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Yr 2 LCRS - Pharm > 27 - Anti-Parkinsonian Drugs & Neuroleptics > Flashcards

27 - Anti-Parkinsonian Drugs & Neuroleptics Flashcards

1
Q

Outline Dopamine synthesis

A

L-Tyrosine (pre-cursor)

  • Tyrosine hydroxylase

L-DOPA

  • DOPA decarboxylase

Dopamine (DA)

TYROSINE HYDROXYLASE

  • rate-limiting enzyme
  • can’t just increase L-tyrosine to increase DA because there isn’t enough enzyme for the conversion
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2
Q

Outline Dopamine metabolism

A

DOPAMINE METABOLISM - 2 mechanisms

MECHANISM 1

DA removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET)

MECHANISM 2

Three enzymes metabolise DA:

  1. Monoamine Oxidase A (MAO-A)
  • metabolises DA, NE and 5-HT
  • intracellular
  • mainly found on cell membranes of mitochondrial cells
  1. Monoamine Oxidase B (MAO-B)
  • metabolises DA
  • intracellular
  • mainly found on cell membranes of mitochondrial cells
  1. Catechol-O-Methyl Transferase (COMT)
  • wide distribution
  • metabolises all catecholamines
  • can be extracellular
  • also found in glial cells and neuronal cells
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3
Q

What are the major locations of dopaminergic pathways?

A

1. NIGROSTRIATAL PATHWAY

  • from: substantia nigra pars compacta (SNc) in brainstem
  • to: the striatum
  • inhibition results in movement disorders
  • associated with Parkison’s

2. MESOLIMBIC PATHWAY

  • from: ventral tegmental area (VTA) in brainstem
  • to: nucleus accumbens (NAcc)
  • brain reward pathway
  • associated with schizophrenia

3. MESOCORTICAL PATHWAY

  • from: ventral tegmental area (VTA) in brainstem
  • to: cerebrum (frontal lobes)
  • imporant in executive functions and complex behavoural patterns
  • associated with schizophrenia

4. TUBEROINFUNDIBULAR PATHWAY

  • from: arcuate nuecleus
  • to: median eminence
  • inhibition results in hyperprolactinaemia
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4
Q

What percentage of individuals have Parkinson’s Disease?

A

1-2% of individuals over 60 years old have Parkinson’s Disease

It is a neurodegenerative disorder

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5
Q

What percentage of cases of Parkinson’s Disease are due to genetic mutations?

A

Approx. 5% of cases are due to mutations in certain genes e.g.

  • SNCA
  • LRRK2

Genetic is associated with early-onset Parkinson’s Disease

However, age is still the main risk factor for Parkinson’s and is associated with late-onset

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6
Q

Outline the pathophysiology of Parkinson’s Disease

A

Severe loss (degeneration) of dopaminergic projection cells in SNc (nigrostriatal pathway)

Lewy bodies & neurites

  • Lewy bodies found in neuronal cell bodies
  • Lewy neutrities found in axon of cells
  • associated with neurodegeneration

Consist of abnormally phosphorylated neurofilaments, ubiquitin & α-synuclein

Neurites start near olfactory area (sensory area) and move towards the substantia nigra (movement disorders)

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7
Q

Outline the clinical presentation of Parkinson’s Disease

A

MOTOR SYMPTOMS - 4 cardinal symptoms

  • resting tremor
  • bradykinesia
  • rigidity
  • postural instability - stooping posture

AUTONOMIC NERVOUS SYSTEM EFFECTS - happen earlier than motor symptoms

  • olfactory deficits
  • orthostatic hypotension
  • constipation

NEUROPSYCHIATRIC - happen later than motor symptoms

  • sleep disorders
  • memory deficits
  • depression
  • irritability
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8
Q

State the main treatment used for Parkinson’s Disease

A

Dopamine replacement

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9
Q

Outline how Dopamine Replacement can treat Parkinson’s Disease

A

L-Tyrosine (TYR) –> Dopamine (DA)

Rate-Limiting Enzyme: Tyrosine Hydroxylase (TH)

DOPAMINE REPLACEMENT = Levodopa (L-DOPA)

  • Increases levels of dopamine
  • Beforehand, neurodegeneration leads to loss of 80% of dopamine neurones
  • Rapidly converted to DA by DOPA decarboxylase (DOPA-D)
  • Can cross blood brain barrier (BBB)
  • However, these cells are also in the periphery
  • Peripheral breakdown by DOPA-D, leads to nausea and vomiting
  • Dopamine activates CTZ (chemoreceptor trigger zone)
  • Long term side-effects: dyskinesias and ‘on-off’ effects. Not disease-modifying
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10
Q

What adjuncts are used alongside dopamine replacement for Parkinson’s treatment?

A

DOPA Decarboxylase Inhibitors: Carbidopa & Benserazide

  • Do not cross BBB and therefore prevent peripheral breakdown of levodopa
  • Reduce required levodopa dosage

COMT Inhibitors: Entacapone & Tolacapone

  • Increase amount of levodopa in the brain
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11
Q

What receptors do dopamine act on and how is it metabolised?

A

RECEPTORS

Dopamine (DA) can act of D1,5 (Gs linked) or D2-4 (Gi-linked) receptors

RE-UPTAKE

DA is re-uptaken by the dopamine transporter (DAT)

METABOLISM

DA is metabolised by monoamine oxidase (MAO) enzymes

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12
Q

Outline the dopamine receptor agonists used as dopamine replacement in Parkinson’s Disease treatment

A

DOPAMINE RECEPTOR AGONISTS

Ergot Derivatives - Bromocriptine & Pergolide

  • Act as potent agonists of D2 receptors
  • Associated with cardiac fibrosis
  • Therefore, can be problematic if given for a long period of time

Non-Ergot Derivatives - Ropinirole & Rotigotine

  • Ropinirole also available as extended-release formulation
  • Rotigotine also available as a patch
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13
Q

Outline the MAOB Inhibitors used in Parkinson’s Disease treatment

A

MONOAMINE OXIDASE B (MAO-B) INHIBITORS

Selegiline (Deprenyl) & Rasagiline

  • Reduce the dosage of L-DOPA required
  • Can increase the amount of time before levodopa treatment is required
  • “cheese-reaction”
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14
Q

What is the life-expectancy for a person with schizophrenia?

A

Their life expectancy is around 20-30 years lower than average

Usually due to recreational drug use which is often used by the patient’s to control their symptoms and to feel relief

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15
Q

What groups of people have a higher incidence of schizophrenia?

A

Higher incidence in ethnic minorities (e.g. Afro-Carribbean immigrants)

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16
Q

What percentage of the population are affected by schizophrenia?

A

Affects 1% of the population

17
Q

What factors affect schizophrenia?

A

Schizophrenia does have genetic influences

  • there is a higher incidence if a family member has the condition
  • therefore, must be a genetic factor

Mainly environmental factors

18
Q

When does the onset of schizophrenia symptoms typically occur?

A

Onset of Symptoms: between 15-35 years old normally

19
Q

What are the symptoms of schizophrenia?

A

POSITIVE SYMPTOMS

  • Increased mesolimbic dopaminergic activity
  • Halluncinations: auditory and visual
  • Delusions: paranoia
  • Thought disorder: denial about oneself having the condition
  • Drugs tend to treat these symptoms

NEGATIVE SYMPTOMS

  • Decreased mesocortical dopaminergic activity
  • Affective flattening: lack of emotion
  • Alogia: lack of speech
  • Avolition/apathy: loss of motivation
20
Q

What are the first-generation antipsychotics?

A

First Generation Antipsychotics = Typical Antipsychotics

Chlorpromazine

Haloperidol

21
Q

Outline the action of Chlorpromazine

A

Discovered whilst developing new antihistamines

Primary mechanism of action – possibly D2 receptor antagonism

‘dirty drug’ = affects lots of pathways, not necessarily ones we want to affect

Side effects

  • High incidence - anti-cholinergic, especially sedation
  • Low incidence - extrapyramidal side-effects (EPS)
22
Q

Outline the action of Haloperidol

A

Very potent D2 antagonist (~ 50x more potent than chlorpromazine)

Therapeutic effects develop over 6-8 weeks

Little impact on negative symptoms

Not very selective

Side effects

  • High incidence - extra-pyramidal side effects (EPS)
  • This causes motor symptom problems
23
Q

What are the second-generation antipsychotics?

A

Second-Generation Antipsychotics = Atypical Antipsychotics

Clozapine

Risperidone

Quetiapine

24
Q

Outline the action of Clozapine

A

CLOZAPINE

Most effective antipsychotic

Very potent antagonist of 5-HT2A receptors

This causes serotonin inhibition

Only drug to show efficacy in treatment resistant schizophrenia & some of the negative symptoms

  • other drugs only effect positive symptoms of schizophrenia

Side effects

  • potentially fatal neutropenia
  • agranulocytosis
  • myocarditis
  • weight gain
25
Q

Outline the action of Quetiapine

A

Very potent antagonist of H1 receptors

Side Effects

  • Lower incidence of EPS than other antipsychotics
26
Q

Outline the action of Risperidone

A

Very potent antagonist of 5-HT2A & D2 receptors

Side Effects

More EPS & hyperprolactinaemia than other atypical antipsychotics

27
Q

State the timeline by which the antipsychotics were discovered

A
28
Q

What is Arpiprazole?

A

Partial agonist of D2 and 5-HT1A receptors

Most drugs block D2 receptors

No more efficacious than typical antipsychotics

Side Effects

  • Reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics
29
Q

What kind of molecules are DA, NA and A?

A

Monoamine neurotransmitters

30
Q

Are drugs used for Parkinson’s Disease disease-modifying?

A

No, they are not disease-modifying but are just symptomatic treatments

Yr 2 LCRS - Pharm (44 decks)

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