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PR3153 FINALS > IC15 Pharmacology (AD, PD) > Flashcards

IC15 Pharmacology (AD, PD) Flashcards

1
Q

What are the 5 means of increasing agonistic effects in neurodegenerative diseases (drug targets)?

A
  1. Increasing neurotransmitter synthesis (by increasing precursor, destroying degrading enzymes)
  2. Increasing release of neurotransmitter molecule
  3. Downregulating feedback inhibition (binding to autoreceptors)
  4. Acting in place of neurotransmitters (binding to postsynaptic receptors to activate them)
  5. Blocking deactivation of neurotransmitters (blocking degradation or reuptake)
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2
Q

Define parkinsons disease

A

neurodegenerative disease with extrapyramidal motor symptoms (dopamine affects motor sx) such as tremors, rigidity and bradykinesia, due to striatal dopaminergic deficiency

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3
Q

What is the main neurotransmitter affected in PD?

A

Dopamine
But others will start to get affected as well as the disease progresses, manifesting as non-motor sx

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4
Q

When is young-onset PD diagnosed

A

21-40 yo

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5
Q

What are the cardinal symptoms of PD?

A
  • Tremors at rest (”pill rolling”)
  • Bradykinesia/Akinesia (slowness of movement)
  • Rigidity (eg. ”cogwheeling” when pressing down on patients arm)
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6
Q

What is another common non-cardinal symptom of PD?

A

Postural instability and gait disturbances

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7
Q

Explain the pathophysiology of PD

A

Impaired clearing of abnormal or damaged intracellular proteins by the ubiquitin-proteasomal system result in the accumulation of aggresomes, leading to apoptosis

degeneration of dopaminergic neurons with Lewy body inclusions in the substantia nigra lead to dysfunctions of the nigrostriatal pathway, causing PD

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8
Q

How is dopamine synthesised? (precursors and enzymes)

A

L-tyrosine → L-dopa (via tyrosine hydroxylase) → dopamine (via DOPA decarboxylase)

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9
Q

How is dopamine broken down? (product and enzymes)

A

dopamine → homovanillic acid (via COMT and MAO-B) (inside presynapse)

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10
Q

Where does dopamine bind on the postsynaptic membrane?

A

D1 and D2 receptors (GPCR)

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11
Q

How do dopamine and L-dopa differ in terms of crossing the BBB?

A

dopamine does not pass through the BBB, only L-dopa does

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12
Q

How does levodopa act?

A

synthetic L-dopa works by feeding the body more precursor in hopes that the enzymes will produce more dopamine

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13
Q

Why should DCIs be given together with levodopa?

A

Levodopa acts on the brain but dopamine can also be found all around the body, hence giving rise to systemic side effects

DCIs allow dopamine to get into the brain to be converted into dopamine first

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14
Q

What are the 2 DCI drugs

A

peripherally active DOPA-decarboxylase inhibitors:
Carbidopa, Benserazide

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15
Q

What are short-term and long-term side effects of levodopa

A
  • Short-term SE → nausea, vomiting, postural hypotension
  • Long-term SE → motor fluctuations and dyskinesia (irreversible)
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16
Q

How to COMT inhibitors exert their effect

A

They block COMT conversion of dopamine or L-dopa into its inactive form

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17
Q

What are the 2 COMTI drugs

A

Entacapone
Tolcapone (not used anymore)

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18
Q

What is the place in therapy for COMT inhibitors?

A

They can be used as adjuncts to levodopa, not useful as monotherapy

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19
Q

What are the 2 advantages of using COMT inhibitors?

A
  1. Allows more levodopa to be available to enter the brain and reduces the required dose
  2. Increases the duration of each dose of levodopa and is therefore beneficial in treating “wearing off” responses
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20
Q

What are the side effects of COMT inhibitors (7+1)

A
  1. increased abnormal movements (dyskinesia)
  2. nausea
  3. diarrhea
  4. urine discolouration
  5. visual hallucinations
  6. daytime drowsiness
  7. sleep disturbances

liver dysfunction (for tolcapone)

21
Q

How do MAO-B inhibitors exert their effect?

A

They inhibit MAO-B and interfere with dopamine breakdown, therefore increasing dopamine levels

22
Q

What are the MAO-B inhibitor drugs?

A

Selegiline
Rasagiline

23
Q

What is the place in therapy for MAO-B inhibitors?

A

Selegiline is efficacious as a symptomatic monotherapy (unlike COMT-i) and may be used in early stages of Parkinson’s disease

24
Q

What are the side effects of MAO-B inhibitors? (7)

A
  1. heartburn
  2. loss of appetite
  3. anxiety
  4. palpitation
  5. insomnia
  6. nightmares
  7. visual hallucinations
25
Q

What are the dopamine agonist drugs?

A

Pramipexole
Rotigotine
Ropinirole

26
Q

What is the place in therapy for dopamine agonists?

A

Dopamine agonists are used to prevent or delay the onset or motor complications and are used before levodopa in younger patients

27
Q

What are the side effects of dopamine agonists? (5)

A
  1. nausea, vomiting
  2. orthostatic hypotension
  3. headache
  4. dizziness
  5. cardiac arrhythmias
28
Q

Why are “ergot” derivative dopamine agonists not used anymore (eg. pergolide)?

A

peritoneal fibrosis and cardiac valve regurgitation

29
Q

What additional side effects do pramipexole and ropinorole have?

A

sedation, somnolence and daytime sleepiness

30
Q

What are the MOAs of amantadine? (4)

A
  1. Enhances the release of stored dopamine (but does not make more DA)
  2. Inhibits presynaptic uptake of catecholamines (not specific for DA but includes DA)
  3. Dopamine receptor agonist
  4. NMDA (glutamate) receptor antagonist (anti-glutamate)
31
Q

Which sx of PD does amantadine help with?

A

Dyskinesia

32
Q

What are the side effects of amandatine? (5)

A
  1. Cognitive impairment (inability to concentrate)
  2. Hallucination
  3. Insomnia
  4. Nightmares
  5. Livedo reticularis
33
Q

Which anticholinergic can be used for PD?

A

Trihexyohenidyl

34
Q

Which sx of PD does trihexyphenidyl help with?

A

Fine tremors and sialorrhea

35
Q

What are the side effects of trihexyphenidyl?

A
  1. Dry mouth
  2. Sedation
  3. Constipation
  4. Urinary retention
  5. Delirium
  6. Confusion
  7. Hallucinations
36
Q

What are the hallmark pathological features of AD

A

senile plaques and neurofibrillary tangles

37
Q

In which system does neurodegeneration mainly occur in AD patients?

A

Cholinergic system

38
Q

What is the anticholinergic hypothesis of AD?

A

Cholinergic pathways include the dorsal tegmental pathway (minor) and projections of the nucleus basalis (major) and if these areas are degenerated, all the signals that distribute ACh will be gone

This leads to deficits in attention and learning

39
Q

Where is ACh broken down?

A

within the synapse by acetylcholinesterase

40
Q

Compare between how the dopaminergic and cholinergic systems break down neurotransmitters

A

dopaminergic degradation enzymes are in the presynapse while cholinergic degradation enzymes are found in the synapse itself

41
Q

Which drugs are indicated for mild to moderate AD

A

acetylcholinesterase inhibitors (AChEIs) (eg. donepezil, galantamine, rivastigmine)

42
Q

How do AChEIs help with AD?

A

modestly improve cognition, ADL and behaviour

43
Q

What are the available dosage forms for rivastigmine and galantamine?

A

Rivastigmine: oral and transdermal patch
Galantamine: oral tablet

44
Q

Compare between the half lives of rivastigmine and galantamine

A

Rivastigmine has a shorter half-life than galantamine

45
Q

How are rivastigmine and galantamine metabolised

A

Galantamine: metabolised by the liver (CYP450)
Rivastigmine: primarily metabolised by the kidneys

Therefore in liver disease use rivastigmine, while in kidney disease use galantamine

46
Q

What are the side effects of AChEIs? (3+4)

A

Cholinergic hyperactivation → nausea, vomiting, diarrhea (opposite from anticholinergic)

Less common → muscle cramp, bradycardia, loss of appetite, increased gastric juice secretion

47
Q

Which drugs are indicated for severe AD?

A

Memantine
Donepezil

48
Q

What is memantine’s MOA?

A

non-competitive NMDA receptor antagonist, blocks NMDA receptor-mediated excitotoxicity

49
Q

What are side effects of memantine? (4)

A

hallucination, confusion, dizziness and headaches

PR3153 FINALS (8 decks)

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