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Year 2 - Pharm Lectures 11+ > Anti-PD & Neuroleptics > Flashcards

Anti-PD & Neuroleptics Flashcards

1
Q

What are the 3 principal dopaminergic pathways in the brain?

A

(1) Nigrostriatal
• substantia nigra zona compacta –> striatum
• control of movement - impacted in PARKINSON’S

(2) Mesolimbic
• VTA –> NAcc, frontal cortez, limbic cortex, olfactory tubercle
• involved in emotion - impacted in SCHIZOPHRENIA

(3) Tuberoinfundibular
• arcuate nucleus –> median eminence, PG
• regulate hormone secretion - inhibition results in hyperprolactinaemia

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2
Q

What is another dopaminergic pathway?

A

(4) Mesocortical pathway
• VTA –> cerebrum
• important in executive functions & complex behavioural patterns

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3
Q

Explain the synthesis of dopamine

A

L-tyrosine –> L-DOPA –> DA

This process utilises the enzymes:
• Tyrosine hydroxylase
• DOPA decarboxylase

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4
Q

What are the 2 families of DA receptors?

A

D1 family
• D1, D5
• Gs-linked

D2 family
• D2, D3, D4
• Gi-linked

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5
Q

Explain the metabolism of DA

A

DA removed from synaptic cleft by:
• dopamine transporter (DAT)
&
• noradrenaline transporter (NET)

Three enzymes metabolise DA:
• Monoamine oxidase A (MAO-A): metabolises DA, NE & 5-HT

  • MAO-B: metabolises DA
  • Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
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6
Q

Epidemiological causes of Parkinson’s?

A

Causes:
• Familial cases of Parkinson’s accounts for ~8% cases

• Idiopathic (unsure of sporadic causes) cases account ~92% of all cases

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7
Q

Explain what the principal area that is affected in Parkinson’s

A

Substantia Nigra (pars compacta)

  • Projects into the Caudate and the Putamen
  • SNpc contains neuro-melanin pigment which we don’t know the function of – there is a loss of this pigment in PD

This SNpc degeneration accounts for the MOTOR features
 Other affected areas – Locus Coeruleus (LC), dorsal vagus nucleus, Nucleus Basalis of Mynert

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8
Q

Explain the pathophysiology of Parkinson’s

A

The specific aetiology of PD is not known

LEWY BODIES & NEURITES define PD and are filled with “Altered Proteins” which are toxic proteins:
 Alpha-Synuclein
 Ubiquitin

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9
Q

Explain the nigra-striatal pathway

A

The nigra-striatal pathway is part of the basal ganglia loop.
o it has an important regulatory role in initiating and fine tuning and ending movement control

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10
Q

What are the 3 broad areas of clinical presentation

A

Motor symptoms

ANS effects

Neuropsychiatric

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11
Q

Explain the ‘Motor Symptoms’ Clinical Presentations

A

o Resting temor
• shaking of limbs when relaxed (opposite of intention termor)

o Rigidity
• stiffness, limbs feel heavy/weak

o Bradykinesia
• slowness of movement

o Postural abnormalities
• cardinal symptoms

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12
Q

What are the onset features of Parkinson’s

A

Unilateral & spreads to both sides of the body

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13
Q

What are the ANS effects of clinical presentations

A

o Olfactory deficits

o Orthostatis hypotension

o Constipation

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14
Q

What are the neuropsychiatric of clinical presentations

A

o Sleep disorders

o Memory deficit

o Depression

o Irritability

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15
Q

What needs to happen for Parkinson’s symptoms to appear

A 
There needs to be decline of at least
 • 80-85% DA neurones 
and 
 • 70% of the striatal DA
before symptoms can appear

o This is due to the compensatory mechanisms of the body which prevent the appearance of clinical symptoms.

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16
Q

What are the 3 broad PD treatment

A

(1) DA replacement
(2) DA Receptor Agonists
(3) Monoamine oxidase B (MAOb) inhibitors

17
Q

What is used as (1) DA Replcaement as a PD treatment

A

DA can NOT cross BBB
• L-DOPA CAN so use this instead

Levodopa!!

18
Q

Explain (1) DA Replacement as a PD treatment

A

L-tyrosine –> DA
• Rate-limiting enzyme: Tyrosine hydroxylase

Levodpoa
• rapidly converted to DA by DOPA decarboxylase (DOPA-D)
• SO use DOPA decarboxylase inhibitor to prevent PERIPHERAL breakdown

19
Q

Explain adjuncts given with (1) DA Replacement

A

DOPA Decarboxylase Inhibitors
• Carbidopa & Benserazide
• prevent peripheral breakdown (& do NOT cross BBB)
• REDUCE Levodopa dose required

COMT Inhibitors
• Entacapone & Tolcapone
• INCREASE amount of levodopa in the brain

20
Q

Example drugs used for (1) DA Replacement

A
  1. Sinamet
    • Carbidopa + L-DOPA
  2. Madopar
    • Benserazide + L-DOPA
21
Q

What does (1) DA Replacement treat?

A

Hypokinesia
Rigidity
Tremor

Still gold-standard treatment
• if response to L-DOPA is poor, question P.D diagnosis
• effectiveness DECREASES w. time

22
Q

SEs associated with (1) DA Replacement?

A

Acute
• nausea & vomiting (due to peripheral breakdown of DOPA-D - treat w. D2-receptor antagonists)

  • hypotension
  • psychological effects (e.g. confusion)

Chronic
• Dyskinesias (abnormal movements of limbs/face)
• ‘On-Off’ effects

NOT disease-modifying

23
Q

Explain (2) DA Receptor Agonists (D2 specifically)

A

Are D2-Receptor Agonists

Ergot Derivatives
• ring structures in drug
• act as potent agonists of D2 receptors
• associated w. cardiac fibrosis (cause problems w. heart valves)

Non-Ergot Derivatives
• Available as extended-release formulation = can cause addictive behaviour

24
Q

Positive actions associated w. (2) DA Receptor Agonists

A
  1. Long T1/2
    • longer than L-DOPA
  2. Has smoother & more sustained response
  3. Action independent of condition of DA neurones (doesn’t rely on synthesis of DA)
  4. Dyskinesia incidence is less
25
Q

Negative actions associated w. (2) DA Receptor Agonsits

A
  1. Confusion, Dizziness, nausea, hallucinations (common)

2. Constipation, headache, dyskinesias (rare)

26
Q

Drugs associated w. (2) DA Receptor Agonists

A

Ergot Derivatives
• Bromocriptine
• Pergolide

Non-Ergot Derivatives
• Ropinirole (extended-release)
• Rotigotine (available as patch)

27
Q

Drugs associated with (3) Monoamine Oxidase B (MAOb) inhibitors?

A

Predominates in DA areas

 Selegiline (deprenyl)
• can be given ALONE in early stages OR in combination with L-DOPA to reduce the latters dosage
• SE are rare but include hypotension, nausea, confusion & agitation

 Rasagiline
• same as above
• shown to have neuroprotective properties by inhibiting apoptosis (promotes anti-apoptotic genes)

28
Q

Epidemiology of Schizophrenia

A

Affects ~1% of population
 has genetic influence

Higher incidence in ethnic minorities

Patient’s life expectancy ~20-30 years LOWER than average

29
Q

Positive symptoms of Schizophrenia?

A

‘add’ something

  • Increased mesolimbic DA activity
  • Hallucinations - auditory & visual
  • Delusions - paranoia
  • Though disorder - denial about oneself
30
Q

Negative symptoms of Schizophrenia?

A

‘take away’ something

  • Decreased mesolimbic dopaminergic activity
  • Affective flattening - lack of emotion
  • Alogia - lack of speech
  • Avoilition/apthay - loss of motivation
31
Q

What were the FIRST GENERATION ANTIPSYCHOTICS that were used?

A

 Chlorpromazine:
• discovered whilst developing new antihistamines
• 1o MoA = possibly D2 receptor antagonism

SEs
• high incidence - anticholinergic, especially sedation
• low incidence - extra-pyramidal SEs (EPS)

 Haloperidol:
• very potent D2 antagonist (~50% more than above)
• therapeutic effects develop over 6-8weeks
• LITTLE IMPACT on -VE symptoms

SEs
• high incidence - EPS

32
Q

Explain EPS

A

Block DA-R in nigro-striatal system –> induces Parkinson’s patients-like side effects

 Acute dystonia – involuntary movements
 Tardive dyskinesias – involuntary movements – made worse by drug withdrawal or anti-cholinergics.
• Must treat dyskinesias by giving MORE drug!

33
Q

What anti-psychotic drug was then introduced in 1970, marking the start of the SECOND GENERATION of ANTI-PSYCHOTICS

A

 Clozapine
• potent antagonist of 5-HT2a receptors
• only drug to show efficacy in treatment resistant schizophrenia & negative symptoms

MOST EFFECTIVE antipsychotic

SEs
• can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain

34
Q

Which drugs followed Clozapine?

A

 Risperidone
• potent antagonist of 5-HT2a & D2 receptors

SEs
• more EPS & hyperprolactinaemia than other atypical antipsychotics

 Quetiapine
• potent antagonist of H1 receptors

SEs
• lower incidence of EPS than other antipsychotics

35
Q

Most recent drug introduced as an antipsychotic?

A

 Aripiprazole
• partial agonist of D2 & 5-HT1a receptors
• NO MORE effcacious than typical antipsychotics

SEs
• reduced incidence of hyperprolactinaemia & weight gain than other antipsychotics

Year 2 - Pharm Lectures 11+ (23 decks)

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