plaques β-secretase (BACE1) APP N-APP β DR6 NORMAL (axon pruning) Apoptosis ABNORMAL (neurodegeneration) TOO MUCH N-APP expression can HIJACK a normal cell death process 8

9 Hypothesis 1: Amyloid plaques γ-secretase (Presenilins?) APP β Alzheimer s Pharmacology What causes AD how can we treat? 42 amino acids γ? Aβ 42 aberrant cholesterol metabolism Senile plaques? Proposed reasons for cell death: Inflammation (microglia, astrocytes) Death receptor activation Reactive Oxygen Species (ROS) 9

10 What causes AD how can we treat? Hypothesis 1: Amyloid plaques Recommended reading: John Hardy et al. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics Science Vol. 297, Issue 5580, pp (2002) 10

11 Hypothesis 2: Neurofibrillary tangles Aβ 42 ACh (M 1 ) (+) Alzheimer s Pharmacology What causes AD how can we treat? (-) GSK-3β (+) Glu (NMDA) τ τ τ P τ τ Microtubules τ P τ P aggregates (meta-stable) τ P τ P τ P τ P τ filaments (stable) P 11

12 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits 1970 s Supportive anatomical findings* Much fewer cholinergic neurons in advanced Alzheimer s Supportive biochemical findings** Reduced choline uptake Reduced choline acetyltransferase (ChAT) levels Diminished ACh release *Davies, P. and Maloney, A.J.F. Selective loss of central cholinergic neurons in Alzheimer s disease. Lancet 2: 1943 (1976) ** Bowen, D.M., Smith, C.B., White, P., and Davison, A.N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99: (1976) 12

13 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits CHOLINE UPTAKE Choline ChT Choline Acetyl-CoA ChAT ACh ACh SYNTHESIS ACh ACh ACh vacht ACh NEURONS ACh LEVELS ACh ACh ACh 13

14 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits ACh ACh AChE Choline + Acetate Pyramidal neuron (cortex, limbic system) machr nachr Cholinesterase Inhibitors Are ACh Deficits a CAUSE or EFFECT of AD??? α γ β?? Plaques, Tangles Cell Death 14

15 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits Does reduced cholinergic activity CAUSE cell death? Arguments AGAINST: a. Cholinergic deficits appear to be associated with LATE STAGE AD only (EARLY AD does NOT show significant cholinergic deficits) a. Cholinergic drugs do NOT dramatically slow disease progression 15

16 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits Does reduced cholinergic activity CAUSE cell death? Arguments FOR: a. Activation of cholinergic receptors INHIBIT the processing of amyloid precursor protein to Aβ b. Activation of cholinergic (M 1 ) receptors INHIBIT the formation of neurofibrillary tangles (NT s) by inhibiting tau (τ) phosphorylation 16

17 What causes AD how can we treat? Hypothesis 3: Cholinergic deficits Diagram of Arguments for Senile Plaques Aβ 42 (+) a. b. PKC (-) (-) APP τ DAG Ca 2+ PLC Gα q M 1 GSK-3β τ P Neurofibrillary tangles 17

18 What causes AD how can we treat? Hypothesis 4: Glutamate toxicity ATP DEPLETION K + ATP Na + Glu Na +, Ca 2+ Trauma Ischemia (stroke) Inflammation EXCITOTOXICTY NMDA receptor Cell Death (apoptosis) CALPAIN ACTIVATION 18

19 FDA-Approved Agents Cholinesterase Inhibitors Tacrine (Cognex ) Donepezil (Aricept ) Rivastigmine (Exelon ) Galantamine* (Razadyne ) NMDA Antagonists *Also modulates nachr α7 activity (may have therapeutic role) Memantine (Namenda )

20 TARGET ORGAN EYE HEART ARTERIOLES BLOOD PRESSURE LUNGS SALIVA GI TRACT URINARY TRACT SWEAT GLANDS Alzheimer s Pharmacology Cholinergic Pharmacology REVIEW EFFECT Pupil constriction (miosis) Ciliary muscle contraction (acommodation, near vision) Intraocular pressure HR (bradycardia) Contractility Vasodilation (endothelial receptors not innervated) BP (may cause reflex tachycardia) Bronchoconstriction Secretion Salivation (watery, high volume) Gastric HCl secretion Smooth muscle contraction (increased peristalsis) Sphincter relaxation Wall muscle (detrusor) contraction Sphincter relaxation Sweating (diaphoresis) 20

21 Cholinesterase Inhibitors How about using physostigmine? calabar beans ACh AChE Physostigmine (Eserine) Choline + Acetate Useful for atropine overdose (IM, IV) Atropine (deadly nightshade) POOR and variable oral bioavailability (5-10%) SHORT half-life: min HIGH incidence of cholinergic adverse effects Bradycardia, palpitations, nausea, salivation, GI pain, bronchospasm, urinary frequency, sweating, miosis 21

22 Cholinesterase Inhibitors ADMINISTRATION Tacrine: Donepezil: Rivastigmine: Galantamine: ORAL ORAL ORAL + TD PATCH ORAL ABSORPTION Tacrine: Donepezil: Rivastigmine: Galantamine: RAPID (peak 1-2 hr) RAPID (peak 3-4 hr) RAPID (peak: 1 hr, oral) RAPID (peak: 1 hr) 22

23 Cholinesterase Inhibitors ORAL BIOAVAILABILITY Tacrine: POOR (17%), variable (+/- 13%) LARGE 1 st PASS EFFECT Donepezil: EXCELLENT (100%) Rivastigmine: MODERATE (40%) Galantamine: VERY GOOD (90%) FOOD EFFECT ON AUC (bioavailability) Tacrine: Donepezil: Rivastigmine: Galantamine: LOWERS AUC 30-40% (BTWN MEALS) NO EFFECT RAISES AUC 30% (W/MEALS) NO EFFECT 23

24 METABOLISM/ELIMINATION Tacrine: Alzheimer s Pharmacology Cholinesterase Inhibitors Donepezil: Rivastigmine: Galantamine: CYP1A2: URINE (active metabolite: 1-hydroxytacrine) CYP2D6 + CYP3A4: URINE ESTERASES: URINE CYP2D6 + CYP3A4: URINE HALF-LIFE Tacrine: Donepezil: Rivastigmine: Galantamine: 2-4 hr 70 hr Highly protein binding: 96% Large Vd: 14 L/kg 1.5 hr (ORAL); 3 hr (TD) 7 hr 24

25 Cholinesterase Inhibitors Which is administered ORAL or TD patch? Rivastigmine Which has the WORST bioavailability? Tacrine Which bioavailability is INCREASED by food? Rivastigmine Which bioavailability is REDUCED by food? Tacrine Which is metabolized by CYP1A2? Tacrine Which is NOT metabolized by P450 s? Rivastigmine Which has the LONGEST half-life? Donepezil 25

26 Adverse effects Alzheimer s Pharmacology Cholinesterase Inhibitors Nausea Vomiting Diarrhea Anorexia, weight loss Dizziness (syncope) Headache Side effects can be DOSE-LIMITING 26

27 Cholinesterase Inhibitors Drug Interactions Antipsychotics (esp. typical: Haldol; Thorazine) + AChE inhibitors can worsen EPS REDUCED DA ACTIVITY Antipsychotics (D 2 antagonists) Cholinesterase Inhibitors INCREASED ACh ACTIVITY Combination = Parkinson s-like symptoms (akinesia, rigidity) Long-term complication = tardive dyskinesia 27

28 Cholinesterase Inhibitors Drug Interactions CYP1A2 inhibitors can decrease the metabolism of Tacrine can increase side effects EXAMPLES: Several Fluoroquinolones Ciprofloxacin (Cipro ) Levofloxacin (Levaquin ) Norfloxacin (Noroxin ) Ofloxacin (Floxin ) Some Antifungals: Ketoconazole Miconazole Cimetidine (Tagamet ) Fluvoxamine (Luvox ) 28

Huperzine A Alzheimer s Pharmacology Cholinesterase

PROPOSED DUAL actions: a. Inhibits AChE b.

gov Paul Aisen, Georgetown, UCSD Firmoss (clubmoss)

16: 1389-1394 (2011) This study provides Class III

29 Huperzine A Alzheimer s Pharmacology Cholinesterase Inhibitors Clinical trials are small and limited PROPOSED DUAL actions: a. Inhibits AChE b. Antagonizes NMDA receptor clinicaltrials.gov Paul Aisen, Georgetown, UCSD Firmoss (clubmoss) Neurology Vol. 76, No. 16: (2011) This study provides Class III evidence that huperzine A 200 μg BID has no demonstrable cognitive effect in patients with mild to moderate AD. 29

30 Memantine Alzheimer s Pharmacology NMDA Antagonists Mechanism (similar structure to Amantidine) Antagonizes NMDA receptor (several other actions) Proposed: inhibition of glutamate EXCITOTOXICITY Pharmacokinetics Administration: ORAL Absorption: RAPID Bioavailability: EXCELLENT (100%) Effect of food: NOT significant Metabolism: NOT metabolized Half-life elimination: 70 hr Excretion: Urine (UNCHANGED) 30

31 Memantine Alzheimer s Pharmacology NMDA Antagonists Adverse effects (few, usually well tolerated) Dizziness Headache Memantine is NOT JUST an NMDA antagonist Other actions: 5-HT 3 antagonist nachr antagonist D 2 agonist Importance in AD therapy is unknown 31

32 Investigational Agents Open, Interventional Clinical Trials (Oct, 2011) Phase I: 27 Phase II: 25 Phase III: 71 Phase IV: 23 Advanced Drug Candidates (Phase II, III) - EXAMPLES γ-secretase inhibitors RO LY (Semagacestat) Amyloid Aβ modulators BAY AZD-103 Monoclonal antibodies (MAb) Bapineuzumab LY (Solanezumab) Metal-protein attenuators PBT-2 Natural Chemoprotectants Epigallocatechin Resveretrol Antihistamines Dimebolin GSK nachr agonists Varenicline 32

Investigational Agents SCH-785532 SCH-1359113 TAK-070 Bind to and DE-STABILIZE Aβ oligomers Tramiprosate (Alzhemed )* R-Flurbiprofen (Tarenflubril)* BAY94-9172 APP β γ Aβ?

33 Investigational Agents SCH SCH TAK-070 Bind to and DE-STABILIZE Aβ oligomers Tramiprosate (Alzhemed )* R-Flurbiprofen (Tarenflubril)* BAY APP β γ Aβ? *Failed phase III RO Semagacestat* Inhibits γ-secretase and DECREASES Aβ production Bapineuzumab Solanezumab Monoclonal antibodies (MAb) Induce immune response to CLEAR Aβ deposits and KILL Aβ-producing cells 33

NO IMPROVEMENT vs. placebo rich in seaweed NUTRACEUTICAL Co.

34 Investigational Agents Tramiprosate (Homotaurine, 3-APS) aka Alzhemed, Vivimind Alzhemed Funded 3 Phase III trials (n > 1000 patients) PHARMACEUTICAL Co. NO IMPROVEMENT vs. placebo rich in seaweed NUTRACEUTICAL Co. Side effects: Nausea, vomiting Dizziness Weight loss Worsening of tau?! Vivimind COST: $1,000 - $2,000 per year! 34

IDENTITY 2 Trial Aug 17, 2010: Lilly HALTS

evaluating treatment of amyloid pathology

35 Investigational Agents Phase III Trials with Semagacestat IDENTITY trial > 2,600 IDENTITY 2 Trial Aug 17, 2010: Lilly HALTS trials. WHY? Drug doing WORSE than placebo. also...increased risk for skin cancer Interrupting Alzheimer's dementia by evaluating treatment of amyloid pathology Illustrates the extreme difficulty in developing novel drugs! 35

36 Aβ Investigational Agents Cu + Cu + Fe 2+ Metal ion hypothesis of AD Inflammation ROS* Production PBT-2 Epigallocatechin Resveratrol SK-PC-B70M *ROS = reactive oxygen species H 2 O 2 O 2 - HO 36

Investigational Agents Antihistamines Blockade of H 3 receptors in CNS has been shown to enhance release of various neurotransmitters: histamine, ACh, dopamine and norepinephrine Histamine Dimebolin*

37 Investigational Agents Antihistamines Blockade of H 3 receptors in CNS has been shown to enhance release of various neurotransmitters: histamine, ACh, dopamine and norepinephrine Histamine Dimebolin* GSK H 3 Gα i coupled ACh ACh ACh *Phase II Trial (in Russia) run by BCM, published in Lancet 372: (2008) looked VERY promising, but... Failed Phase III Trails in 2010 ( CONNECTION Trial) 37

38 Varenicline (Chantix ) Nicotinic receptor AGONIST Na +, Ca 2+ Investigational Agents nachr Fyn ANTI-APOPTOTIC Proteins α 7 nicotinic receptors can mediate CELL SURVIVAL by increasing the expression of anti-apoptotic proteins Adverse effects Nausea Headache Insomnia Suicidal ideation 38

Alzheimer s Disease. Pathophysiology: Alzheimer s disease (AD) is a progressive dementia affecting cognition, behavior,

Alzheimer s Disease. Pathophysiology: Alzheimer s disease (AD) is a progressive dementia affecting cognition, behavior, 2 Alzheimer s Disease Alzheimer s disease (AD) is a progressive dementia affecting cognition, behavior, and functional status with no known cause or cure. Patients eventually lose cognitive, analytical,