Anti-Parkinson's Drugs & Neuroleptics Flashcards
what are the 4 prinicipal dopaminergic pathways of the brain?
- nigrostriatal
- mesolimbic
- mesocorticol
- tubero-infundubular
what is the nigrostriatal pathway?
substanstia nigra pars compacta –>corpus striatum.
what is the role of the nigrostriatal pathway? which condition is it impacted in?
control of movement (initiating and fine tuning and ending movement control)
impacted in Parkinsons
what is the role of mesolimbic pathway?
which condition is it impacted in?
brain reward pathway
affected in schizophrenia
what is the mesolimbic pathway?
ventral tegmental area (VTA) –> NAcc (ventral striatum)
what is the mesocortical pathway?
VTA–> cortical areas like frontal cortex, limbic cortex
what is the role of the mesocortical pathway?
executive function
what is the tubero-infundibular pathway?
arcuate nucleus–> median eminence–> pituitary gland
arcuate nucleus is in the hypothalamus
used in appetite control via orexinergic pathways
what is the role of the tubero- infundibular pathway?
hormone secretion regulation (endocrine)
e.g prolactin (inhibited by dopamine)
what are the precursors of dopamine?
L-tyrosine to L-DOPA via Tyrosine hydroxylase
L-Dopa to DA via DOPA decarboxylase
what are the 2 families of DA receptors? which are the members?
o D1 family – D1, D5.
o D2 family – D2, D3, D4.
what is the mean age of onset of PD?
65
4:1 males to females
can affect younger people however
what is the main pathogenesis of PD?
degeneration of the nigrostriatal pathway (dopaminergic projections) from the substantial niagra to the corpus striatum
what are the 2 main causes of PD?
o Familial cases (8%) geneslead to earlier onset of the disease
- SNCA (alpha synuclein)
- LRRK2
o Idiopathic (92%)
what are the clinical signs of PD?
o Resting tremor (early)
– shaking of the limbs when relaxed (opposite of intention tremor).
o Rigidity (late) – stiffness, limbs feel heavy/weak.
o Bradykinesia
– slowness of movement.
o Postural abnormalities.
features can be unilateral and spread bilaterally
what are the motor symptoms of PD?
o Pill-rolling tremor at rest. o Difficulty with fine movements – micrographia. o No blinking and a blank face. o Monotone speech. o Disorder of posture – flexion of neck and trunk. o Lack of arm swing. Postural hypotension. o Loss of balance – lack of a righting reflex. o Short steps, shuffling gait.
what are the non-motor/autonomic symptoms of PD?
o Depression. o Sleep disturbances. o Taste/smell disturbances. o Dementia. o Constipation. o Postural hypotension. o Urinary urgency. o Impotence and hyper-hydrosis.
what is the main area affected in PD?
Substantia nigra (pars compacta)
loss of neuro-pigment and degeneration
what does the Substantia nigra project into?
Caudate and the Putamen
dorsal striatum
what visible change occurs in the SubNig in PD?
neuro-melanin pigment is lost
what physical change in the brain leads to the motor features of PD?
Substantia nigra degeneration
other: Locus Coeruleus (LC), dorsal vagus nucleus, Nucleus Basalis of Mynert.
what proteins can be found in the brain with PD?
- Lewy Bodies (contain Synuclein and Ubiquitin)
- Neurites
- abnormally phosphorylated neurofilaments (altered proteins)
these are not targeted in therapy
what are the sets of symptoms in PD?
- motor
- non-motor/ autonomic
how does PD progress (pathological changes with stage)?
Synuclein is part of Lewy Bodies (also ubiquitin)
characteristic to Parkinsons
Stages 1 & 2 – Synuclein deposition in the Dorsal motor nucleus of Vagus Raphe Nucleus Locus Coerulus – pre-symptomatic.
Stages 3
– Synuclein deposition in Substantia Nigra – onset of motor deficits.
Stage 4, 5, 6
– deposition in the amygdala and cortical areas e.g. cingulate cortex, frontal, temporal etc
how much damage has been done to neurones before symptoms of PD appear?
damage to at least 80-85% DA neurones and 70% of the striatal DA before symptoms appear
due to the compensatory mechanisms of the body which prevent the appearance of clinical symptoms.
by which 3 mechanisms can we treat PD symptoms?
1) dopamine replacement to account for neurodegeneration (increase DA supply)
2) activation of DA receptors (induce DA effects)
3) reducing DA metabolism (to increase DA survival)
what drug can be given to replace dopamine in PD?
Levodopa (L-DOPA)
precursor of dopamine
NB L-tyrosine–> DOPA–> Dopamine
how does Levodopa enable replacement of dopamine?
provides the DA precursor L-DOPA so it can be converted by DOPA decarboxylase to DA
this drug is capable of crossing the BBB to enter the CNS and work given that the DA receptors are intact (PD affects presynaptic transmission)
Dopamine CAN NOT cross the BBB
why is L-DOPA precursor given rather than more DA?
why not more tyrosine?
L-DOPA can cross the BBB while DA can NOT cross the BBB
Giving more tyrosine has no effect as the amount of tyrosine hydroxylase is constant
how is dopamine replacement therapy (Levodopa) provided?
Levodopa is given with an adjuvant Carbidopa
combo known as Sinamet
what is carbidopa and why is it given with Levodopa?
carbidopa is a DOPA decarboxylase inhibitor
this will ensure that L-DOPA (Levodopa) is not metabolise into DA in the periphery and enables the maximum amount of L-DOPA to cross the BBB.
summary: increase L-DOPA in the CNS
examples of combined dopamine replacement drugs?
- Sinamet (Carbidopa + L-DOPA)
- Madopar (Benserazide + L-DOPA).
what effect does L-DOPA have on symptoms?
Treats – hypokinesia, rigidity and tremor
if symptoms do not improve with Levodopa , the PD diagnosis needs to be questioned
however effectiveness does decrease with time
why are adjuvants given with Levodopa?
to reduce side effects namely nausea and vomiting
DA can bind to receptors of CTZ
what drugs are used to replace DA (increase initial supply) in the CNS?
Levodopa along with carbidopa (enhancer)
DA is indirectly increased by reducing metabolism (not by boosting DA supply)
- COMT inhibitors
- MAO inhibitors
COMT and MAO degrade monoamines like DA so their inhibition means there is more DA available
what do COMT inhibitors do in the CNS? example of drug
prevent breakdown of DA
Tolocapone (works periphery aswell)
what does COMT usually do in the periphery?
what effect would inhibition of COMT have?
example of drug
- peripheral COMT converts L-DOPA to 3-OMD
- 3-OMD competes with L-DOPA to cross the BBB
- therefore inhibition means more L-DOPA can cross the BBB
example: Entacapone
what are the side effects of L-DOPA/Levodopa treatment?
o Acute
– nausea (DA to CTZ)
(treat with D2-receptor antagonists), hypotension, psychological effects (e.g. confusion)
o Chronic
– dyskinesias (abnormal movements of limbs/face)
“On-Off” effects (fluctuations in clinical state).
what drug is given to increase DA receptor activation (one of the methods in treating PD)?
Dopamine Receptor Agonists
D2 specifically
e.g. bromocriptine
MAO inhibitor drug example
Selegiline: MAO-B inhibitor
MAO-B preferentially degrades DA therefore inhibition is ideal for PD
MAO-A degrades 5HT and NA therefore inhibition would be ideal for anti-depressants where serotonin and noradrenaline are in deficit especially
what are side effects of MAOi?
orthostatichypotension
nausea
confusion
agitation.
at overdose: limited by the Cheese Reaction involving tyramine (competes with NA for MAO so enhanced NA in the cleft leading to a hypertensive crisis)
name examples of D2 receptor agonists and their categories
Bromocriptine, Pergolide
- Ergot Derivatives
Ropinerol, Rotigotine
- Non-Ergot Derivatives
why do D2 receptor agonist work in treating PD?
in PD, the postsynaptic receptors are intact. Degeneration of PREsynaptic transmission is the problem so receptors can be stimulated by agonists
what is the different in side effects between Ergot derivative D2R agonists and Non-Ergot derivative drugs in terms of side effect?
Non-Ergot derivatives don’t have the cardiac fibrosis side effect (valve issue) unlike Ergot derivatives
however Non-Ergot derivatives lead to addictive behaviours (general impulse control)
what is the advantage of using D2 receptor agonists over L-DOPA?
- long T1/2 (longer than L-DOPA)
- have a smoother and more sustained response
- the action is independent of condition of DA neurones (doesn’t rely on synthesis if DA)
- dyskinesia incidence is less.
what are the negative side effects of D2 receptor agonists?
e.g Bromocriptine, Pergolide, Ropinerol
commom: confusion, dizziness, nausea, hallucinations,
rare: constipation, headache, dyskinesias
dyskinesia is impairment of voluntary movement
what are the positive symptoms of schizophrenia? what causes these symptoms?
increased mesoLIMBIC DA activity via D2 :
- Hallucinations
- delusions
- disorganised thoughts (though disorder)
[mesolimbic: VTA–> NAcc]
positive symptoms are added aspects
what are the negative symptoms of schizophrenia?
decreased mesoCORTICAL DA activity via D1
- alogia= Reduced speech
- affective flattening= lack of expression
- avolition= diminished ability to begin and sustain activities (motivation)
- anhedonia=
decreased ability to find pleasure in everyday activities
- asociality= social withdrawal
what is meant by a positive and negative symptom in schizophrenia?
positive: adds a behaviour/feeling/thought
negative: takes away a behaviour/feeling/thought
what are the negative symptoms of schizophrenia?
- alogia
- affective flattening
- avolition
- anhedonia
- asociality
what are the cognitive deficits associated with schizophrenia?
deficits in – memory, attention, planning and decision making.
what causes the positive symptoms of schizophrenia?
increased mesolimbic DA activity via D2 receptors
what causes the negative symptoms of schizophrenia?
decreased mesocortical DA activity (DA deficit is seen in pre-frontal regions mediated by D1 receptors )
what symptoms of schizophrenia do anti-schizophrenia drugs usually target?
how do these drugs specifically address these symptoms?
the positive symptoms
- anti-schizophrenic drugs are normally dopamine antagonists
- easily targets positive symptoms as they are caused by dopamine hyperactivity in the mesolimbic system
- via D2 receptors
negative symptoms are hard to target (due to dopamine hyPOactivity, therefore antagonism would make these symptoms worse)
what is schizophrenia?
a long-term mental disorder of a type involving a breakdown in the relation between thought, emotion, and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a sense of mental fragmentation.
what are the neurochemical theories for schizophrenia?
1) Dopamine theory
2) Glutamate theory
what classes of drugs are used in treating schizophrenia?
Neuroleptics
1) D2-receptor antagonists
– ALL neuroleptics.
2) Block other receptors e.g. 5-HT
– MOST neuroleptics.
Antipsychotics/Neuroleptics:-apine, -idone, -azole.
what are the first generation of drugs treat the positive symptoms of Schizophrenia?
what are the side effects?
D2 receptor antagonists:
1) chlorpromazine
side effect: sedative & anti-muscarinic effects
2) haloperidol
side effect: extrapyramidal
what drug can be used for negative symptoms of schizophrenia?
clozapine (only one)
5HT2a receptor antagonist
side effects: potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain side effect
what are the 2nd generation of drugs used to treat the positive symptoms of schizophrenia?
1) Risperidone [5-HT2A & D2 receptors antagonist]
side effect: EPS & hyperprolactinaemia
2) Quetiapine
[H1 receptors antagonist]
side effect: Lower incidence of EPS
3) Aripiprazole
[partial AGONIST of D2 & 5-HT1A receptors]
side effect: Reduced incidences of hyperprolactinaemia & weight gain
what are the general side effects of neuroleptics (schiz)?
- due to DA receptor blockage
- due to blockage of other receptors
1) effect of blocking DA receptors:
- extrapyramidal effects aka Parkinson’s like symptoms (Block DA-R in nigro-striatal system )
- sedation
- hyperglycaemia
- prolactin secretion (DA inhibition removed)
2) effect of blocking other receptors:
- orthostatic hypotension (blocking alpha-adrenoceptors)
- peripheral anti-muscarinic side effects (blocking mAChr)
- weight gain (blocking 5-HTr)
which is the only partial agonist neuroleptic?
aripiprazole
partial AGONIST of D2 & 5-HT1A receptors
no more efficacious
where is synuclein deposition seen in stage 1 of PD progression?
Dorsal motor nucleus of Vagus
Raphe nucleus
Locus Coerulus
all pre synaptic
