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Pharmacology > L15 Drugs for Dementia and Parkinson's Disease > Flashcards

L15 Drugs for Dementia and Parkinson's Disease Flashcards

1
Q

Learning Outcomes (for general perusal)

A
  • Describe the essential features of dementia and Parkinson’s disease
  • Describe the neurotransmitters involved in the action of drugs used to treat dementia and Parkinson’s disease
  • Describe the mode of action, desired and adverse effects of these drugs
  • Describe how these drugs are used
  • Relate the pathophysiology of Parkinson’s disease with the pharmacological rationale for treatment.
  • Pharmacological approaches to the treatment of dementias and evidence for the efficacy of inhibitors of acetylcholinesterase.
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2
Q

Outline the pathological processes causing neuronal cell death

What is the protein called in

  1. Alzheimer’s Disease
  2. Parkinson’s Disease
A
  • Misfolding of normal physiological proteins
  • which can aggregate to form oligomers
  • which aggregate further to form neurotoxic insoluble aggregates
  1. Beta amyloid protein
  2. Alpha synuclein protein
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3
Q

What are the mechanisms of neuronal cell death?

A
  • Excitotoxicity - mainly through activation of NMDA receptors
  • Apoptosis
  • Oxidative Stress - hypoxia
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4
Q

What is Dementia?

A

Global term and refers to a set of symptoms with decline in memory and thinking of a degree sufficient to impair functioning in daily living.

Symptoms must be present for 6 months or more

Associated changes in personality and behaviour

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5
Q

What are the different types of dementia?

A

Alzheimer’s Disease - 60%

Vascular Dementia - 15-20%

Lewy Body Dementia - 15%

Fronto-temporal Dementia

Rarer Dementias (Huntington’s Disease, CJD)

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6
Q

How does a person with Alzhiemer’s present?

A
  • Early changes in mood and memory
  • Gradual decline in short term memory

Other features then begin to appear:

  • Loss of ability to conduct complex tasks e.g. finances
  • Impaired concentration, disorientation
  • Behavioural and psychological symptoms emerge
  • Increased dependency on others
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7
Q

Describe the pathogenesis of Alzhiemer’s Disease

A
  • Amyloid plaques, neurofibrillary tangles
  • Gliosis. Loss of neurones
  • Reduction of the cerebral cortex subcortical white matter.
  • Hippocampus and temporo-parietal regions affected firstly
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8
Q

Pathogenesis of Alzhiemer’s Disease

What is the ‘Amyloid Cascade Hypothesis’?

  1. Physiologically
  2. Pathologically
A
  1. Amyloid Precursor Protein (APP) is cleaved by α-secretase to produce soluble Amyloid Precursor Protein (sAPP)
  2. Amyloid Precursor Protein is abnormally cleaved by β-secretase or ɤ-secretase
    1. To form Beta-amyloid peptide (Aβ)
    2. To form oligomers and then amyloid plaques (extracelluar)
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9
Q

Pathogenesis of Alzhiemer’s Disease

How are neurofibrillary tangles created?

A
  • The microtubule protein, Tau, is phosphorylated
  • It dissociates from microtubules to form paired helical filaments and then neurofibrillary tangles (intracellular)
  • NF tangles result in neuronal death
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10
Q

What are the principle neurotransmitters in Alzheimer’s disease?

A
  • Acetylcholine
    • ​depletion of cholingeric neurons is the primary abnormality
    • Choline acetyl transferase and choline are all reduced
  • Noradrenaline - reduced in cortex and hippocampus
  • Serotonin - Serotonergic neuron loss in the frontal and temporal lobes
  • GABA
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11
Q

Cholinergic neurotransmission

  1. What is Acetylcholine synthesized from?
  2. What catalyses the reaction?
  3. What are the two types of receptors?
  4. What breaks down Ach in the synpase
A
  1. Acetyl CoA and Choline
  2. Choline acetyltransferase
  3. Nicotinic and muscarinic
  4. Acetylcholinesterase
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12
Q

What are the drugs used to treat Alzheimer’s Disease?

A
  • Acetylcholinesterase Inhibitors
    • Donepezil, Rivastigmine, Galantamine
  • NMDA Antagonist
    • Memantine
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13
Q

Acetylcholinesterase Inhibitors

  1. How do they act?
  2. Name three
  3. Which shows R modulation?
  4. What is the chemical class of
    1. Donepezil
    2. Rivastigmine
    3. Galantamine
  5. They all inhibit acetylcholinesterase, but which also acts to inhibit butyrylcholinesterase
  6. Which has the longest half life?
  7. What are the elimination pathways?
  8. Which have metabolism by cytochrome P450?
  9. All have caution in Hepatic impairment, what is another caution in R?
A
  1. delay the degradation of acetylcholine released at the synapse, prolonging it’s effectiveness. (most widely studied)
  2. Donepezil, Rivastigmine, Galantamine
  3. Galantamine
  4. Chemical Class
    1. Piperidine Alkaloid
    2. Carbamate
    3. Phenanthrene
  5. Rivastigmine
  6. Donepezil (70) (R=1, G=6)
  7. D= Liver, R= Kidney, G = 50% Kidney
  8. D and G
  9. Renal Impairment
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14
Q

Acetylcholinesterase Inhibitors

  1. Give some adverse effects
  2. Give some cautions
A
  1. Nausea, vomiting, diarrhoea

Insomnia, agitation

Syncope, bradycardia, heart block

Muscle cramps

Rarely EPS

  1. Sick sinus syndrome/conduction abnormalities

Peptic ulceration

Asthma/COPD

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15
Q

Glutamate in Alzheimer’s Disease

What is the role of glutamate?

A

A neurotransmitter turned neurotoxin

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16
Q
  1. What type of drug is Memantine?
  2. What are it’s effects?
  3. What are the side effects?
A
  1. A NMDA antagonist (glutamate receptor)
  2. Modest improvement in cognition in moderate to severe Alzheimer’s disease. Long half life.
  3. Constipation

Hypertension

Drowsiness

Seizures (rarely)

Pancreatitis

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17
Q
  1. What is Parkinson’s Disease?
  2. What projects from the substantia nigra?
  3. What does this normally do?
  4. What is Parkinson’s Disease characterised by in terms of NTs?
A
  1. A disease resulting from cell degeneration within the substantia nigra (neurodegenerative)
  2. The nigrostriatal dopamine pathway
  3. modulates voluntary movement
  4. Depletion of NT dopamine
    1. ​-depletion of 60% nigral neurones
      • depletion of 80% of striatal dopamine
18
Q

Parkinson’s Disease

  1. What is it characterized by?
  2. What are the caused of parkinsonism?
A
  1. bradykinesia, rigidity and tremor
  2. Idiopathic is the largest cause
    1. Others:
  • Drug induced parkinsonism
  • Post encephalitic parkinsonism
  • MPTP parkinsonism
  • Toxins e.g. manganese, carbon monoxide
19
Q

Parkinson’s Disease

  1. What are the motor symptoms?
  2. What are Non-motor symptoms?
A
  1. •Resting pill rolling tremor
  • Bradykinesia
  • Rigidity
  • Festinant (pertaining to a gait pattern that accelerates involuntarily as a result of a nervous system disorder)/shuffling gait
  1. •Fatigue, depression
  • Dysarthria, sialorrhoea (an abnormally high production of saliva)
  • Micrographia
  • Cognitive impairment
20
Q

Dopamine

  1. What type of molecule is it?
  2. Tyrosine is made into..
  3. Dopa is made into
  4. Dopamine is broken down to give?
A
  1. A monoamine
  2. Dopa
  3. Dopamine
  4. Dopamine 3-methoxytyramin, and Dopamine Homovanillic acid
21
Q

Describe the DA/Ach imbalance in Parkinson’s Disease?

A
  • Acetylcholine and dopamine are normally in ‘balance’
  • Acetylcholine - excitatory effect stimulates muscle contraction
  • Dopamine inhibitory effect - inhibits muscle contraction
  • Acetylcholine release from the striatum is strongly inhibited by dopamine
  • Acetylcholine excess or dopamine depletion results in parkinsonism
22
Q

What are the drugs used for Parkinson’s Disease?

A
  • Dopamine Enhancing Drugs
    • ​Levodopa
    • Dopamine agonists
    • Apomorphine
    • COMT inhibitors
    • MAO-B inhibitors
    • Amantadine
  • Anticholinergics
    • ​procyclidine
23
Q

Levodopa

  1. What is Levidopa administered with?
  2. Why?
  3. What is the principle behind Levidopa?
A
  1. dopa decarboxylase inhibitor (benserazide, carbidopa)
  2. to reduce the peripheral metabolism of levodopa to dopamine - Reducing peripheral side effects of dopamine and results in effective brain concentrations of dopamine
  3. Dopamine does not cross the blood brain barrier (BBB) but levodopa does cross BBB. Converted to Dopamine in the brain by action of Dopa decarboxylase
24
Q

Levodopa

  1. What are the peripheral side effects?
  2. Central side effects?
  3. Problems with long term use?
A
  1. •Nausea, vomiting
  • Postural hypotension
  • Sweating
  • Discolouration of urine/sweat
  1. •Confusion
  • Hallucinations
  • Psychosis
  1. (may appear after 5 years)
  • motor fluctuations - ‘Wearing off’, ‘on/off phenomenon’, ‘end of dose deterioration’, ‘freezing’
  • dyskinesia - i.e. involuntary movements
25
Q

Dopamine Agonists

  1. What do they act upon?
  2. What is their duration of action like?
  3. What are the two groups?
  4. What are the benefits with non-ergot derivatives?
A
  1. Act directly on post synaptic dopamine receptors
  2. Longer than Levidopa
  3. •Ergot derivatives e.g. Pergolide, Cabergoline

•Non-ergot derivatives e.g. Ropinirole, pramipexole, rotigotine

  1. better tolerated and do not show the flucutations in efficacy shown with levodopa
26
Q

Dopamine Agonists

What are the

  1. Peripheral Adverse Effects?
  2. Central Adverse Effects?
A
  1. •Nausea/constipation
  • Postural hypotension
  • Cardiac arrhythmia
  • Peripheral oedema
  • Retroperitoneal, pulmonary pericardial fibrosis - associated with erogt derivatives, requires monitoring
  1. •Drowsiness (sudden onset of sleep)
  • Hallucinations
  • Psychotic reactions
  • Impulse control disorders
27
Q

Dopamine Agonist

  1. What is a potent Dopamine Agonist used in advanced disease?
  2. When is it used?
  3. How is it administered?
  4. What are the adverse effects?
A
  1. apomorphine
  2. Used to treat ‘off’ period with levodopa
  3. Administered subcutaneously
  4. nausea and vomiting

drowsiness

neuropsychiatric problems

28
Q

COMT Inhibitors

  1. What is their mechanism of action?
  2. Give examples
  3. What is are the adverse effects?
  4. Which is hepatoxic?
A
  1. Prevents the peripheral breakdown of levodopa by inhibiting catechol –O-methyltransferase. •Reduces variations in plasma levodopa levels •continuous dopaminergic stimulation’
  2. Entacapone, tolcapone
  3. Similar to Ldopa
  4. Tolcapone
29
Q

MAO-B inhibitors

  1. What is the action of MAO (Monoamine oxidase B) on dopamine metabolites?
  2. What is the mode of action of MAO-B inhibitors?
  3. Give examples
  4. What is a benefit?
  5. What are the adverse effects?
A
  1. Converts them to Dopamine
  2. Protects dopamine from extra-neuronal degradation, therefore increasing the extent and duration of the response to levodopa
  3. selegeline, Rasagiline
  4. Do not cause cheese reaction of non selective monoamine oxidase inhibitors (MAOI – antidepressant)
  5. Adverse effects resulting from increased dopaminergic effect

Selegiline is metabolised to amphetamine - anxiety, insomnia

30
Q

Amandatine

  1. What is Amandatine?
  2. What are the adverse effects?
A
  1. Antiviral agent and aWeak dopamine agonist
    1. •Various mechanisms of action suggested
  • Less effective than levodopa and tolerance to its effects develop
  • Side effects less severe but similar to levodopa
    1. Confusion, hallucinations

Peripheral oedema

Livedo reticularis (dilation of capillary blood vessels and stagnation of blood within these vessels causes mottled discolouration of the skin)

31
Q

Anticholingeric Drugs

  1. Give examples
  2. How do they act?
  3. When are they most likely to be used?
  4. What are the adverse effects?
A
  1. Orphenadrine, procyclidine
  2. Muscarinic acetylcholine receptors have an inhibitory effect on dopamine nerve terminals

Suppression of acetylcholine by acetylcholine antagonists (anticholinergics) helps to compensate for the lack of dopamine in Parkinson’s disease

  1. Rarely used in Parkinson’s disease but can be used to treat the parkinsonian side effects of anti-psychotic drugs
  2. Central – hallucinations, cognitive impairment, delirium

Peripheral – blurred vision, dry mouth, urinary retention

32
Q

Parkinson’s Disease

What are the first line options (in order of symptom control) for…

  1. Early Parkinson’s Disease?
  2. Late Parkinson’s Disease?
A
  1. Levodopa +++

Dopamine agonists ++

MAOB inhibitors +

(Anticholingerics and Amantadine - lack of evidence)

  1. Dopamine agonists ++

COMT inhibitors ++

MAOB inhibitors ++

(Amantadine and Apomorphine - not used)

33
Q

Why should Anti-parkinsonian medication never be stopped abruptly?

A

due to the small risk of neuroleptic malignant syndrome.

  • Hyerthermia, increased muscle rigidity, coma, death.
34
Q

What is the clinical course of parkinson’s disease?

A
  • Early treatment
  • Fluctuations (on/off)
  • Loss of dopamine responsiveness
  • Akinetic freezing
  • End stage disease
35
Q

Parkinson’s Disease Recap (for general perusal)

A
  • Loss of dopaminergic neurones in substantia nigra in PD
  • Drug therapies attempt to enhance dopamine
  • Dopamine cannot cross the blood brain barrier
  • Levodopa administered with dopa decarboxylase inhibitor to reduce peripheral metabolism to dopamine
  • Levodopa has peripheral, central adverse effects and problems with long term use
  • Dopamine agonists – adverse effects of ergot derivatives
  • Apomorphine is a potent dopamine agonist
  • COMT - prevent the peripheral breakdown of levodopa
  • MAO-B inhibitors - protects dopamine from extra-neuronal degradation
36
Q

What is Parkinson’s disease characterised by?

A

•Loss of dopaminergic neurones in substantia nigra

37
Q

What do drug therapies in Parkinson’s Disease attempt to do?

A

•enhance dopamine

38
Q

Parkinson’s Disease

What can’t cross the BBB?

How is this overcome?

A

Dopamine

Levodopa administered with dopa decarboxylase inhibitor to reduce peripheral metabolism to dopamine

39
Q

What is Levodopa administered with?

A

dopa decarboxylase inhibitor

40
Q

What do Dopamine agonists do?

A

adverse effects of ergot derivatives

41
Q

What is Apomorphine

A

a potent dopamine agonist

42
Q
  1. What do COMT (Catechol-O-methyltransferase) inhibitors do?
  2. What MAO-B (monoamine oxidase) inhibitors do?
A
  1. prevent the peripheral breakdown of levodopa
  2. protects dopamine from extra-neuronal degradation

Pharmacology (26 decks)

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