Anti-PD & Neuroleptics Flashcards
What are the 3 principal dopaminergic pathways in the brain?
(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
What is another dopaminergic pathway?
(4) Mesocortical pathway
• VTA –> cerebrum
• important in executive functions & complex behavioural patterns
Explain the synthesis of dopamine
L-tyrosine –> L-DOPA –> DA
This process utilises the enzymes:
• Tyrosine hydroxylase
• DOPA decarboxylase
What are the 2 families of DA receptors?
D1 family
• D1, D5
• Gs-linked
D2 family
• D2, D3, D4
• Gi-linked
Explain the metabolism of DA
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
Epidemiological causes of Parkinson’s?
Causes:
• Familial cases of Parkinson’s accounts for ~8% cases
• Idiopathic (unsure of sporadic causes) cases account ~92% of all cases
Explain what the principal area that is affected in Parkinson’s
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
Explain the pathophysiology of Parkinson’s
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
Explain the nigra-striatal pathway
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
What are the 3 broad areas of clinical presentation
Motor symptoms
ANS effects
Neuropsychiatric
Explain the ‘Motor Symptoms’ Clinical Presentations
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
What are the onset features of Parkinson’s
Unilateral & spreads to both sides of the body
What are the ANS effects of clinical presentations
o Olfactory deficits
o Orthostatis hypotension
o Constipation
What are the neuropsychiatric of clinical presentations
o Sleep disorders
o Memory deficit
o Depression
o Irritability
What needs to happen for Parkinson’s symptoms to appear
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.
What are the 3 broad PD treatment
(1) DA replacement
(2) DA Receptor Agonists
(3) Monoamine oxidase B (MAOb) inhibitors
What is used as (1) DA Replcaement as a PD treatment
DA can NOT cross BBB
• L-DOPA CAN so use this instead
Levodopa!!
Explain (1) DA Replacement as a PD treatment
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
Explain adjuncts given with (1) DA Replacement
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
Example drugs used for (1) DA Replacement
- Sinamet
• Carbidopa + L-DOPA - Madopar
• Benserazide + L-DOPA
What does (1) DA Replacement treat?
Hypokinesia
Rigidity
Tremor
Still gold-standard treatment
• if response to L-DOPA is poor, question P.D diagnosis
• effectiveness DECREASES w. time
SEs associated with (1) DA Replacement?
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
Explain (2) DA Receptor Agonists (D2 specifically)
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
Positive actions associated w. (2) DA Receptor Agonists
- Long T1/2
• longer than L-DOPA - Has smoother & more sustained response
- Action independent of condition of DA neurones (doesn’t rely on synthesis of DA)
- Dyskinesia incidence is less
Negative actions associated w. (2) DA Receptor Agonsits
- Confusion, Dizziness, nausea, hallucinations (common)
2. Constipation, headache, dyskinesias (rare)
Drugs associated w. (2) DA Receptor Agonists
Ergot Derivatives
• Bromocriptine
• Pergolide
Non-Ergot Derivatives
• Ropinirole (extended-release)
• Rotigotine (available as patch)
Drugs associated with (3) Monoamine Oxidase B (MAOb) inhibitors?
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)
Epidemiology of Schizophrenia
Affects ~1% of population
has genetic influence
Higher incidence in ethnic minorities
Patient’s life expectancy ~20-30 years LOWER than average
Positive symptoms of Schizophrenia?
‘add’ something
- Increased mesolimbic DA activity
- Hallucinations - auditory & visual
- Delusions - paranoia
- Though disorder - denial about oneself
Negative symptoms of Schizophrenia?
‘take away’ something
- Decreased mesolimbic dopaminergic activity
- Affective flattening - lack of emotion
- Alogia - lack of speech
- Avoilition/apthay - loss of motivation
What were the FIRST GENERATION ANTIPSYCHOTICS that were used?
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
Explain EPS
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!
What anti-psychotic drug was then introduced in 1970, marking the start of the SECOND GENERATION of ANTI-PSYCHOTICS
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
Which drugs followed Clozapine?
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
Most recent drug introduced as an antipsychotic?
Aripiprazole
• partial agonist of D2 & 5-HT1a receptors
• NO MORE effcacious than typical antipsychotics
SEs
• reduced incidence of hyperprolactinaemia & weight gain than other antipsychotics
