ic14 AD/PD pharmacology

Question 1

define parkinsons disease and epidemiology

Answer 1

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.

Question 2

what are the motor symptoms of PD

Answer 2

tremor at rest (pill rolling)

bradykinesia (slowness of movement)

rigidity (cogwheeling)

^ above 3 are the cardinal features of PD.

postural instability and gait disturbance

Question 3

PD disease course

Answer 3

from initial motor fluctuations, and dyskinesias to

non-motor symptoms = falls, postural instability, postural hypotension, confusion, dementia, suboptimal nutrition, speech, sleep disorders… 1

Question 4

pathophysiology of PD

Answer 4

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

Question 5

synthesis and breakdown of dopamine

Answer 5

L tyrosine –> L dopa via tyrosine hydroxylase

L dopa –> dopamine via DOPA decarboxylase

breakdown
dopamine –> homovanilic acid via catechol-o-methyltransferase, COMT, MAO.

Question 6

which are dopamine receptors in the basal ganglia

Answer 6

D1 and D2

Question 7

BBB for dopamine and others…

Answer 7

dopamine passes through the BBB while L-dopa does not.

Question 8

what is the gold standard of treatment for pD

Answer 8

LEVODOPA
synthetic L DOPA

Question 9

what combination products with levodopa?

Answer 9

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)

Question 10

levodopa side effects

Answer 10

short term: N/V, postural hypotension

long term: motor fluctuations, dyskinesia

Question 11

adjunct to levodopa? MOA and how it helps

Answer 11

COMT inhibitors:
entacapone, tolcapone

blocks COMT conversion of dopamine to the inactive form

increases duration of each dose of levodopa

Question 12

side effect of COMT inhibitors

Answer 12

1) increase abnormal movements (dyskinesia)
2) daytime drowsiness, sleep disturbance
3) urinary discolouration
4) visual hallucination
5) nausea, diarrhoea

specific to tolcapone: liver dysfunction

Question 13

another method to inhibit dopamine breakdown

Answer 13

MAO-B inhibitor
selegiline, rasagiline

Question 14

side effects of MAO-B inhibitors

Answer 14

heartburn, loss of appetite

anxiety, palpitation, insomnia

nightmares, visual hallucinations

Question 15

dopamine agonist agents (list, moa)

Answer 15

pramipexole
pergolide
ropinirole

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

Question 16

when should dopamine agonists be used first line

Answer 16

for younger PD patients to prevent or delay onset of motor complications with use of levodopa

Question 17

dopamine agonist side effects

Answer 17

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

Question 18

MOA of amantadine (and indication)

Answer 18

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)

Question 19

side effects of amantadine

Answer 19

cognitive impairment (inability to concentrate)
hallucination
insomnia
nightmares
livedo reticularis (venule swelling due to thromboses = mottled reticulated discolouration of limbs)

Question 20

moa of trihexyphenidyl

Answer 20

anticholinergic

adv: may be effective in controlling tremors, peripherally acting agents useful in treating sialorrhoea (excessive saliva flow)

Question 21

side effects of trihexyphenidyl

Answer 21

especially in e;derly
- dry mouth, constipation, sedation, urinary retention, delirium, confusions, hallucinations

Question 22

what is AD characterised by?

Answer 22

senile plaques
neurofibrillary tangles
brain atrophy (in areas critical to cognition eg neocortex, hippocampus)
neuronal death (neurodegeneration) of neurotransmitter systems

Question 23

methods for AD clinical diagnosis

Answer 23

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

Question 24

what is the treatment drugs for mild to moderate dementia?

Answer 24

AChEIs
acetylcholinesterase inhibitors

DONEPEZIL
GALANTAMINE
RIVASTIGMINE

inhibit the breakdwon of ACh to choline and acetate in the synpatic cleft

Question 25

compare between galantamine and rivastigmine (formulation, Half life, additional MOA, metabolism)

Answer 25

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.

Question 26

side effects of AChEIs

Answer 26

cholinergic hyperactivation
= nausea/vomiting/diarrhoea

less common:
- MSK: muscle cramp
- CVS: bradycardia
- GI: loss of appetite, increased gastric acid secretion

Question 27

memantine MOA

Answer 27

non competitve NMDA receptor antagonist = blocks NMDA receptor mediated excitotoxicity

Question 28

SE of memantine

Answer 28

CNS related side effects:
- hallucination,
- confusion,
- dizziness,
- headache