Alzheimers disease

what is AD, AD and brain, two major hypothesis for AD, classification of anti-alzheimers disease

1. ALZHEIMER’S
DISEASE
Presented by
Miss. Ashvini Vijay Govande
Assistant Professor
Kandhar College of Pharmacy, Kandhar

2. AlthoughtheriskofdevelopingADincreaseswithage–in
mostpeoplewithAD,symptomsfirstappearafterage60–
ADisnotapartofnormalaging.Itiscausedbyafatal
diseasethataffectsthebrain.
Alzheimer’sdiseaseisanirreversible,progressivebrain
diseasethatslowlydestroysmemoryandthinkingskills.
What is AD?
Slide 4

3. •Plaques and Tangles
•The Changing Brain in AD
AD and the Brain
Slide 15

4. Plaques and Tangles: The Hallmarks of AD
The brains of people with AD have an abundance of two
abnormal structures:
An actual AD plaque An actual AD tangle
•beta-amyloid plaques, which are dense deposits of protein and
cellular material that accumulate outside and around nerve
cells
•Neurofibrillary tangles, which are twisted fibers that build up
inside the nerve cell
AD and the Brain
Slide 16

5. Two Major Hypotheses for AD:
b amyloid protein (BAP) v. tau
1.BAPtists:
Theaccumulationofafragmentoftheamyloidprecursor
proteinorAPP(theamyloidbeta42residuefragment)leadsto
theformationofplaquesthatsomeonekillneurons.
2.TAUists:
Abnormalphosphorylationoftauproteinsmakesthem
“sticky,”leadingtothebreakupofmicrotubules.Theresulting
lossofaxonaltransportcausescelldeath.

6. Amyloid Hypothesis
(it’s the plaques)
1.Theamyloidprecursorprotein(APP)isbrokendownbyaseriesof
secretases. .
2.Duringthisprocess,anon-solublefragmentoftheAPPprotein
(calledAb-42)accumulatesandisdepositedoutsidethecell.
3.Thenon-solubleor“sticky”natureofAb-42helpsotherprotein
fragments(includingapoE,apolipoproteinE)togatherinto
plaques
4.Somehowtheplaques(orpossiblethemigrationofAb-42outside
thecell)causeneuronaldeath.

7. Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or
Ab.

8. Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell,
forming the plaques seen in the AD brain.

9. ba gg
APP Protein:
a-secretase cuts APP protein, giving:
g-secretase cuts this residue, giving:
or
Soluble
Soluble
a-secretase Pathway:

10. ba gg
APP Protein:
(1)b-secretase cuts APP protein, giving:
(2)g-secretase cuts this residue, giving:
or
Ab40Fragment
Soluble
Ab42Fragment
Un-soluble,
aggregates into
plaques
b-secretase Pathway:
(not drawn to scale)

11. Tau Hypothesis
(it’s the tangles)
1.Ordinarily,thetauproteinisamicrotubule-associatedproteinthat
actsasathree-dimensional“railroadtie”forthemicrotubule.The
microtubuleisresponsibleforaxonaltransport.
2.Accumulationofphosphateonthetauproteinscause“paired
helicalfilaments”orPHFs(liketworopestwistedaroundeach
other)thataccumulateandleadtotheneurofibrillarytangles
(NFT).PHFsarethemaincomponentinNFTs.
3.Impairedaxonaltransportistheprobablecauseofcelldeath.
4.FocusonMAPTgene(microtubule-associatedproteintau)

12. Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins
act as “ties” that stabilize the structure of the microtubules. In AD, tau proteins become
tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell
death.

13. Preclinical AD
SignsofADarefirstnoticed
intheentorhinalcortex,then
proceedtothehippocampus.
Affectedregionsbeginto
shrinkasnervecellsdie.
Changescanbegin10-20
yearsbeforesymptomsappear.
Memorylossisthefirstsign
ofAD.
AD and the Brain
Slide 20

14. Mild to Moderate AD
ADspreadsthroughthebrain.The
cerebralcortexbeginstoshrinkas
moreandmoreneuronsstop
workinganddie.
MildADsignscanincludememory
loss,confusion,troublehandling
money,poorjudgment,mood
changes,andincreasedanxiety.
ModerateADsignscaninclude
increasedmemorylossand
confusion,problemsrecognizing
people,difficultywithlanguage
and thoughts,restlessness,
agitation,wandering,andrepetitive
statements.
AD and the Brain
Slide 21

15. Severe AD
InsevereAD,extremeshrinkage
occursinthebrain.Patientsare
completelydependentonothersfor
care.
Symptomscanincludeweightloss,
seizures,skininfections,groaning,
moaning,orgrunting,increased
sleeping,lossofbladderandbowel
control.
Deathusuallyoccursfrom
aspirationpneumoniaorother
infections.Care-giverscanturntoa
hospitalforhelpandpalliative
care.
AD and the Brain
Slide 22

16. Classification of Anti-Alzheimer’s agents
Anti-Alzheimer’s agents are the agents which improve the
function of dementia and loss of cognitive abilities.
Slide 5
Reversible
Acetylcholinesteraseinhibitor
Antialzheimer’s
NonselectiveSelective
Rivastigmine
Galantamine
Donepezil
Tacrine Memantine

17. Rivastigmine
Itiscarbamatederivatives
Itisparasympathomimeticsorcholinergicagentforthe
treatmentofmildtomoderatedementia.
MOA-
ItinhibitstheenzymesbothButerylcholinesterase
(BuChE)andacetylcholinesterase(AChE)presentinCNS
Itpreventthehydrolysisofacetycholine,andthus
leadingtoanincreasedconcentrationofacetylcholineat
cholinergicsynapses.
Acetycholineisanimportantneurotransmiterinbrain
regioninvolvedinmemory
Slide 6

18. Side effect-
Nausea,vometing,decreasedappetite,weightloss,bloodyandtarry
stools,coughingupbloodorvomitthatlookslikeblood,feeling
light-headed,fainting,chestpain,confusion,agitationandextreme
fear.
Pharmacokinetics-
Wellabsorbedorally
Bioavailabilityofabout40%in3mgdose
Eliminationthroughurine
Uses-
Fortreatmentofalzheimerdisease
Slide 9
Continue...

19. Itisbenzazepinederivedfromnorbelladine
Itischolinesteraseinhibitorthathasbeenusedtoreservethe
musculareffectsofgallaminetriethiodideandtubocurarine
MOA-
Itinvolvethereversibleinhibitionofacetylcholinesteras,
whichpreventsthehydrolysisofacetylcholine
Leadstoincreaseinconc.ofAchatcholinergicsynapses
Itbindsallostericallywithnicotinicacetylcholinereceptor
andmaypotiantiatetheactionofagonists(suchasAch)at
thesereceptor
Galantamine
Slide 10

20. Itisacentrallyactingreversibleacetylcholinesterase
inhibitor
Itispiperdinederivative
MOA-
Itinvolvethereversibleinhibitionofacetylcholinesteras,
whichpreventsthehydrolysisofacetylcholine
Leadstoincreaseinconc.ofAchatcholinergicsynapses
Donepezil
Slide 11

21. Itiscentrallyactivecholinesteraseinhibitorthathasbeen
usedtocountertheeffectsofmusclerelaxant,respiratory
stimulantandintreatmentofalzheimerdiseaseandother
CNSdisorder
MOA-
Mechanismisnotfullyknown
Butitisproposedthatthedrugisananticholinesterase
agentwhichreversiblybindswithandinactivates
cholinesterase
ThisinhibitthehydrolysisofAch,thusleadingtoan
accumulationofAchatcholinergicsynapse
Uses-totreatmildtomoderatedementiaofAD
Tacrine
Slide 12

22. Itisanamantadinederivativewithlowtomoderateaffinity
forNMDAreceptor.
ItisnoncompetitiveNMDAreceptorantagonistthatbinds
preferentiallytoNMDAreceptor-operatedcationchannel
Itblockstheexcessivelevelofglutamatethatmayleadsto
neuronaldysfunction.
MEMANTINE
Slide 13

23. MOA-
ContinuousactivationoftheN-methyl-D-aspartate(NMDA)receptorsin
thecentralnervoussystemcausedbyglutamateisthoughttocausesome
oftheAlzheimer'sdiseasesymptoms.Thisoveractivationisthoughtto
contributetoneurotoxicityduetotheexcitatorypropertiesofglutamate.
Thepharmacologicaleffectofmemantinelikelyoccursviathedrug's
behaviorasanuncompetitive(open-channel)NMDAreceptorantagonist,
preventingglutamateactiononthisreceptor.
MemantinehasapreferencefortheNMDAreceptor-operatedcation
channels.Despitetheseantagonisteffects,memantinehasnotbeenproven
topreventorretardtheneurodegenerationseeninpatientsdiagnosedwith
Alzheimer’sdisease
Continue...
Slide 16

24. Continue...
Pharmacokinetic-
Wellabsorbedorally
Bioavailabiltyapproximately100%
Peakplasmaconc.Arereachedin3-7hrs
Foodhasnoeffectonabsorption
Volumeofdistributionis9to11L/kg
Proteinbinding45%
Excreatedthroughurine.

25. Thank you