Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Flashcards
What are the three main dopaminergic pathways in the brain?
Nigrostriatal
Mesolimbic
Tuberoinfundibular system
Where are each of these pathways found?
Nigrostriatal– projecting from the substantia nigra pars compacta to the striatum
Mesolimbic– projecting from the ventral tegmental area to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle
Tuburoinfundibular system– projecting from the arcuate nucleus in the hypothalamus to the median eminence and pituitary gland
What are the roles of these pathways?
Nigrostriatal – control of movement
Mesolimbic – involved in emotion
Tuburoinfundibular system – regulate hormone secretion
What are the two families of dopamine receptors and which receptors fall into each of these families?
D1 family – D1 + D5
D2 family – D2, D3 + D4
Describe dopamine synthesis.
Tyrosine is converted by tyrosine hydroxylase to DOPA
DOPA is converted by DOPA decarboxylase to Dopamine
Is Parkinson’s disease more common in males or females?
Males – 4:1
What percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?
8%
The rest are idiopathic
What are the possible causes of idiopathic Parkinson’s disease?
Possibly a combination of environmental, oxidative stress, altered protein metabolism and risk genes
What are the cardinal signs of Parkinson’ disease?
Resting tremor (pill-rolling tremor)
Rigidity (stiffness – limbs feel weak and heavy)
Bradykinesia (slowness of movement)
Postural abnormality
What are the presenting symptoms of Parkinson’s disease?
Pill-rolling resting tremor
Difficulty with fine movements (micrographia)
Poverty of blinking
Hypomimic face
Monotony of speech and loss of volume of voice
Disorders of posture – flexion of the neck and trunk
Lack of arm swing
Loss of balance – lack of righting reflex, retropulsion
Short steps, shuffling gait
Describe the initial distribution of symptoms across the body.
Unilateral onset
Symptoms spread to both sides
Generally symptoms worsen with some patients becoming severely disabled
What are some non-motor symptoms of Parkinson’s disease?
Depression Pain Taste/smell disturbances Cognitive decline/dementia Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)
What is the main area of the brain that is affected by Parkinson’s disease?
Substantia nigra
Other brain areas affected: locus coeruleus, dorsal vagus nucleus, nucleus basalis of Mynert
Describe the neuropathology of Parkinson’s disease.
Putamen-projecting pathways degenerate significantly Lewy bodies (large circular structure with bright core and white surrounding, packed with alpha-synuclein) also present – this is probably a defensive mechanism to protect against toxic altered proteins
What are the stages of Parkinson’s disease?
1-2 = dorsal motor nucleus of vagus, raphe nucleus, locus coeruleus 3 = substantia nigra pars compacta 4 = amygdala, nucleus of Meynert, hippocampus 5-6 = cingulate cortex, temporal cortex, frontal cortex, parietal cortex, occipital cortex
What is the main biochemical change seen in Parkinson’s disease?
Marked reduction in the caudate nucleus/putamen dopamine content
What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?
80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear
What is the reason for this?
There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors
What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why?
Peripheral DOPA decarboxylase inhibitor
This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (this can cause nausea and vomiting)
State two different preparation of dopamine replacement therapy.
Sinamet = Carbodopa + L-DOPA Madopar = Benserazide + L-DOPA
What does L-DOPA treat?
Hypokinesia
Tremor
Rigidity
Describe how the dosage of L-DOPA is changed with continued treatment.
It is started low and increased until maximum benefit of drug is achieved without side effects
Effectiveness of L-DOPA declines with time
What are the acute side effects of L-DOPA?
Nausea (prevented by domperidone) Hypotension Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)
What are the chronic side effects of L-DOPA?
Dyskinesias (abnormal movement of limbs and face – can occur within 2 years of treatment – disappear with reduced dose)
Rapid fluctuations in clinical state (off periods may last for minutes to hours
Name three dopamine agonists.
Bromocriptine
Ropinerol
Pergolide
Which receptors do they act on?
D2 receptor
What are the benefits of dopamine agonists over L-DOPA?
Longer duration of action Smoother and more sustained response Actions independent of dopaminergic neurones Incidence of dyskinesias is less NOTE: L-DOPA is still the gold standard
What are the adverse effects of dopamine agonists?
Common – confusion, dizziness, nausea/vomiting, hallucinations
Rare – constipation, headache, dyskinesia
What structure used to be present in older dopamine agonists that caused quite serious clinical problems?
Ergot ring
This caused problems with heart valves
What has been the consequence of the removal of this structure within dopamine agonists?
Development of addictive behaviour e.g. gambling
Name two MAO inhibitors.
Deprenyl (selegiline)
Rasagiline
What are the effects of Deprenyl?
Selective for MAO-B (this predominates in dopaminergic areas of CNS)
Does NOT have the peripheral side effects of non-selective MAO inhibitors
Can be given in combination with L-DOPA (reduce dose of L-DOPA by 30-50%)
What are the side effects of Deprenyl?
RARE
Hypotension
Nausea/vomiting
Confusion and agitation
What are the effects of Rasagiline?
It has neuroprotective properties by inhibiting apoptosis (promotes anti-apoptosis genes)
NOTE: early clinical trials show this drug might slow down the progression of disease but subsequent studies haven’t been so promising
Name two COMT inhibitors.
Tolocapone (CNS + PNS)
Entacapone (PNS)
What are the effects of COMT inhibition in the CNS?
Prevents breakdown of dopamine in the brain
What are the effects of COMT inhibition in the peripheral nervous system?
Peripheral COMT converts L-DOPA to 3-O-methyl DOPA (3-OMD) 3-OMD competes with L-DOPA for the transport system that transports it across the BBB
COMT inhibitors stop 3-OMD production and hence there is less competition for L-DOPA
Result: REDUCE L-DOPA DOSAGE
What are the side effects of COMT inhibitors?
Cardiovascular complications
What percentage of the general population is affected by schizophrenia?
1%
What are the symptoms of schizophrenia?
Positive Symptoms (overt symptoms that should NOT be present)
Hallucinations
Delusions
Disorganised thoughts
Negative Symptoms (lack of characteristics that SHOULD be present)
Reduced speech
Lack of emotional and facial expression
Diminished ability to begin and sustain activity
Decreased ability to find pleasure in everyday life
Social withdrawal
Cognitive deficits
Memory
Attention
Planning
Decision making
What appears to have quite a strong contribution to the development of schizophrenia?
Genetics
Once schizophrenia has been diagnosed, what are the four main outcomes for patients?
1 – illness resolves completely, with or without treatment and never returns (10-20%)
2 – illness recurs repeatedly with full recovery between episodes (30-35%)
3 – illness recurs repeatedly with incomplete recovery and a persistent defective state develops, becoming more profound with each successive relapse (30-35%)
4 – illness pursues down a downhill course from the beginning (10-20%)
NOTE: most cases are relapsing and remitting
Describe the involvement of dopamine in schizophrenia.
Positive symptoms – results from excessive dopamine transmission in the mesolimbic and striatal region (D2-mediated)
Negative symptoms – results from dopamine deficit in the pre-frontal region (D1-mediated)
What evidence has arisen that supports this hypothesis?
Dopamine agonists can induce various psychotic reactions
Typical antipsychotics are dopamine receptor antagonists (blocking D2 receptors)
Describe the involvement of glutamate in schizophrenia.
NMDA is a glutamate receptor
Glutamate exerts an excitatory influence over the GABA-ergic striatal neurones and dopamine exerts an inhibitory influence
These GABA-ergic striatal neurones project to the thalamus and constitute a sensory ‘gate’
Too little glutamate or too much dopamine disables this gate, allowing uninhibited sensory input to reach the cortex
NOTE: you find reduced glutamate concentration and reduced glutamate receptors in post-mortem schizophrenic brains. Also NMDA receptor antagonists can produce psychotic symptoms
What is the most robust gene associated with schizophrenia?
Neuregulin-1
What are all the susceptibility genes for schizophrenia associatedwith?
Dopamine and glutamate neurotransmission
What type of drug are all neuroleptics?
Dopamine receptor antagonists (D2 receptors)
NOTE: most neuroleptics block other receptors
Which symptoms do neuroleptic drugs treat?
Positive symptoms ONLY
What are the initial effects of neuroleptic drugs?
Initial increase in dopamine synthesis and neuronal activity – this declines with time
What is meant by an atypical antipsychotic?
Newer antipsychotics are given this term – they have fewer extrapyramidal side effects
Name an atypical antipsychotic.
Clozapine
Name a typical antipsychotic.
Haloperidol
What is an important other action of neuroleptics?
Anti-emetic
Because they block dopamine receptors in the chemotactic trigger zone
Phenothiazine is a neuroleptic that is really good at preventingnausea/vomiting caused by drugs
NOTE: many neuroleptics also block histamine receptors – this is effective at controlling motion sickness
What are the extrapyramidal side effects of antipsychotics caused by?
Blockade of dopamine receptors in the nigrostriatal system can induce
Parkinson-like side effects
What are the two main extra-pyramidal side effects? Acute Dystonia
Involuntary movements
Muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc.
Often accompanied by Parkinson’s like features
Occur in the FIRST FEW WEEKS and often decline with ongoing therapy
Reversible with withdrawal of the drug or anti-cholinergics
Tardive Dyskinesias
Involuntary movements
Involving the face and tongue, but also trunk and limbs
Occur in 20% of patients after SEVERAL MONTHS/YEARS of therapy
Made WORSE by drug withdrawal or anti-cholinergics
What are the unwanted effects of antipsychotics?
Endocrine effects – loss of inhibition of prolactin secretion leads to hyperprolactinaemia (can lead to breast swelling and sometimes lactation)
Blocking alpha-adrenoceptors – postural hypotension
Blocking 5-HT receptors – weight gain
Blockade of muscarinic receptors – typical anti-muscarinic effects e.g. blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention
