ic14 AD/PD pharmacology Flashcards
define parkinsons disease and epidemiology
progressive neurodegenerative disease
with extrapyramidal motor symptoms (tremors, rigidity, bradykinesia) due to striatal dopaminergic deficiency
avg onset age early-mid 60s
Young onset: 21-40 (5-10%)
juvenile onset: before 20 years, usually associated with genetically inherited PD.
what are the motor symptoms of PD
tremor at rest (pill rolling)
bradykinesia (slowness of movement)
rigidity (cogwheeling)
^ above 3 are the cardinal features of PD.
postural instability and gait disturbance
PD disease course
from initial motor fluctuations, and dyskinesias to
non-motor symptoms = falls, postural instability, postural hypotension, confusion, dementia, suboptimal nutrition, speech, sleep disorders… 1
pathophysiology of PD
impaired clearing of abnormal/damaged intracellular proteins by the ubiquitin proteasomal system.
= (i) apoptosis of surrounding cells
= (ii) accumulation of aggresomes (lewy bodies) = degeneration of dopaminergic neurons in substantial nigra = dysfunction of nigrostriatal pathway (no release of inhibition = hypokinetic state)
- basal ganglia involved in motor control and stops the continuous firing of motor signals
- involves both excitatory D1 and inhibitory D2 receptors
synthesis and breakdown of dopamine
L tyrosine –> L dopa via tyrosine hydroxylase
L dopa –> dopamine via DOPA decarboxylase
breakdown
dopamine –> homovanilic acid via catechol-o-methyltransferase, COMT, MAO.
which are dopamine receptors in the basal ganglia
D1 and D2
BBB for dopamine and others…
dopamine passes through the BBB while L-dopa does not.
what is the gold standard of treatment for pD
LEVODOPA
synthetic L DOPA
what combination products with levodopa?
DOPA decarboxylase inhibitors
eg
benserazide, carbidopa
peripheral DOPA decarboxylase inhibitor to prevent systemic side effects of excess DA in the periphery
(a lot of L DOPA gets wasted in the periphery and less goes to the brain)
levodopa side effects
short term: N/V, postural hypotension
long term: motor fluctuations, dyskinesia
adjunct to levodopa? MOA and how it helps
COMT inhibitors:
entacapone, tolcapone
blocks COMT conversion of dopamine to the inactive form
increases duration of each dose of levodopa
side effect of COMT inhibitors
1) increase abnormal movements (dyskinesia)
2) daytime drowsiness, sleep disturbance
3) urinary discolouration
4) visual hallucination
5) nausea, diarrhoea
specific to tolcapone: liver dysfunction
another method to inhibit dopamine breakdown
MAO-B inhibitor
selegiline, rasagiline
side effects of MAO-B inhibitors
heartburn, loss of appetite
anxiety, palpitation, insomnia
nightmares, visual hallucinations
dopamine agonist agents (list, moa)
pramipexole
pergolide
ropinirole
act directly on dopamine receptors in the brain to reduce PD symptoms
when should dopamine agonists be used first line
for younger PD patients to prevent or delay onset of motor complications with use of levodopa
dopamine agonist side effects
common: n/v, orthostatic hypotension, headache, dizziness, cardiac arrhythmia
specific to pergolide: peritoneal fibrosis, cardiac valve regurgitation
specific to pramipexole and ropinirole: sedation, somnolence, daytime sleepiness
MOA of amantadine (and indication)
monotherapy or adjunct
moa:
- enhance release of stored dopamine,
- inhibit presynaptic uptake of catecholamine
- dopamine receptor agonist
- NMDA receptor antagonist (anti-glutamate)
mild antiparkinsonian effect (antidyskinetic)
side effects of amantadine
cognitive impairment (inability to concentrate)
hallucination
insomnia
nightmares
livedo reticularis (venule swelling due to thromboses = mottled reticulated discolouration of limbs)
moa of trihexyphenidyl
anticholinergic
adv: may be effective in controlling tremors, peripherally acting agents useful in treating sialorrhoea (excessive saliva flow)
side effects of trihexyphenidyl
especially in e;derly
- dry mouth, constipation, sedation, urinary retention, delirium, confusions, hallucinations
what is AD characterised by?
senile plaques
neurofibrillary tangles
brain atrophy (in areas critical to cognition eg neocortex, hippocampus)
neuronal death (neurodegeneration) of neurotransmitter systems
methods for AD clinical diagnosis
1) patient history
2) cognitive deficits via mini MSE, neuropsychological tests
3) functional deficits
4) absence of alternative conditions
4) CSF and blood biomarkers of Aβ and pTAU (not routine)
IF VERY SYMPTOMATIC = neuroimaging via CT, MRI
what is the treatment drugs for mild to moderate dementia?
AChEIs
acetylcholinesterase inhibitors
DONEPEZIL
GALANTAMINE
RIVASTIGMINE
inhibit the breakdwon of ACh to choline and acetate in the synpatic cleft
compare between galantamine and rivastigmine (formulation, Half life, additional MOA, metabolism)
FORMULATION
galantamine: oral and transdermal
rivastigmine: oral only
T1/2
galantamine has longer half-life
ADDITIONAL MOA
galantamine may also act on nicotinic receptors
METABOLISM
galantamine is metabolism by CYP (LIVER) while rivastigmine is metabolised by the KIDNEYS.
side effects of AChEIs
cholinergic hyperactivation
= nausea/vomiting/diarrhoea
less common:
- MSK: muscle cramp
- CVS: bradycardia
- GI: loss of appetite, increased gastric acid secretion
memantine MOA
non competitve NMDA receptor antagonist = blocks NMDA receptor mediated excitotoxicity
SE of memantine
CNS related side effects:
- hallucination,
- confusion,
- dizziness,
- headache
