ANTI DEMENTIA DRUGS

MODERATOR: DR. RAMASUBBAREDDY SIR

PRESENTER: DR. RAVIKISHORE
PLAN OF PRESENTATION
OBJECTIVES
INTRODUCTION
TREATMENT MODALITIES
SUMMARY
OBJECTIVES
Understand the use of cholinesterasse inhibitors in
the treatment of Alzheimers type, Vasular, Dementia
with Lewy body, mild cognitive impairment, and other
dementias
Review the current literature regarding the use of
Cholinesterases, Memantine for severe dementia.
Review the appropriate use of antipsychotics for
psychosis and behavioral symptoms in dementia.
Discuss possible means of preventing dementia.
INTRODUCTION
Dementia is a progressive syndrome affecting around 5% of
those aged over 65yrs and increases to 20% in those aged over
80yrs.
Characterized by cognitive decline, memory disturbances, and
thinking. associated with gradual loss of skills needed to carry
out activities of daily living.
Most common cause of dementia is Alzheimers disease (AD)-
60%.
Vascualr dementia and Dementia with Lewy bodies are
responsible for most other cases.
Dementia also present in 30-70% of patients with Parkinsons
disease.
ALZHEIMERS DISEASE
CHOLINERGIC HYPOTHESIS: Cognitive deterioration in AD
mainly results due to cholinergic neuronal loss and decreased levels
of acetylcholine in the brain. Hence cholinergic hypothesis states
that by restoring cholinergic levels in the brain will enhance
cognitive functioning. However, it is not solely responsible for the
symptoms of AD.
Acetylcholinesterase (AChE) inhibitors: act by above hypothesis.
3 approved drugs for mild to severe AD are Donepezil, Rivastigmine
and Galantamine.
Rivastigmine also approved for mild to moderate dementia
associated with Parkinsons disease.
Memantine: used for the treatment of Moderate to Severe
Dementia in AD.
DOSING AND FORMULATION
RIVASTIGMINE TRANSDERMAL PATCH: 9.5mg/24hrs showed superior efficay
and tolerability than oral preparation .
FDA approved DONEPEZIL SUSTAINED RELEASE (23mg) for moderate to severe
cases AD. it showed greater cogniitve benefits than 10mg/day molecule. increse in
the incidence of GI side effects found to be more with the higher doses.
Step-wise Dose escalation strategy: 5mg + 10mg once daily for 1 to 2 month.
followed by 23mg daily or 10mg and 23mg on alternate days could address the GI
side effects.
MEMANTINE EXTENDED RELEASE (28mg) once daily capsule approved in 2010.
in a large multicenter phase 3 trial found that extended realease capsule along
with cholinesterase inhibitors found improved outcome in cognition rather than
mono therapy. common adverse events were headache, diarrhoea and dizziness.
NICE (National Institute for Heath and Care Excellence) and EAN ( European
Academy of neurology) recommends combination therapy rather than mono
therapy.

TOLERABILITY
Tolerability affected by speed of titration. most side
effects were due to rapid titration. Hence, slow
titration is recommended. among all three AChE-Is
donepezil is better tolerable
orally>rivastigmine>galantamine.
Rivastigmine Patches are most tolerable than oral
preparation.
SWITCHING BETWEEN DRUGS IN
DEMENTIA
Benefits with AChE-Is are rapidly lost when drug administration is interrupted and may
not be fully regained when drug treatment is re initiated.
Poor tolerability with one agent does not rule out good tolerability with other. there are
no significant differences in efficacy between all three drugs. only difference found
being frequency and type of adverse events.
Systematic reviews suggested that in case of intolerance to one drug switching to
another agent should be done only after complete resolution of side effects following
discontinuation of the initial agent.
In case of lack of efficacy switching can be done overnight. also switching to another
agent is not benficial if no improvement noticed over several years of therapy.
switching between capsules to patches stratergy: high dose of rivastigmine
(>6mg/day) switch directly to 9.5mg/24hrs patche., while those on lower doses
(<6mg/day) should start on 4.6mg/24hrs patch for 4weeks before increasing to
9.4mg/24hrs patch. this type of switch can also be indicated for patients those on other
cholinesterase inhibitors but should have a washout periiod of 1week for susceptible
individuals with low body weight and H/o bradycardia.
ADVERSE EFFECTS
most common adverse effects reported with AchE-I were
Neuropsychiatric (31.4%), GI disorders (15.9%), and general
disorders and administration site infections (11.9%).
Caution should taken while using AChE-I’s in patients with COPD,
Asthma, Sick sinus syndrome, Supraventricular conduction
abnormalities, bladder outflow obstructions.
FDA issued warning restricting Galantamine in patients with Mild
cognitive impairment due to increased risk cardiovascular
abnormalities.
Memantine appears to be well tolerated caution should be taken in
patients with severe hepatic impairment and Epilepsy/seizures.
Isolated cases of increased INR reported when memantine
administered with warfarin.
EFFICACY OF COGNITIVE ENHANCERS USED
IN DEMENTIA
Currently no treatment exists to modify or reverse disease progession in
dementia.
All the AChE inhibitors have similar effects measured by MMSE, and Alzhiemrs
disease assessment scale- Cognitive subscale (ADAS-cog), they will help to slow
the decline in cognitive function.
Memantine: Cochrane review concluded that it had small beneficial effects at 6
months in mild to moderate cases by improving cognition in dementia due to AD
not useful in dementia due to vascular disease.
2020 study found that medication stabilised cognitive performance for 2-
5months, this effect is enhanced in
more cognitively declined patients and attenuated in those taking antipsychotics.
furthermore, those who were switched at least once tended to continue decline in
cognitive functions.
Most frequent side effects in combination therapy with donepezil and memantine
are bradycardia and convulsions.
DRUG INTERACTION
NICE RECOMMENDATIONS
OTHER TREATMENTS (less evidence)
GINKGO BILOBA: Appears to be safe with no excess side effects. overview of
systematic reviews found that beneficial effects occur when it is administered at
a doses greater than 200mg/day (240mg/day) for at least 5months. Side effect
being increased risk of bleeding.
VITAMIN E: at a dose of 2000IU/day showed improvement in ADL's in mild to
moderate cases of AD's and delayed disease progression by 6months but no
improvement notived in cognition according to RCT by TEAM-AD. but side
effects with the heacy doses increased risk of stroke, prostate cancer, heart
failure, and higher mortality.
FOLIC ACID: Recent review found that Folic acid supplementation could
improve cognition by reducing the levels of Homocysteine (Hcy), attenuating
inflammation, modification of cerebral folic acid deficiency and anti oxidation.
specifically in people with high levels of homocysteine.
FOLIC ACID and VITAMIN B 12 or B6: May help in lowering the levels of
homocysteine, however no improvement in cognition noticed.
OMEGA 3- FATTY ACIDS: No trials showed improvement in cognition, ADL's, quality
of life or mental health and also has no effects on the over all ratings of severity.
GINSENG: Open label study on 97 patients showed ginseng for a period of 12 weeks
showed significant improvement in cognitive scales (MMSE), but declined after
stopping of treatment.
DIMEBON (LATREPIRIDINE): Non-selective antihistamine, also acts as a weak
inhibitor of BuChE and AChE, weakly blocks NMDA receptor signalling pathway and
inhibits mitochondrial transitional pore opening. Recent review found that there is o
benefit in cognitive improvement in mild to moderate AD, but appeared to be modest
benefit in behavior.
HIRUDIN: isolated from a salivary glands of leech, natural direct thrombin inhibitor.
Small study done on 84 patients with donepezil alone or donepezil plus hirudin
(3g/day) found that patients on combination showed significant decrease in ADAS-Cog
scores and significant increase in ADL scores. However, hemorrhage and
hypersensitivity reactions were more found in the combination group.
HUPERZINE A: An Alkaloid isolated from chinese herb Huperzia Serrata, potent
highly selective reversible AChE-I used for treating AD. Meta analysis found that 300-
500micrograms daily for 8-24 weeks led to significant improvement in MMSE and ADL.
Most adverse effects are cholinergic in nature, no serious adverse effects noticed. It is
not useful in vascular dementia but useful in mild to moderate in cognitive function in
MCI.
CROCUS SATIVUS (SAFFRON): Recent review and meta analysis of
RCT revealed that saffron significantly improved cognitive function
measured by ADAS-Cog and Clinical Dementia Rating Scale. Saffron
useful in MCI and AD. No serious adverse events reported.
CEREBROLYSIN: Parenterally administered, porcine brain derived
peptide preparation has pharmacodynamic properties similar to
those of endogenous neurotrophic factors. 30mg/day for a period of
4 weeks to 6 months of cerebrolysin along with donepezil showed
significant improvement in cognition and global outcome. Cochrane
review in 2019 found that intravenous cerebrolysin improved
cognition and general function in people living with vascular
dementia with no significant adverse effects. Most common adverse
effects are headache, dizziness, hyper and hypotension.
STATINS: Systematic review and meta analysis found that use of
statins reduce the risk of all type of dementia, AD and MCI but not
of incident vascular dementia.
CHOCOLATE: Prospective study done on elderly age >65yrs with normal
MMSE for 48months found that chocolate intake associated with lower risk of
cognitive decline. This protective effect was observed only among subjects
with an average daily consumption of coffee <75mg.
IDALOPIRDINE: 5-HT6 receptor antagonist expressed in areas of CNS
involved in memory. Blocking these receptors induces release of Ach. Recent
review suggested that it might be effective in moderate AD groups at high
doses.
TRAZODONE: Trazodone is an antidepressant in the SSRI class, has
additional anxiolytic, hypnotic has been shown to reduce behavioral and
psychological symptoms of dementia in AD. Also enhances slow wave sleep
cycle.
DIBENZOYLMETHANE: Minor constitute of liquorice that has anti-
neoplastic effects. Efficacy against prostate and mammary tumors. Showed
significant benefits in memory deficits, prevented neurodegeneration and
significantly prolonged survival in prion diseased mice.
Both trazodone and DBM found to be neuroprotective, rescued memory
deficits and reduced hippocampal atrophy in taupathy frontotemporal
dementia mice.
NOVEL TREATMENTS
Several new drugs failed to improve clinical outcomes in phase
III trials for AD these include
Semagacestat (gamma-secretase inhibitor), Solanezumab
(humanized monoclonal antibody), Bapineuzumab (humanized
anti-amyloid beta monoclonal antibody.
ADUCANUMAB: It is an antibody works by targeting A-beta.
Thus, reduce the buildup of beta-amyloid. FDA approval
pending for the approval (march 2021).
Recently most Tau- targeting therapies are under clinical
research. 4 monoclonal antibodies – GOSURANEMAB,
TILAVONEMAB, SEMORINEMAB, and ZAGOTENEMAB and
one ANTI-TAU VACCINE (AADvac1) have reached phase II.
VASCULAR DEMENTIA
It was reported in 10-50% of dementias. Second most
common type of dementia. Caused by ischemic damage
to the brain associated with cognitive impairment and
behavioral disturbances.
Cholinesterase inhibitors Donepezil, Rivastigmine
showed some benefit in cognitive functioning, global
impression and activities of daily living.
Recent systematic review found that significant efficacy
for Donepezil, Galantamine and Rivastigmine on
cognition. Memantine was found to provide significant
efficacy on global status.
DEMENTIA WITH LEWY BODIES
Accounts for 15-25% of cases.
Characteristic symptoms dementia with fluctuation in
cognition, early and persistent visual hallucinations, and
spontaneous motor features of parkinsonism. Falls,
syncope, transient disturbances in consciousness,
neuroleptic sensitivity, hallucinations in other modality
also common.
Meta analysis showed rivastigmine, donepezil improved
cognition, global function. Memantine efficacy in DLB is
limited it is well tolerated. Might be helpful.
MILD COGNITIVE IMPAIRMENT
It is hypothesized as pre-clinical stage of dementia. It
has variable prognosis.
AchE-I’s found to be little effective in MCI, but
majority of studies suggests no intervention was
effective because of safety issues.
OTHER DEMENTIAS
Systematic reviews found that few drugs Trazodone
and SSRI’s were effective in reducing the behavioral
symptoms for Frontotemporal Dementia but none
were effective against cognition.
SUMMARY (BAP GUIDELINES)
TYPE OF DEMENTIA FIRST CHOICE SECOND CHOICE
ALZHEIMERS DISEASE AChE-I MEMANTINE
VASCULAR DEMENTIA NONE NONE
MIXED DEMENTIA AChE-I MEMANTINE
DEMENTIA WITH LEWY BODY Ach-I MEMANTINE
MILD COGNITIVE IMPAIRMENT NONE NONE
DEMENTIA WITH PARKINSONS AChE-I MEMANTINE
FRONTOTEMPORAL DEMENTIA NONE NONE