parkinson & alzheimer disease pharmacology

Question 1

what is neurodegenerative disease?

Answer 1

nerve cells in brain or PNS lose functions and ultimately die
progressive & incurable

Question 2

what is parkinson disease?

Answer 2

• Progressive neurodegenerative disease
• Extrapyramidal motor symptoms (tremors, rigidity and bradykinesia) due to striatal dopaminergic deficiency
• Various other neurotransmitters involved in non-motor symptoms (autonomic, psychiatric, sensory, ocular, gait imbalance)

Question 3

what are the motor symptoms of PD?

Answer 3

• Tremor at rest (“pill-rolling”)
• Bradykinesia (slowness of movement)
• Rigidity (“cogwheeling”)
• Postural instability and gait disturbances

Question 4

what is the pathophysiology of PD?

Answer 4

Impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomalsystem.
- Failure to clear toxic proteins –> accumulation of aggresomes –> apoptosis
- Lewybodies ≈ aggresome, containing α-synucleinand ubiquitin
- Degeneration of dopaminergic neurons with Lewybody inclusions in substantia nigra –> dysfunction of nigrostriatalpathway

Question 5

what is the function of basal ganglia?

Answer 5

motor control
Involved in “action selection”
– Normally inhibit a number of motor systems
– Substantia nigra-mediated release of inhibition permits a motor system to become active
– Involves both excitatory D1 and inhibitory D2 receptors

Question 6

how is dopamine synthesis?

Answer 6

-L-tyrosine –> L-dopa (tyrosine hydroxylase)
-L-dopa –> dopamine (DOPA decarboxylase)

Question 7

how is dopamine broken down?

Answer 7

dopamine –> homovanillicacid (catechol-O-methytransferase,
COMT & monoamine oxidase, MAO)

Question 8

which (dopamine or L-dopa) crosses BBB?

Answer 8

L-dopa
dopamine dont cross BBB

Question 9

what drugs can be used to treat parkinson?

Answer 9

increase synthesis: levodopa
inhibit breakdown: COMT inhibitor, MAOI
dopamine receptor agonist

others: NMDA antagonist, anticholinergic

Question 10

what is the MOA of levodopa?

Answer 10

increase synthesis of dopamine
can cross blood brain barrier
gold standard

Question 11

what is levodopa administered together with to minimise side effects?

Answer 11

carbidopa, bensarazide = peripherally DOPA-decarboxylase inhibitor

Question 12

what are the side effects of levodopa?

Answer 12

short term: nausea, vomiting, postural hypotension
long term: motor fluctuations, dyskinesia

Question 13

what are the COMT inhibitor available?

Answer 13

entacapone
tolcapone

Question 14

what is the MOA of COMT inhibitor?

Answer 14

inhibit conversion of dopamine/L-dioa into inactive form –> more levodopa available

Question 15

indication of COMT inhibitor

Answer 15

adjunct with levodopa
increase duration of each dose of levodopa, help with “wearing off” responses

Question 16

what are the side effects for COMT inhibitor?

Answer 16

increase abnormal movements (dyskinesia)
liver dysfunction (tolcapone)
nausea, diarrhea
urinary discoloration
visual hallucinations
day time drowsiness, sleep disturbances

Question 17

what are the MAOI used in PD?

Answer 17

irreversible MAOB inhibitor
selegiline, rasagiline

Question 18

what are the indication for MAOI?

Answer 18

mild antiparkinson activity
monotherapy in early stages

Question 19

what is the MOA of MAOI

Answer 19

inhibit enzyme monoamine oxidase B & interferes with the breakdown of dopamine
may delay nigral brain cell degeneration

Question 20

what are the side effects of MAOI?

Answer 20

heartburn, loss of apetite
anxiety, insomnia, palpitation
nightmare, visual hallucinations

Question 21

what are the dopamine agonist available?

Answer 21

pramipexole
pergolide
ropinirole

Question 22

what is the MOA for dopamine agonist?

Answer 22

act directly on dopamine receptors in brain to reduce symptoms of PD

Question 23

place in therapy for dopamine agonist?

Answer 23

prevent or delay onset of motor complications
preferred choice in younger indiv

Question 24

what are the side effects for dopamine agonist?

Answer 24

common: nausea, vomiting, orthostatic hypotension, headache, dizziness & cardiac arrhythmia
pergolid: ‘ergot’ derivative, peritoneal fiborsis, cardiac valve regurgitation
pramipexole & ropinirole: sedation, somnolence, daytime sleepiness

Question 25

what is the MOA for amantadine?

Answer 25

enhance release of stored dopamine inhibit presynaptic uptale cathecolamine dopamine receptor agonist NMDA receptor antagonist

Question 26

what is amantadine use for?

Answer 26

antidyskinetic reduce dyskinesia in those with motor fluctuations

Question 27

what are the side effects for amantadine?

Answer 27

cognitive impairment hallucination insomnia nightmares livedo reticularis

Question 28

what is the anticholinergic used in PD?

Answer 28

trihexyphenidyl (benzhexol)

Question 29

what is anticholinergic used for in PD?

Answer 29

may be effective in controlling tremor peripherally acting agents may be useful in treating sialorrhoea

Question 30

what are the side effects of anticholinergics?

Answer 30

dry mouth, sedation, constipation, urinary retention, delirum, confusion, hallucinations

Question 31

the pathological characteristic of AD?

Answer 31

1. senile plaques: aggregates of beta-amyloid, formed from cleavage of amyloid precursor protein 2. neurofibrillary tangles: hyper-phosphorylated tau protein --> paired helical filament

Question 32

pathophysiology of AD?

Answer 32

neurodegeneration --> brain atrophy neurochemical deficits & alterations --> cognitive decline & neuropsychiatric behaviours

Question 33

what is the difference between MAO vs cholinergic synapse?

Answer 33

MAO reuptake into presynpatic --> broken down by COMT/MAO acetylcholine broken down to choline & acetyl by acetylcholinestearse in the synapse then choline reuptake

Question 34

what is the goal of AD management?

Answer 34

disease modifying (currently not possible) slow progression delay need to institutionalization

Question 35

what is use in mild to moderate AD?

Answer 35

acetylcholinesterase inhibitors - donepezil - galantamine - rivastigmine

Question 36

compare between galantamine vs rivastigmine

Answer 36

formulation: galantamine available as PO tablet only, rivastigmine available as PO & transdermal half life: rivagstigmine shorter t1/2 than galantamine other receptor activity: galantamine may also act on nicotinic receptor brain clearance: galantamine metabolized by liver CYP450, rivastigmine primarily cleared by kidneys

Question 37

what are the side effects for acetylcholinesterase inhibitors?

Answer 37

nausea, vomiting, diarrhea muscle cramp, bradycardia, loss of appetite, increased gastric juice secretion

Question 38

what is used for moderate to severe AD?

Answer 38

memantine

Question 39

what is memantine?

Answer 39

noncompetitive NMDA receptor antagonist

Question 40

what are the side effects of memantine?

Answer 40

hallucination, confusion, dizziness, headaches

Question 41

what is the clinical implication of the cholinergic synapse?

Answer 41

drug that work in synapse to inhibit breakdown of acetylcholine to prevent choline from being reuptake, dont need enter cells