IC14 Pharmaco III (PD, AD) Flashcards
PD definition
neurodegenerative disease where nerve cell lose function over time and die, progressive, incurable, increases with age
degeneration of basal ganglion neurons causes
decrease dopamine -> PD
degeneration of neuro cortex
decrease acetylcholine -> AD
epidemiology of PD
- incidence increases with age
- avg onset: 60s
- young onset PD: 21-40yo
- juvenile onset PD: <20
motor sx of PD
TRAP (TRA - cardinal features of PD)
- tremor at rest
- rigidity (cogwheel)
- akinesia/ bradykinesia (slow movement)
- postural instability/ gait disturbances
pathophysiology of PD
- aggregation of misfolded alpha-synuclein -> form Lewy body
- failure to clear Lewy body (contains alpha-synuclein and ubiquitin)
- Effect: degeneration of dopaminergic neurons with Lewy body inclusion in the substantia nigra -> dysfunction of the nigrostriatal pathway
diagnostic test to confirm PD
Lewy body eosinophilic cytoplasmic inclusions in basal ganglia
function of substantia nigra
involved in action selection
- basal ganglia normally inhibit a number of motor sx
- substantia nigra mediated release of inhibition -> allows action to occurs
what happen when there is a loss of substantia nigra?
no release of inhibition -> hypokinetic state (decreased in motor movements)
how is dopamine synthesised endogenously?
- L-tyrosine -> L-DOPA (tyrosine hydroxylase)
- L-DOPA -> dopamine (DOPA carboxylase)
Dopamine and L-DOPA which one can pass BBB?
Dopamine - cannot pass BBB
L-DOPA - can pass BBB
Drug of choice for PD
levodopa (synthetic L-DOPA) + DCI (carbidopa/ benserazide)
Function of DCI
peripherally DOPA carboxylase inhibitor -> prevent systemic SE due to excessive dopamine
SE of levodopa
short term: N/V/ postural hypotension
long term: motor functions, dyskinesia (does not go away after discontinuation)
eg of COMT inhibitors and MOA
entacapone, tolcapone
- MOA: block COMT from breaking down dopamine/ L-DOPA to inactive form -> more levodopa enter brain
can COMT be used as monotx
no, must be taken with levodopa
SE of COMT
dyskinesia, nausea, diarrhoea, urinary discolouration, visual hallucinations, daytime drowsiness, sleep disturbances
- tolcapone: liver dysfunction
MAO-Bi eg
seligiline, rasagiline
- inhibit MAO-B that breakdown dopamine
can MAO-Bi be used as a monotx
yes for mild PD
SE of MAO-Bi
heart-burn, loss of appetite, anxiety, palpitation, insomnia, nightmares, visual hallucinations (too much dopamine)
dopamine agonist eg and MOA
ropinirole, pergolide, pramipexole, rotigotine (patch), apomorphine (SC)
- MOA: act directly on dopamine receptors to reduce sx of PD
why is dopamine agonist preferred over levodopa for young onset PD?
prevent or delay motor complications with levodopa (eg dyskinesia)
SE of dopamine agonsit
common: N/V/OH, headache, dizziness, cardiac arrhythmia
- pergolide ‘ergot’ derivative: peritoneal fibrosis, cardiac valve regurgitation
pramipexole, ropinirole: sedation, somnolence, daytime sleepiness
non-dopamine pharmacological approach for PD
amantadine and anticholinergics (trihexyphenidyl/benzhexol)
MOA of amantadine
- release stored dopamine
- inhibit presynaptic uptake of catecholamine
- dopamine agonist
- NMDA receptor antagonist
amantadine place in tx for PD
- monotx or adjunct to levodopa
- can reduce dyskinesia
SE of amantadine
cognitive impairment (inability to concentrate), hallucination, insomnia, nightmares, livedo reticularis (venule swelling due to thrombosis)
advantages of anticholinergics
- can control tremor, treat sialorrhoea/ drooling
- used as an adjunct to levodopa to treat tremors in PD
SE of anticholinergics
dry mouth, sedation, constipation, urinary retention, confusion, hallucinations
dementia vs delirium
dementia- occurs for at least 6mths
delirium <6mths
sx of dementia
cognition impairment (at least 2):
- memory
- language
- attention
- problem solving
Pathophysiology of AD
aggregation of abnormal proteins
1. senile plaques (aggregates of beta-amyloid peptides)
2. neurofibrillary tangles (aggregates of hyperphosphorylated tau proteins)
3. brain atrophy to aggregation at neuro cortex (shrinking of hippocampus)
4. neurodegeneration of neurons at cortex affecting multiple NT (acetylcholine, 5HT, glutamate)
what are the neurotransmitters affected in AD. which NT causes clinical features of AD?
acetylcholine
5HT
glutamate
- cholinergic deficits causes clinical features of AD
difference btw monoaminergic and cholinergic synapse
breakdown of acetylcholine occurs in synapse but breakdown of dopamine and 5HT occurs in presynaptic neurons after reuptake
goals of tx for AD
delay need to institutionalise, improve QOL for both patients and caregivers
pharmacological tx for AD
AChEI, NMDA receptor antagonist
Eg of AChEI and MOA
donepezil (best), rivastigmine, galatamine
- MOA: inhibit AChE -> increase ACh in synapse
rivastigmine vs galatamine (tested)
- rivastigime: PO, patch, shorter half life, metabolised by kidneys
- galatamine: PO, longer half life, also act on nicotinic receptors, metabolised by liver
SE of AChEI (tested)
Cholinergic hyper-activation: N/V/D
less common: (parasympathetic -> rest and digest) muscle cramp, bradycardia, loss of appetite, increase gastric acid secretion
which AChEI can be used for moderate AD?
donepezil, rivastigmine, galantamine
which AChEI can be used for severe AD?
donepezil
memantine MOA, indication
non competitive NMDA receptors antagonist -> block excitotoxicity
- for moderate to severe AD
mx of BPSD
prescribe the lowest dose possible to alleviate sx and adjust dosage as necessary
