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MBBS II HNNS > L52 – Drugs Used for Neurodegenerative Diseases > Flashcards

L52 – Drugs Used for Neurodegenerative Diseases Flashcards

1
Q

Classify neurodegenerative diseases into 2 groups?

A
  • Movement impairment i.e. Parkinsons

- Memory impairment i.e. Alzheimers

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2
Q

Prevalence of Parkinsons? Which age group affected most?

A

most common movement disorder affecting 1-2% of general population > age 65

Prevalence increases at age 60, plateaus off at age 70

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3
Q

Four main characteristics of Parkinson’s?

A

Resting tremors in limbs: aymmetric

Muscle rigidity: Muscle tone increases in both flexor and extensor muscles

Bradykinesia

Abnormal posture and gait

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4
Q

First symptom of Parkinson’s?

A

Usually asymmetric Resting tremors in limbs (hands, legs, extremities)

Most evident in one hand with the arm at rest

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5
Q

Describe symptoms under bradykinesia?

A

 Difficulty with daily activities, e.g. writing, shaving, using knife and fork, opening buttons

 Decreased blinking

 Slowed chewing and swallowing

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6
Q

Describe the abnormal posture and gait seen in parkinsons?

A

forward tilt of trunk, reduced arm swinging, shuffling gait with short steps

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7
Q

Describe the neurogeneration in idiopathic Parkinson’s

A

Nigrostriatal dopamine pathway in brain:

  • from substantia nigra to basal ganglia
  • Input from motor cortex
  • Stimulated by dopamine, inhibited by Ach

In PD: degeneration of dopaminergic neurons in basal ganglia

  • Imbalance of dopamine and Ach cause more output to spinal cord = increased muscle tension and tremor
  • Less dampening effect on reticular formation
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8
Q

List 5 causes of Parkinsonism.

A
  1. idiopathic parkinsonism (Parkinson’s disease)
  2. Drug-induced parkinsonism (antipsychotics)
  3. Toxin damaging dopaminergic neurons
  4. Viral infection – encephalitis
  5. Trauma-repeated head injury
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9
Q

List 2 drugs that can cause Parkinsonism?

A

i. Haloperidol (antipsychotics, dopaminergic blocker)

ii. Reserpine (hypertensive med, depletes dopamine store)

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10
Q

Principal of all drugs for treating Parkinsons?

A

re-establish the balance between dopamine and acetylcholine in brain:

  1. Increase dopamine activity in nigrostriatal system
  2. Reduce muscarinic cholinergic activity in striatum
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11
Q

MoA of Levodopa.

A

Metabolic precursor of dopamine

Transported into CNS and converted by DOPA decarboxylase

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12
Q

Pharmacokinetics of L-dopa?

A

Well absorbed in GI
High therapeutic index, Large dose required
Extremely short half-life&raquo_space; On/off symptoms

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13
Q

D/D interaction with L-dopa?

A

Nonselective monoamine oxidase (MAO) inhibitors (e.g. phenelzine)

Pyridoxine (vitamin B6)

Antipsychotics

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14
Q

Describe the D/D reaction between non-selective MAOI and L-Dopa?

A

(MAO) inhibitors (e.g. phenelzine): block both MAOA, MAOB

> > excess dopamine in periphery

> > modified into epinephrine, norepinephrine

> > hypertensive crisis (life-threatening)

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15
Q

Describe the D/D interaction between L-dopa and Pyridoxine (Vit B6) and Antipsychotics?

A

Pyridoxine (vitamin B6): = cofactor for DOPA decarboxylase&raquo_space; increase peripheral breakdown of L-dopa

Antipsychotics: block dopamine receptors&raquo_space; parkinsonian-like symptoms

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16
Q

ADR of L- dopa?

A 
- Excess dopamine in perhiphery:
 Nausea 
 Vomiting 
 Arrhythmias 
 Postural (orthostatic) hypotension (common)

Due to overstimulation of central dopamine receptors:
 Dyskinesia (recall L53: withdrawal problems)
 Hallucinations
 Restlessness
 Confusion

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17
Q

Name 2 DOPA decarboxylase inhibitors and preparations?

A

Carbidopa : Sinemet® (L-dopa + carbidopa in 4:1 ratio) = can reduce dose of L-dopa

Benserazide = Madopar® (L-dopa + benserazide in 4:1 ratio) = treat Parkinson’s disease

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18
Q

MoA of DOPA decarboxylase inhibitors?

A

Inhibit DOPA decarboxylase in the periphery

> > decrease metabolism of L-dopa into dopamine in periphery (into dopamine)
more L-dopa can cross BBB
increase availability of dopamine to CNS / brain

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19
Q

List 4 dopamine receptor agonists? Which are ergot derivatives?

A

Ergot derivative:

  • Bromocriptine
  • Pergolide

Non-ergot synthetics:

  • Pramipexole, ropinirole
  • Rotigotine
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20
Q

Which dopamine receptors are acted on by the dopamine receptor agonists?

A

Ergot derivative:

  • Bromocriptine > D2
  • Pergolide > D1 + D2

Non-ergot synthetics:

  • Pramipexole, ropinirole > D2
  • Rotigotine > D2
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21
Q

Indication and preparation of Bromocriptine?

A

Useful in younger patients (to delay use of L-dopa = delay psychosis ADR)

Elderly: in conjunction with L-dopa / carbidopa:
 Relieve tremor, rigidity
 Minimal effects on bradykinesia

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22
Q

ADR of Bromocriptine?

A

1) Peripheral:
 Nausea  Vomiting  Cardiac arrhythmia, postural hypotension

2) CNS: Hallucination, Delirium (sudden confusion)
3) Erythromelalgia**: Red, painful, swollen feet / hands

ADR Resolves when drug is stopped

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23
Q

Preparation of Pergolide?

A

In combination with:
 L-dopa / carbidopa
 Anticholinergic drugs

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24
Q

ADR of Pergolide?

A

 Postural hypotension
 Hallucinations
 Confusion
 Urinary tract infection *****

25
Q

Select the first-line therapy for parkinsonism in young patients? Preparation?

A

Pramipexole and ropinirole

Adjunct to Levodopa

26
Q

Indication of Parmipexole and ropinirole?

A

= 1st-line therapy in younger patients (fewer GI side effects)

advanced Parkinson’s disease (especially elderly): = adjunct to L-dopa / carbidopa treatment

27
Q

ADR of Parmipexole and ropinirole?

A

 Postural hypotension
 Dyskinesia
 Dizziness
 Insomnia / somnolence (drowsiness) (Fewer GI side effects)

28
Q

Preparation of Rotigotine?

A

Transdermal patches (Neupro® patch) when used to treat Parkinson’s disease

> > good for elderly patients

29
Q

ADR of Rotigotine?

A

 Nausea
 Dizziness
 Application site reactions: hypersensitivity reactions, (e.g. redness, rashes..)
 Headaches

30
Q

List 2 Selective monoamine oxidase B inhibitors and MoA?

A

Selegiline and rasagiline

Inhibit monoamine oxidase B (MAOB) to metabolize dopamine into DOPAC

> > lower metabolism of dopamine in periphery, brain

> > Increase T1/2 of dopamine and dopamine levels

31
Q

Indication and ADR of MAOI-B?

A

added after patient grows tolerant to L-dopa / carbidopa

enhance the effects of:
 L-dopa / carbidopa (Sinemet®)
 L-dopa / benserazide (Madopar®)

High dosages: dopamine in periphery can be metabolized into epinephrine, norepinephrine&raquo_space;> hypertensive crisis

32
Q

List 2 Catechol- O - Methyl transferase inhibitors (COMT) and MoA?

A

Entacapone, Tolcapone

Inhibit catechol-O-methyl transferase (COMT):

  1. Block peripheral degradation of levodopa
    (L-dopa) to 3-O-methyldopa (which competes with L-dopa for an active carrier that transports levodopa across BBB) &raquo_space; Less 3-O- methyldopa compete = more L-dopa can cross BBB
  2. Block degradation of dopamine to 3-methoxytyramine (also by COMT)
33
Q

Preparation of COMT inhibitors? Indication?

A

Stalevo® (L-dopa + carbidopa + entacapone) = triple therapy (good for elderly)

Adjunct to L-dopa / benserazide

used at a later stage of PD, use entacapone in liver failure

34
Q

ADR of COMT inhibitor? C/O?

A 
Postural hypotension  
Dyskinesia  
Hallucinations  
Sleep disorders  
Diarrhea 
Hepatic necrosis (for tolcapone only)

C/O Tolcapone with liver failure patients

35
Q

Name one dopamine facilitator and MoA?

A

Amantadine (anti-viral agent)

Exact MoA unknown:
 Enhances release/ exocytosis of dopamine from surviving nigral neurons
 Inhibits reuptake of dopamine at synapses

36
Q

Preparation of Amantadine?

A

More effective than anticholinergic agents in improving rigidity, bradykinesia when used along with:

 L-dopa / carbidopa (Sinemet®)
 L-dopa / benserazide (Madopar®)

(But no effect on tremor)

37
Q

ADR of Amantadine?

A

 Postural hypotension
 Restlessness, agitation, confusion
 Skin rash
 Peripheral edema

38
Q

Name 2 central anti-chlonergics and MoA?

A

 Benztropine
 Biperidine
 Trihexyphenidyl (benzhexol)

Decrease cholinergic output of striatum

39
Q

Preparation of central anti-cholinergics?

A

 Much less efficacious than levodopa / carbidopa

 Commonly used adjuvantly in parkinsonian therapy
» Treat Primary symptoms (e.g. tremor, rigidity, akinesia (not bradykinesia)) + Secondary symptom (e.g. drooling)

40
Q

ADR of central anti-cholinergics?

A 
 Dry mouth  
 Urinary retention 
 Constipation 
 Sedation 
 Mental confusion
41
Q

Pathogenesis of Huntington’s?

A

single defective gene on chromosome 4, Htt protein with polyglutamate CAG repeats accumulate to damage Medium spiny GABAergic neurons in striatum:

> > diminished GABA functions in basal ganglia
hyper-reactivity of dopaminergic pathways (opposite to PD)
Movement and psychiatric disorders

42
Q

Describe the physiological connection between Corpus striatum and Substantia nigra?

A

Substantia nigra to Corpus striatum = Dopaminergic, excitatory&raquo_space; affected in Parkinsons

Corpus striatum to Substantia nigra = GABAnergic, inhibitory&raquo_space; affected in Huntingtons

43
Q

Symptoms of Huntington’s?

A

Movement + psychiatric disorders:

 Involuntary movements (cannot control)
 Dementia, cognitive decline
 Depression

44
Q

Medication for treating movement disorder in Huntington’s?

A

1) Tetrabenazine: “dopamine-depleting”
» suppress involuntary jerking, writhing movement (chorea)

2) Antipsychotic drugs (e.g. haloperidol (dopaminergic blocker), risperidone (newer)):
» Use side effect = suppress movements

45
Q

Medication for treating psychiatric disorder in Huntington’s?

A

 Antidepressants (e.g. fluoxetine (SSRI)): treat depression

 Mood-stabilizing drugs (e.g. carbamazepine): treat irritability

46
Q

Pathogenesis of Alzheimer’s disease?

A

neurodegenerative condition – neurons in cerebral cortex, hippocampus degenerate, severe shrinkage

> > chronic, progressive dementia + mobility problems

47
Q

3 distinct neuronal features of Alzheimer’s?

A
  1. B-amyloid plaque accumulations
  2. Formation of numerous neurofibrillary tangles (surround amyloid plaques)
  3. Loss of cortical cholinergic neurons (= drug target)
48
Q

Symptoms of Alzheimer’s?

A 
 Forgetfulness  
 Getting lost in familiar setting 
 Lose interest in family 
 Deterioration of work performance  
 Disorientation (time and place)  
 Behavioral changes (e.g. depression) 
 Slower walking / falls
49
Q

Prevalence of Alzheimer’s?

A

Generally diagnosed in people >65 years of age: ~ 13%

> > > number 1 degenerative condition

50
Q

Describe the stages in progression of Alzheimer’s?

A

1) Pre-dementia: mild cognitive impairment (forget things)
2) Mild (early): difficulty remembering newly learned information
3) Moderate: Disorientation; deepening confusion about events, time and place (e.g. forgets eaten meal) + Mood and behavior changes
4) Severe (advanced): difficulty speaking, swallowing, walking

51
Q

List the 2 classes of drugs used to treat Alzheimer’s and give examples?

A 
Acetylcholinesterase inhibitors (AChEI) / anticholinesterases (= 1st line): 
Donepezil, Galantamine, Rivastigmine (transdermal)

NMDA-R antagonist: Memantine

52
Q

MoA of AChEI in treating alzheimer’s?

A

prevent breakdown of acetylcholine (ACh) within synaptic cleft

> > Increase amount of ACh available

53
Q

ADR of AChEI?

A

 Nausea, vomiting  Diarrhea  Abdominal cramps  Anorexia (appetite and weight loss)  Dizziness  Urine incontinence  Agitation

54
Q

MoA of NMDA receptor antagonist?

A

uncompetitive NMDA receptor antagonist
» protects CNS neurons from the excitotoxic effects of glutamate
» improves cognitive ability

55
Q

ADR of NMDA receptor antagonist?

A 
 Diarrhea 
 Dizziness 
 Headache 
 Confusion 
 Constipation
56
Q

List the classes of drugs used to treat Huntington’s and give examples?

A

Treat movement disorder:
Dopamine depleting = Tetrabenazine
Antipsychotics = Haloperiodol, Risperidol

Treat psychiatric disorder:
Antidepressant = Fluoxetine SSRI
Mood stabilizer = Carbamazepine

57
Q

Select the drug for mild to moderate Alzheimer vs moderate to severe ALzheimer?

A

Mild to moderate = Galantamine/ Rivastigmine

Moderate to sever = Memantine

58
Q

Select the drug for all stages of Alzheimer?

A

Donepezil

Rivastigmine

MBBS II HNNS (57 decks)

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