Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
TREATMENT 
OF 
DEMENTIA
OUTLINE 
Definition and 
Criteria 
Classification of 
Dementia 
Staging of Dementia 
Classification 
Types and causes of 
...
Dementia 
Term dementia in Latin means “devoid of the 
mind.” 
It is defined as an acquired deterioration in 
cognitive ab...
DSMD –SIMV -CIrVit eCrirai tfoerr Diaementia 
Memory Impairment plus at least one of the 
following 
APHASIA (Deterioratio...
Mild cognitive impairment (MCI) 
Original Criteria 
Memory complaint 
preferably qualified by an 
informant 
Memory impair...
ROAD TO DEMENTIA
Staging of Dementias 
MILD: difficulties with checkbook maintenance, 
complex meal preparations, complicated medication 
s...
Mini Mental State 
Examiation : 
Staging of Disease by 
MMSE 
Normal 27-30 
Mild 25-26 
Mild- Moderate 10-24 
Moderate- Se...
MMSE
MMSE ‘norms’ by Age and 
Educational Level 
Educational level 
AGE 0-4y 5-8y 9-12y >12y 
18-24 23 28 29 30 
35-39 23 27 29...
Classification of Dementias 
Primary versus secondary based on the 
pathophysiology leading to damaged brain tissue 
Corti...
Primary Degenerative Dementia: 
•Alzheimer’s Disease 
Causes of Dementia 
•Fronto temporal dementia 
Parkinsons disease 
H...
Secondary Dementia: 
VITAMIN 
Deficiency 
ENDOCRINE Chronic 
Infections 
Vit B12/Folic 
acid 
Hypothyroidism HIV 
Thiamine...
Secondary Dementia 
TOXIC Head 
Trauma/diffuse 
brain damage 
Neoplastic 
DIALYSIS 
DEMENTIA 
Aluminum 
Chronic Subdural 
...
Secondary Dementia 
Miscellaneous Additional conditions in 
children or adolescents 
Sarcoidosis 
Vasculitis 
CADASIL 
Acu...
Overall Situation: USA DATA 
Alzheimer’s 
70 % 
disease 
Vascular 
Dementia 
15-20% 
70% of dementia is Alzheimer’s 
10-15...
Year : 2012 | Volume : 60 | Issue : 6 | Page : 618-624
Types 
CORTICAL SUBCORTICAL MIXED 
Alzheimer’s Parkinson’s Vascular Dementia 
Frontotemporal 
Dementia 
Huntington’s 
dise...
REVERSIBLE ( 
DEMENTIA[10-20%] 
IRREVERSIBLE 
DEMENTIA[80-90%] 
D= Drugs Alzheimer 
E= Endocrine disorders Lewy Body demen...
BASELINE TESTS: 
Baseline 
investigations for 
Dementia: 
CBC, ESR S. Electrolytes 
Calcium, Phosphate Syphilis 
Chest X r...
Cholinergic deficit 
– progressive loss of cholinergic 
neurones 
– progressive decrease in 
available ACh 
– impairment i...
Alzeimer’s 
Disease 
Loss of 
cholinergic 
neurons 
Senile plaques & 
neurofibrillary 
tangels 
Glutamate 
transmission 
d...
Alzheimer’s Staging:
Management :Dementia 
Reduce Cognitive 
Symptoms 
Reduce Behaviour 
Symptoms 
Slow disease progression 
Delay the Onset of...
PHARMACOLOGIC MANAGEMENT OF 
DEMENTIA 
Three broad categories of dementia 
pharmacotherapy: 
Symptomatic treatment of mem...
Symptomatic Treatment of AD 
. The mainstay of symptomatic treatment of AD, so 
far, is the cholinergic treatment strategi...
Cholinesterase inhibitors: 
two classes exist for the treatment of Dementia 
Class Inhibit 
Dual ChE inhibitors 
– Rivasti...
FDA-approved drugs 
Drug Target dose Approved for year 
Tacrine 40 mg/day Mild to 
moderate 
1993 
Donepezil 10 mg daily A...
TACRINE 
In 1993 first Drug approved for the treatment 
of Alzheimer's disease 
marketed under the trade name Cognex. 
Tac...
Tacrine Pharmacokinetis 
Bioavailability 2.4–36% (oral) 
Protein binding 55% 
Metabolism Hepatic (CYP1A2) 
Half-life 2–4 h...
Tacrine dose 
Initiation of Treatment Dose Titration 
Cognex® is supplied as 
capsules of tacrine 
hydrochloride containin...
Tacrine Adverse Effects 
Very Common >10% Common 1-10% incidence 
Increased LFTs 
Hepatitis 
Nausea 
Vomiting 
Diarrhea 
H...
Tacrine Overdose 
nausea, vomiting, 
salivation, sweating, 
bradycardia, hypotension, collapse, 
convulsions. 
Atropine is...
Studies found that it may have a small beneficial 
effect on cognition and other clinical measures 
though study data was ...
DONEPEZIL 
In 1996, donepezil, a selective cholinesterase 
inhibitor, was approved for use in Alzheimer disease. 
marketed...
Pharmacokinetics 
Bioavailability 100 (%) not affected by the time of 
day or food intake 
Protein binding 96% 
Half-life ...
Dosage 
In mild to moderate A D Moderate to severe AD 
Disease, a starting dose 
of 5 mg given once 
daily should be used....
DONEPEZIL 
CONTRAINDICATIONS ADVERSE EFFECTS 
cardiac disease, cardiac 
conduction disturbances, 
chronic obstructive 
pul...
Clinical Trials of Donepezil 
Study (Rogers et al 1996). 
Double-blind, placebo-controlled, 
30-week, 
parallel study invo...
Clinical Trials of Donepezil 
Study (Doody et al 2009) 
A 48-week, randomized, 
placebo-controlled trial of 
donepezil for...
Rivastigmine (Rx) - Exelon 
Mechanism of Action 
PHARMACOKINETICS 
Reversible 
acetylcholinesterase 
inhibitor that causes...
Rivastigmine - Adverse effects 
common UNCOMMON 
Nausea (PO 47%; patch 21%) 
Vomiting (PO 31%; patch 6- 
19%) 
Dizziness (...
Rivastigmine Cautions 
Renal impairment 
Hepatic impairment 
Sick sinus syndrome 
Conduction abnormalities. 
H/O Asthma or...
Transdermal Patch Technology: 
Reservoir versus Matrix 
Backing 
Drug 
Reservoir 
Nitti VW, et al Urology. 2006;67:657–64 ...
Exelon Transdermal 
9.5 mg/24 h Patch
Where to Apply Exelon Patch 
Apply to: 
Upper and lower back 
Upper arm 
Chest 
The skin should be clean, 
dry and hair...
Exelon Transdermal Patch: 
Smooth Continuous Delivery Through the Skin 
Exelon 9.5 mg/24 h patch 
Exelon 6 mg BID capsule ...
Starting transdermal ChEI therapy 
Rivastigmine 
4.6 mg/24 h 
patch 
Rivastigmine 
9.5 mg/24 h 
patch 
One-step dose incre...
Clinical trials Rivastigmine 
Study (Burns et al 
2004) 
A retrospective analysis of 
pooled data from 3 
randomized, plac...
Clinical trials Rivastigmine 
Results of a 6-month, 
double-blind, randomized, 
placebo-controlled study of a 
transdermal...
Galantamine (Nivalin, Razadyne, Razadyne 
ER, Reminyl, Lycoremine) 
It is an alkaloid that is 
obtained synthetically 
or ...
Galantamine-MOA 
weak competitive 
and reversible choline 
sterase inhibitor in all 
areas of the body. 
It increases the ...
Pharmacokinetics 
Galantamine 
DOSAGE 
Bioavailability - 80 to 
100% 
Protein binding- 18% 
Metabolism-Hepatic 
Half-life-...
Clinical Trials with Galantamine 
Study (Raskind et al 2004). 
Patients with mild-to-moderate 
Alzheimer disease 
who had ...
Galantamine-Adverse effects 
common Rare 
Nausea, vomiting,Diarrhea, 
abdominal pain, upper 
abdominal pain, dyspepsia, 
s...
Memantine 
Memantine is the first in a novel class 
of Alzheimer's disease medications acting on 
the glutamatergic system...
Memantine 
Pharmacokinetic MOA 
Bioavailability~100% 
Metabolism- 
Hepatic (<10%) 
Half-life- 60–100 
hours 
Excretion - R...
Memantine -Adverse effects 
Common Less common 
confusion, dizziness, 
drowsiness, 
headache, insomnia, 
agitation 
halluc...
Clinical trials Memantine 
The M-Best Study 
The M-Best Study (Benefit and 
Efficacy in Severely demented 
patients during...
The DOMINO-AD clinical trial 
This study looked at 295 people 
with moderate to severe Alzheimer's 
disease 
All of the st...
The DOMINO-AD clinical trial 
RESULTS 
There were benefits to cognitive function of taking donepezil (about 
32% less cogn...
RCT of donepezil &/or memantine &/or 
placebo in patients with moderately 
severe/severe AD (MMSE 5-13) who have 
been on ...
RESULTS 
DELAY OF 
PROGRESSION: 
Duration 
Memantine alone 2-3 years 
Memantine + Ch E 
5-6 years 
inhibitors 
Ch E Inhibi...
TREATMENT OPTIONS IN DEMENTIA 
AD VaD FTD LBD 
DONEPEZIL ChE Inhibitors No ChE 
inhibitors 
ChE 
inhibitors 
RIVASTIGMIE H...
Disease-Modifying Agents 
Proposed or unregulated drugs which 
require further studies 
Selegeline 
Vit-E 
Oestrogen 
Pred...
Disease-Modifying Agents 
Vitamin E 
 Limits free-radical formation, oxidative stress and lipid 
peroxidation 
 Promotes...
Disease-Modifying Agents 
Anti-Inflammatory drugs 
 Pathophysiological studies demonstrate a marked 
inflammatory reactio...
Disease-Modifying Agents 
Statins 
 Direct association between amyloid processing and 
cholesterol in the brain 
 An ind...
Disease-Modifying Agents 
Idebenone 
 Synthetic analogue to Co-Q10, known to have anti-oxidant 
properties 
 Controlled ...
The amyloid cascade hypothesis & drugs in 
clinical trials 
Statins - promotes 
alpha secretase 
Flurizan - modulates 
gam...
Active and passive beta amyloid immunisation 
against AD 
Vaccination against Aβ42 
has proved highly efficacious in 
mous...
Bapineuzumab (anti-amyloid antibody)
Bapineuzumab (anti-amyloid antibody) 
“I think the data are pretty clear from this trial that 
bapineuzumab is not effecti...
Behavioral Problems in AD 
 depression (occurs in 20-40% - esp. AD and 
VaD) 
 psychosis (occurs in 30- 50%) - usually s...
Depression and Alzheimer’s 
Common early in the course of the illness 
Incidence 40-50% 
Use SSRIs first; avoid anticholin...
Treatment of Depression 
Recognize that irritability and/or apathy 
/withdrawal may be indicative of depression 
Allow pat...
Agitation 
Non-aggressive 
 verbal: complaining, constant requests for 
attention, repetition of words, constant talk, 
s...
Medications for Agitation 
Buspirone – Takes a while to work 
Antidepressants (SSRIs, Trazodone) 
Anticonvulsants (esp. va...
Treatment of Psychosis 
Traditional antipsychotics 
 Low potency (chlorpromazine)– orthostasis, sedation, 
anticholinergi...
Treatment of Insomnia 
Sleep hygiene (avoid caffeine, etc.) 
Treat causative psychiatric or medical disorders 
Phsysiologi...
Use of Atypical Antipsychotics 
Older, “typical” agents such as haloperidol and 
thioridazine (mellaril) associated with s...
Risperidone 
Evidence demonstrates efficacy in treatment of psychotic 
and behavior symptoms in patients with dementia 
Ex...
Olanzapine 
Evidence that it is effective in AD patients 
Increases motor symptoms in PD patients 
Recommended not to use ...
Quetiapine 
Showing promise in patients with AD and PD 
Does not exacerbate movement disorder of PD 
May be first line for...
Ziprasidone 
New, clinical data lacking 
Non dose-dependent QT prolongation
Clozapine 
Very effective in treating psychosis in PD patients 
The most effective agent in treatment of drug 
induced psy...
Caregiver Burden 
Alzheimer’s caregivers spend an average of 69 to 
100 hours per week providing care 
Caregivers of patie...
Behavioral Strategy 
Scheduled toileting, 
prompted voiding 
for incontinence. 
Graded assistance, & 
positive 
reinforcem...
Other Drugs in the Pipeline 
Tau protein modulators (to prevent abnormal 
phosphorylated ‘tau’ protein 
Bryostatin – drug ...
Dementia and clinical trials 
Where next? 
Disease modifying drugs need to start early 
 Much of the damage been done by ...
Take Home Points 
Cholinesterase Inhibitors are MODESTLY 
effective in treatment of mild to moderate AD 
Cholinesterase In...
Treatment of dementia
Treatment of dementia
Treatment of dementia
Treatment of dementia
Treatment of dementia
Treatment of dementia
Treatment of dementia
Treatment of dementia
Upcoming SlideShare
Loading in …5
×

Treatment of dementia

4,401 views

Published on

Published in: Health & Medicine
  • Be the first to comment

Treatment of dementia

  1. 1. TREATMENT OF DEMENTIA
  2. 2. OUTLINE Definition and Criteria Classification of Dementia Staging of Dementia Classification Types and causes of dementia Pathophysiology Management of dementia PHARMACOLOGIC MANAGEMENT OF DEMENTIA  Symptomatic  Disease-modifying treatments  treatment of behavioral disturbance NON PHARMACOLOGIC MANAGEMENT OF DEMENTIA
  3. 3. Dementia Term dementia in Latin means “devoid of the mind.” It is defined as an acquired deterioration in cognitive abilities from a previously higher level of functioning that impairs the successful performance of activities of daily living. In 2010, there are 3.7 million Indians with dementia and the total societal costs is about 14,700 crore(ALZHEIMER'S & RELATED DISORDERS SOCIETY OF INDIA ARDSI 2010)
  4. 4. DSMD –SIMV -CIrVit eCrirai tfoerr Diaementia Memory Impairment plus at least one of the following APHASIA (Deterioration of Language function) APRAXIA (inability to Execute Motor function) AGNOSIA (inability to Recognise or Naming of Object) Disturbance in executive functioning with • Impairment in occupational or social functioning • Represent a decline from a previous higher level of functioning
  5. 5. Mild cognitive impairment (MCI) Original Criteria Memory complaint preferably qualified by an informant Memory impairment for age Preserved general cognitive function Intact activities of daily living Not demented By Peterson R, Negash S. CNS Spectr. vol 13 2008 Once the memory loss becomes noticeable to the patient and spouse and falls 1.5 standard deviations below normal on standardized memory tests, the term MCI is applied. approximately 50% of patients with MCI (roughly 12% per year) will progress to AD over 4 years. 10% of persons >70 and 20–40% of individuals >85 have clinically identifiable memory loss. Harrison's 18 ed > Chapter 371. Dementia
  6. 6. ROAD TO DEMENTIA
  7. 7. Staging of Dementias MILD: difficulties with checkbook maintenance, complex meal preparations, complicated medication schedules MODERATE: difficulties with simple food preparation, household or yard work. May need some assistance with self-care SEVERE: Need considerable assistance with feeding, grooming and toileting PROFOUND: Largely oblivious to surroundings, totally dependent TERMINAL: Bed bound; require constant care
  8. 8. Mini Mental State Examiation : Staging of Disease by MMSE Normal 27-30 Mild 25-26 Mild- Moderate 10-24 Moderate- Severe 6-9 Very Severe <6
  9. 9. MMSE
  10. 10. MMSE ‘norms’ by Age and Educational Level Educational level AGE 0-4y 5-8y 9-12y >12y 18-24 23 28 29 30 35-39 23 27 29 30 50-54 22 27 29 30 70-74 21 26 28 29 80-84 19 25 26 28
  11. 11. Classification of Dementias Primary versus secondary based on the pathophysiology leading to damaged brain tissue Cortical versus sub-cortical depending on the cerebral location of the primary deficits Reversible versus irreversible depending on treatment expectations Early (before age 65) versus late onset
  12. 12. Primary Degenerative Dementia: •Alzheimer’s Disease Causes of Dementia •Fronto temporal dementia Parkinsons disease Huntington’s disease •Dementia with Lewy Body •Parkinsons disease •Huntington’s disease •Progressive supranuclear palsy •Corticobasal degeneration • ALS Parkinson's dementia complex of Guam •Multisystem atrophy
  13. 13. Secondary Dementia: VITAMIN Deficiency ENDOCRINE Chronic Infections Vit B12/Folic acid Hypothyroidism HIV Thiamine B1 hyperthyroidism Neurosyphilis Nicotinic acid (pellagra) Cushing Syndrome PML, Prion Tuberculosis, fungal, and protozoal Hypoparathyroidism Whipple's disease
  14. 14. Secondary Dementia TOXIC Head Trauma/diffuse brain damage Neoplastic DIALYSIS DEMENTIA Aluminum Chronic Subdural Hematoma/Deme ntia pugilistica Primary Brain Tumor Drug Poisoning Alcoholism Postencephalitis/ Postanoxia Metastatic brain tumors Heavy metal Poisoning Mercury,lead Normal Pressure Hydrocephalus Paraneoplasti c limbic encephalitis
  15. 15. Secondary Dementia Miscellaneous Additional conditions in children or adolescents Sarcoidosis Vasculitis CADASIL Acute intermittent porphyria Recurrent nonconvulsive seizures Pantothenate kinase-associated neurodegeneration Subacute sclerosing panencephalitis Metabolic disorders (e.g., Wilson's and Leigh's diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations)
  16. 16. Overall Situation: USA DATA Alzheimer’s 70 % disease Vascular Dementia 15-20% 70% of dementia is Alzheimer’s 10-15% is Vascular dementia 10-15% Lewy Body dementias 5-10% Others Lewy Body Dementia 10-15 % Others 5 %
  17. 17. Year : 2012 | Volume : 60 | Issue : 6 | Page : 618-624
  18. 18. Types CORTICAL SUBCORTICAL MIXED Alzheimer’s Parkinson’s Vascular Dementia Frontotemporal Dementia Huntington’s disease Lewy body dementia CJD Normal pressure hydrocaphalus Neurosyphilis
  19. 19. REVERSIBLE ( DEMENTIA[10-20%] IRREVERSIBLE DEMENTIA[80-90%] D= Drugs Alzheimer E= Endocrine disorders Lewy Body dementia M= Metabolic Frontotemporal Dementia (Picks disease) E= Emotional Parkinson disease N= Nutritional Huntington’s disease T = Toxic, Tumor, Trauma Creutzfeldt-Jakob disease A= Alcohol others
  20. 20. BASELINE TESTS: Baseline investigations for Dementia: CBC, ESR S. Electrolytes Calcium, Phosphate Syphilis Chest X ray HIV CT, MRI Thyroid Function test B12, Folate Liver function tests EEG, ECG Renal Function Tests
  21. 21. Cholinergic deficit – progressive loss of cholinergic neurones – progressive decrease in available ACh – impairment in ADL, behaviour and cognition Hippocampus Cortex N. basalis Meynert Pathophysiology of AD (Biochemical)
  22. 22. Alzeimer’s Disease Loss of cholinergic neurons Senile plaques & neurofibrillary tangels Glutamate transmission dysfunctiion 30% symptoms 70% Symptoms
  23. 23. Alzheimer’s Staging:
  24. 24. Management :Dementia Reduce Cognitive Symptoms Reduce Behaviour Symptoms Slow disease progression Delay the Onset of Disease
  25. 25. PHARMACOLOGIC MANAGEMENT OF DEMENTIA Three broad categories of dementia pharmacotherapy: Symptomatic treatment of memory disturbance Disease-modifying treatments Symptomatic treatment of behavioral disturbance
  26. 26. Symptomatic Treatment of AD . The mainstay of symptomatic treatment of AD, so far, is the cholinergic treatment strategies and most widely used, till now, are the Cholinesterase (ChE) inhibitors. . These agents •Reduce the metabolism of acetylcholine •Prolonging its action at cholinergic synapses.
  27. 27. Cholinesterase inhibitors: two classes exist for the treatment of Dementia Class Inhibit Dual ChE inhibitors – Rivastigmine Both AChE – Tacrine and BuChE Single ChE inhibitors – Donepezil AChE – Galantamine Weinstock, 1999
  28. 28. FDA-approved drugs Drug Target dose Approved for year Tacrine 40 mg/day Mild to moderate 1993 Donepezil 10 mg daily All stages 1996 Rivastigmine 6 mg twice daily or 9.5-mg patch daily All stages 2000 Galantamine target dose 24 mg daily, extended-release Mild to moderate 2001 Memantine 10 mg twice daily Moderate to severe 2003
  29. 29. TACRINE In 1993 first Drug approved for the treatment of Alzheimer's disease marketed under the trade name Cognex. Tacrine was first synthesised by Adrie Albert at the University of Sydney. Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist (parasympathomimetic).
  30. 30. Tacrine Pharmacokinetis Bioavailability 2.4–36% (oral) Protein binding 55% Metabolism Hepatic (CYP1A2) Half-life 2–4 hours Excretion Renal
  31. 31. Tacrine dose Initiation of Treatment Dose Titration Cognex® is supplied as capsules of tacrine hydrochloride containing 10, 20, 30, and 40 mg of tacrine. Cognex® brand of tacrine hydrochloride is 40 mg/day (10 mg QID). This dose should be maintained for a minimum of 4 weeks with every other week monitoring of transaminase levels beginning 4 weeks after initiation of treatment. Following 4 weeks dose to be increased to 80 mg/day (20 mg QID), providing there LFT is normal Patients should be titrated to higher doses (120 and 160 mg/day, in divided doses on a QID schedule) at 4-week intervals on the basis of tolerance.
  32. 32. Tacrine Adverse Effects Very Common >10% Common 1-10% incidence Increased LFTs Hepatitis Nausea Vomiting Diarrhea Headache Dizziness Indigestion,Belching Abdominal pain Myalgia Confusion Ataxia Insomnia Weight loss Constipation Somnolence Tremor Anxiety
  33. 33. Tacrine Overdose nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, convulsions. Atropine is a popular treatment for overdose.
  34. 34. Studies found that it may have a small beneficial effect on cognition and other clinical measures though study data was limited and the clinical relevance of these findings was unclear. Tacrine has been discontinued due to hepatotoxicity
  35. 35. DONEPEZIL In 1996, donepezil, a selective cholinesterase inhibitor, was approved for use in Alzheimer disease. marketed under the trade name Aricept by its is a centrally acting reversible acetylcholinesterase inhibitor devoid of peripheral cholinomimetic adverse effects.
  36. 36. Pharmacokinetics Bioavailability 100 (%) not affected by the time of day or food intake Protein binding 96% Half-life 70 hours peak plasma concentration is reached in 3 to 5 hours. It is extensively metabolized by the hepatic isoenzymes CYP2D6 and CYP3A4. minimally affected by hepatic or renal disease and no dose adjustment is necessary for these conditions.
  37. 37. Dosage In mild to moderate A D Moderate to severe AD Disease, a starting dose of 5 mg given once daily should be used. a minimum of four to six weeks, an increase to 10 mg is recommended. The usual dose is 5 to 10 mg once daily. indicates the same regimen, but in a minimum of three months, a patient may receive a dose of 23 mg once daily. The maximum daily dose is 23 mg once daily. In the UK, the maximum licensed dose is 10 mg
  38. 38. DONEPEZIL CONTRAINDICATIONS ADVERSE EFFECTS cardiac disease, cardiac conduction disturbances, chronic obstructive pulmonary disease, asthma, severe cardiac arrhythmias and sick sinus syndrome. gastrointestinal disorders should use caution because nausea or vomiting may occur. predisposition to seizures should be treated with caution. Common side effects include bradycardia cardiac conduction disturbances nausea, diarrhea, anor exiaabdominal pain vivid dreams and Several cases of mania induced by Donepezil have been reported
  39. 39. Clinical Trials of Donepezil Study (Rogers et al 1996). Double-blind, placebo-controlled, 30-week, parallel study involving 450 patients with Alzheimer disease Results Significant improvement on cognitive and clinical global assessments. Study (Rogers and Friedhoff 1996). Dose-ranging study on 161 patients with mild to moderate Alzheimerdisease who received donepezil 1, 3, or 5 mg, or placebo, daily for 12 weeks Results Patients who received donepezil 5 mg showed significant improvement in the Alzheimer Disease Assessment Scale Cognitive Subscale.
  40. 40. Clinical Trials of Donepezil Study (Doody et al 2009) A 48-week, randomized, placebo-controlled trial of donepezil for treatment of patients with mild cognitive impairment Results Donepezil produced small but significant improvement on the primary measure of cognition, but there was no change on the primary measure of global function Study (Farlow et al 2011). A pivotal phase 3 study of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d Results Good safety and tolerability profile of donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe Alzheimer disease.
  41. 41. Rivastigmine (Rx) - Exelon Mechanism of Action PHARMACOKINETICS Reversible acetylcholinesterase inhibitor that causes an increase in concentrations of acetylcholine, which in turn enhances cholinergic neurotransmission Absorption Bioavailability: 36% (PO) Duration: 10 hr (PO); 24 hr (patch) Peak plasma time: 1 hr (PO); 8 hr (patch) Distribution Protein bound: 40% Vd: 1.8-2.7 L/kg Metabolism Metabolized by cholinesterase Elimination Half-life: 1.5 hr (PO), 3 hr (patch) Total body clearance: 1.2-2.4 L/min Excretion: Urine (97%)
  42. 42. Rivastigmine - Adverse effects common UNCOMMON Nausea (PO 47%; patch 21%) Vomiting (PO 31%; patch 6- 19%) Dizziness (PO 21%; patch 2- 7%) Diarrhea (PO 19%; patch 6- 10%) Headache (PO 17%; patch 3- 4%) Anorexia (PO 17%; patch 3- 9%) Abdominal pain (PO 13%; patch 2-4%) Decreased weight (3-8%) Insomnia (PO 9%; patch 1-4%) Anxiety (PO 5%; patch 3%) Asthenia (PO 6%; patch 2-3%) Vertigo (2%) Fatigue (2%)
  43. 43. Rivastigmine Cautions Renal impairment Hepatic impairment Sick sinus syndrome Conduction abnormalities. H/O Asthma or COPD Pregnancy .
  44. 44. Transdermal Patch Technology: Reservoir versus Matrix Backing Drug Reservoir Nitti VW, et al Urology. 2006;67:657–64 Backing Drug + Polymer + Adhesive Drug contained in adhesive layer along with polymer Smaller and thinner than reservoir patches Reservoir Matrix Drug contained in separate layer, with a rate-controlling membrane Matrix Diffusion Controlled Patch Release Liner Rate-Controlled Reservoir/Membrane Patch Dermal Layer Release Liner Adhesive Layer
  45. 45. Exelon Transdermal 9.5 mg/24 h Patch
  46. 46. Where to Apply Exelon Patch Apply to: Upper and lower back Upper arm Chest The skin should be clean, dry and hairless before the patch is applied Normal daily activities, such as bathing, are permitted 1Lefèvre G, et al. J Clin Pharmacol 2007;47:471–8.
  47. 47. Exelon Transdermal Patch: Smooth Continuous Delivery Through the Skin Exelon 9.5 mg/24 h patch Exelon 6 mg BID capsule Plasma concentration (ng/mL) 25 20 15 10 5 0 0 6 12 18 24 Time (hours) Exelon 9.5 mg/24 h patch delivered comparable average concentrations (AUC) to those provided by an oral dose of 6 mg BID (12 mg/day)* * Model-predicted analysis based on actual patient data corrected for body weight.
  48. 48. Starting transdermal ChEI therapy Rivastigmine 4.6 mg/24 h patch Rivastigmine 9.5 mg/24 h patch One-step dose increase 4 weeks Starting dose Target dose
  49. 49. Clinical trials Rivastigmine Study (Burns et al 2004) A retrospective analysis of pooled data from 3 randomized, placebo-controlled, double-blind, 6- month trials involving 2126 patients with Alzheimer disease suggests that rivastigmine 6 to 12 mg/day may benefit subjects with more severe disease as well as subjects with mild to moderate impairment In an open-label, comparative study of rivastigmine with donepezil and galantamine, there were no statistically significant differences between the 3 drugs at 3 months (Aguglia et al 2004). In a placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson disease but also with higher rates of nausea, vomiting, and tremor (Emre et al 2004).
  50. 50. Clinical trials Rivastigmine Results of a 6-month, double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer disease shows that the patch provides efficacy similar to the highest doses of capsules with a superior tolerability profile and may offer convenience important to many caregivers and patients (Winblad et al 2007). A retrospective analysis of a large randomized, placebo-controlled trial of Alzheimer disease patients treated with transdermal rivastigmine or rivastigmine capsule compared to placebo showed greatest treatment effects in patients with more advanced dementia who received rivastigmine, and these were considered to be most likely due to greater decline in the patients treated with placebo (Farlow et al 2011).
  51. 51. Galantamine (Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine) It is an alkaloid that is obtained synthetically or from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop) Galantamine hydrobromide was approved in 2001 by the FDA Indicated for the treatment of mild to moderate dementia IN Alzheimer's.
  52. 52. Galantamine-MOA weak competitive and reversible choline sterase inhibitor in all areas of the body. It increases the concentration and thereby action of acetylcholine in certain parts of the brain. It has shown activity in modulating the nicotinic cholinergic receptors on cholinergic neurons to increase acetylcholine release.
  53. 53. Pharmacokinetics Galantamine DOSAGE Bioavailability - 80 to 100% Protein binding- 18% Metabolism-Hepatic Half-life-7 hours Excretion - Renal (95%, of which 32% unchanged), fecal (5%) in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution. The tablets come in 4 mg, 8 mg, and 12 mg forms. The capsules come in 8 mg, 16 mg, and 24 mg forms.
  54. 54. Clinical Trials with Galantamine Study (Raskind et al 2004). Patients with mild-to-moderate Alzheimer disease who had been randomized to galantamine therapy in previous trials received open-label continuous galantamine therapy for up to 36 months(Raskind et al 2004). Results Cognitive decline over 36 months with continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients. Study (Suh et al 2004) Prospective, randomized multicenter, double-blind study of patients with mild-to- moderate Alzheimer disease: dose 8 mg/day, 16 mg/day, or 24 mg/day ). Results All dose schedules were well tolerated with significant improvements in all 3 treatment groups.
  55. 55. Galantamine-Adverse effects common Rare Nausea, vomiting,Diarrhea, abdominal pain, upper abdominal pain, dyspepsia, stomach discomfort, abdominal discomfort Bradycardia,First degree atrioventricular block, palpitations, sinus bradycardia, supraventricular extrasystoles, flushing, hypotension Dizziness, headache, tremor, syncope, lethargy, somnolence Blurred vision confusion decreased urination dizziness, faintness, or lightheadedness dry mouth fainting fast, irregular, pounding, or racing heartbeat or pulse feeling of warmth rapid breathing redness of the face, neck, arms, and occasionally, upper chest sunken eyes,sweating, thirst
  56. 56. Memantine Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA receptor. Memantine is approved by the U.S. F.D.A and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease
  57. 57. Memantine Pharmacokinetic MOA Bioavailability~100% Metabolism- Hepatic (<10%) Half-life- 60–100 hours Excretion - Renal Memantine is a low-affinity voltage dependent uncompetitive antagonist at glutamatergic NMDA receptors non-competitive antagonist at the 5-HT3 receptor, this serotonergic activity in the treatment of Alzheimer's disease is unknown.
  58. 58. Memantine -Adverse effects Common Less common confusion, dizziness, drowsiness, headache, insomnia, agitation hallucinations. vomiting, anxiety, hypertonia cystitis, increased libido rare extrapyramidal side effects(such as dystonic reactions etc.) may occur, in particular, in the younger population
  59. 59. Clinical trials Memantine The M-Best Study The M-Best Study (Benefit and Efficacy in Severely demented patients during treatment with memantine) was a double-blind, placebo-controlled, phase III trial of memantine conducted in Sweden on care-dependent patients with severe dementia (Winblad and Poritis 1999). The trial population consisted of 161 patients, 51% with vascular dementia and 49% with Alzheimer disease. Treated patients were given 10 mg memantine per day for 12 weeks, and evaluation was done using Clinical Global Impression of Change by the physician and Behavioral Rating Scale for Geriatric Patients by the nursing staff. The results supported the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.
  60. 60. The DOMINO-AD clinical trial This study looked at 295 people with moderate to severe Alzheimer's disease All of the study participants had been prescribed donepezil for at least three months, and had been taking a dose of 10mg for at least the six weeks prior to the trial. The trial lasted for 52 weeks. Participants were divided into four different groups and were each given two drugs. These groups were: donepezil and memantine donepezil and placebo memantine placebo donepezil and memantine placebo donepezil and placebo memantine Standardised Mini- Mental State Exam (SMMSE) and their abilities in daily life using the Bristol Activities of Daily Living Scale (BADLS). All of these measures were taken at the start of the study, after six weeks, at 18 weeks, at 30 weeks and finally after 52 weeks.
  61. 61. The DOMINO-AD clinical trial RESULTS There were benefits to cognitive function of taking donepezil (about 32% less cognitive decline than those on placebo). Memantine also showed these benefits, although smaller (about 20% less decline than those on placebo). Compared to placebo, memantine led to fewer behavioural symptoms developing, showing about 83% fewer symptoms. The functional benefits of continuing donepezil showed about 23% less deterioration than those on placebo. The functional benefits of memantine were about 11% less deterioration than those on placebo. There were also small reductions in caregivers' psychological symptoms with either of the drugs, although these were not large enough to be measured reliably with statistics. Combined treatment with both donepezil and memantine was not better than treatment with donepezil alone for any of the measures.
  62. 62. RCT of donepezil &/or memantine &/or placebo in patients with moderately severe/severe AD (MMSE 5-13) who have been on donepezil for at least 12 months Howard et al 2012
  63. 63. RESULTS DELAY OF PROGRESSION: Duration Memantine alone 2-3 years Memantine + Ch E 5-6 years inhibitors Ch E Inhibitors alone 1.5 years
  64. 64. TREATMENT OPTIONS IN DEMENTIA AD VaD FTD LBD DONEPEZIL ChE Inhibitors No ChE inhibitors ChE inhibitors RIVASTIGMIE HMG CoA SSRI SSRI GALANTAMINE Stroke Prevent Antipsychotics Memantine MEMANTINE Memantine Memantine Levodopa SSRI Antipsychotic Avoid Antipsychot ics
  65. 65. Disease-Modifying Agents Proposed or unregulated drugs which require further studies Selegeline Vit-E Oestrogen Prednisolone NSAIDs Ginkgo biloba Statins IVIg Glycogen syntehtase kinase 3 (GSK 3) β-secretase inhibitors γ-secretase inhibitors α-secretase enhancers Immunotherapy
  66. 66. Disease-Modifying Agents Vitamin E  Limits free-radical formation, oxidative stress and lipid peroxidation  Promotes survival of cultured neurons exposed to beta amyloid  Clinical trials have not be overwhelmingly convincing Selegiline  MAO-B inhibitor, increases brain catecholamines  Also has antioxidant properties  Clinical trials – alone and in combination with Vit. E not effective
  67. 67. Disease-Modifying Agents Anti-Inflammatory drugs  Pathophysiological studies demonstrate a marked inflammatory reaction induced by amyloid with microglial activation and cytokine release  Case-control studies of subjects taking NSAIDs regularly for arthritis demonstrate a reduced odds-ratio for developing AD  Recently developed NSAIDS currently in clinical trials of AD Estrogen  Body of preclinical evidence that estrogen enhances cerebral blood flow, prevents atrophy of cholinergic neurons, reduces oxidative stress, and modulates the effects of nerve growth factors
  68. 68. Disease-Modifying Agents Statins  Direct association between amyloid processing and cholesterol in the brain  An indirect effect via decreasing the risk of stroke, since even small vascular lesions worsen the severity of Alzheimer's disease Ginkgo Biloba  A single placebo-controlled trial with an extract of ginkgo biloba showed a very modest improvement on cognitive testing  Only 50 percent of the treatment group completed the trial  Use of ginkgo not recommended due to limited efficacy and lack of regulation, including variability in the dosing and contents of herbal extracts
  69. 69. Disease-Modifying Agents Idebenone  Synthetic analogue to Co-Q10, known to have anti-oxidant properties  Controlled clinical trials have shown modest improvement in cognitive function with highest doses  Side effects including liver enzyme abnormalities (non-serious) along with predominant G-I upset Negative trials  Propentofylline (stimulates synthesis and release of NGF)  Acetyl-L-carnitine (promotes ACh release, increases acetyltransferase activity, has antioxidant properties)
  70. 70. The amyloid cascade hypothesis & drugs in clinical trials Statins - promotes alpha secretase Flurizan - modulates gamma secretase Lilly - inhibits gamma secretase Alzhemed - anti-fibrillar Active and passive immunisation ? Adapted from Biochem. Soc. Trans. (2005) 33, 553-558
  71. 71. Active and passive beta amyloid immunisation against AD Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation. In human trials, this approach led to life-threatening complications, including meningoencephalitis modifications of the vaccine approach using passive immunization with monoclonal antibodies are currently being evaluated in phase 3 trials.
  72. 72. Bapineuzumab (anti-amyloid antibody)
  73. 73. Bapineuzumab (anti-amyloid antibody) “I think the data are pretty clear from this trial that bapineuzumab is not effective for mild to moderate dementia, and the company was wise to stop the ongoing trials in that population,” said Salloway, who leads one of the trial sites. Another antibody (solanezumab) also showed cognitive & functional benefit in mild AD.results awaited
  74. 74. Behavioral Problems in AD  depression (occurs in 20-40% - esp. AD and VaD)  psychosis (occurs in 30- 50%) - usually see paranoid delusions (theft, infidelity)  wandering/purposeless activity  agitation/threatening behavior  sleep disturbances  delirium - minor insults can lead to major decompensations
  75. 75. Depression and Alzheimer’s Common early in the course of the illness Incidence 40-50% Use SSRIs first; avoid anticholinergic antidepressants ECT can be helpful but may temporarily worsen cognitive symptoms
  76. 76. Treatment of Depression Recognize that irritability and/or apathy /withdrawal may be indicative of depression Allow patient choices and control Identify pleasurable activities (such as singing old songs, pet therapy, etc.) Cognitive enhancers (e.g. Aricept) may help
  77. 77. Agitation Non-aggressive  verbal: complaining, constant requests for attention, repetition of words, constant talk, screaming  physical: pacing, disrobing, stereotypies, trying to get to a different place Aggressive  Verbal: threats, name calling, obscenities  Non-verbal: biting, scratching, spitting, kicking, pushing, swinging fists
  78. 78. Medications for Agitation Buspirone – Takes a while to work Antidepressants (SSRIs, Trazodone) Anticonvulsants (esp. valproate) Atypical Antipsychotics (stroke risk concerning) Low dose narcotics? Estrogen?
  79. 79. Treatment of Psychosis Traditional antipsychotics  Low potency (chlorpromazine)– orthostasis, sedation, anticholinergic  High potency (haloperidol)– EPS/TD but otherwise well tolerated New generations drugs (e.g. olanzapine, quetiapine, risperidone)- less EPS/TD but still see anticholinergic, BP and sedative effects
  80. 80. Treatment of Insomnia Sleep hygiene (avoid caffeine, etc.) Treat causative psychiatric or medical disorders Phsysiological remedies - melatonin, warm milk, lavendar oil Medications - Benadryl, benzos, sedating antidepressants or antipsychotics (all these drugs can make memory and confusion worse) Light Therapy - to reset natural circadian rhythms for sleep
  81. 81. Use of Atypical Antipsychotics Older, “typical” agents such as haloperidol and thioridazine (mellaril) associated with significant extrapyramidal symptoms Theoretically combination of dopamine and serotonin effects of atypical agents allow treatment of positive and negative psychotic symptoms with less EPS
  82. 82. Risperidone Evidence demonstrates efficacy in treatment of psychotic and behavior symptoms in patients with dementia Exacerbates movement disorder in patients with Parkinson’s Start .25/day, average daily dose 1-1.5mg/day EPS in dose dependent manner (6mg/day) Insomnia, hypotension, weight gain Elevation of prolactin levels
  83. 83. Olanzapine Evidence that it is effective in AD patients Increases motor symptoms in PD patients Recommended not to use with PD Start: 1.25-2.5/day, increase to 5/day (dosages of 10-15/day are not more effective!) More sedating than others (more anticholinergic effects) Sedation, weight gain, orthostatic hypotension, seizures, glucose intolerance
  84. 84. Quetiapine Showing promise in patients with AD and PD Does not exacerbate movement disorder of PD May be first line for PD patients with psychosis 12.5 QHS, titrate every 3-5 days Sedation, HA, orthostatic hypotension ?Cataract formation
  85. 85. Ziprasidone New, clinical data lacking Non dose-dependent QT prolongation
  86. 86. Clozapine Very effective in treating psychosis in PD patients The most effective agent in treatment of drug induced psychosis in PD Some efficacy with AD patients Start: 6.5mg/day Agranulocytosis, frequent monitoring limits use
  87. 87. Caregiver Burden Alzheimer’s caregivers spend an average of 69 to 100 hours per week providing care Caregivers of patients suffering from dementia(compared to control subjects) reported:  46% more physician visits  Over 70% more prescribed drugs  More likely to be hospitalized More than 50% of caregivers are at risk for clinical depression
  88. 88. Behavioral Strategy Scheduled toileting, prompted voiding for incontinence. Graded assistance, & positive reinforcement to increase functional independence Music, esp. during meals, bathing Walking , Light Exercise
  89. 89. Other Drugs in the Pipeline Tau protein modulators (to prevent abnormal phosphorylated ‘tau’ protein Bryostatin – drug that stimulates brain protein production. Reduces B-amyloid levels in mice, enhances memory and learning. New generation NSAIDS (flubiprofen) – testing in humans looks promising Immune enhancers (immunoglobulin) New vaccines and new anticholinesterases (huperzine A) LADOSTIGIL-multimodal drug
  90. 90. Dementia and clinical trials Where next? Disease modifying drugs need to start early  Much of the damage been done by the time the patient presents with dementia We need to consider new targets  Is amyloid the cause, or just a byproduct? What about tau? What about inflammation? We need to have better outcome measures  Current assessments do not always reflect outcomes that matter to patients and families. We need more patients to enter clinical trials  Recruitment into dementia clinical trials is a fraction of the number entering cancer trials
  91. 91. Take Home Points Cholinesterase Inhibitors are MODESTLY effective in treatment of mild to moderate AD Cholinesterase Inhibitors are probably effective in more severe AD No large difference in efficacy between agents, but Donepezil more easily titrated and tolerated Evidence to support use of cholinesterase inhibitors for vascular and vascular/AD dementia Memantine looks to be effective for more severe AD and vascular dementia, will likely be used in combination with cholinesterase inhibitors

×