Anti-Parkinsonian drugs and neuroleptics Flashcards
What dopaminergic pathways are there?
Nigrostriatal
Mesolimbic
Tuberoinfundibular system
What is the nigrostriatal pathway and what is it involved in?
Cell bodies originate in the substantia nigra compact (black pigment can be viewed with eye) and projects to striatum-
Control of movement and is affected in parkinsons
What is the mesolimbic pathway and what is it involved in?
Cell bodies originate in the ventral segmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle- involved in emotion and affected in schizophrenia
What is the tuberoinfundibulnar system and what is it involved in?
Short neurones running from arcuate nucleus of the hypothalamus to medial eminence and pituitary gland- Regulates hormone secretion
How is dopamine synthesised?
It starts with tyrosine which is converted by tyrosine hydroxylase to DOPA, DOPA decarboxylase then converts DOPA to dopamine
What receptors does dopamine act on?
D1 family (D1+D5) and D2 family (D2,3+4)
What is reuptake of dopamine followed by?
Either recycling, negative feedback on DA release or metabolism by MAO
What is the epidemiology of Parkinson’s like?
3rd most prevalent neurological disorder
4:1 males:females (oestrogen is protective)
What percentage is familial and idiopathic?
Familial- 5-7%
Idiopathic- 93%
What is the definition of Parkinson’s?
Progressive neurodegenerative disorder of movement. First describe by James Parkinson
What does diagnosis require at least 2 of?
Resting tremor- shaking of limbs when released
Rigidity- stiffness, limbs feel heavy
Bradykinesia- Slowness of movement and initiating movement after thought
Postural abnormality e.g. loss of arm swing
What other presenting symptoms are there for Parkinson’s?
Difficulty with fine movements- micrographic
Poverty of blinking
Impassive face
Monotony of speech and loss of volume of voice
Loss of balance
What are secondary manifestations of Parkinsons?
Non-motor signs:
Depression (approximately 45%)
Pain in limbs due to build up of lactic acid from tremor
Taste disturbances and loss of olfaction
Dementia
Autonomic dysfunction: Constipation, postural hypotension, urinary frequency, importance, increased sweating
What is the neuropathology of Parkinson’s?
Putamen-projecting pathways degenerate significantly. Lewy bodies also present
Cell loss in substantia nigra
Cell loss in locus coeruleus
Dorsal vagus nucleus, nucleus basalts of miners and other sub nuclei affected in some cases
What is thought to be the role of Lewy bodies?
They are large circular structures with bright core and white surrounding, packed with alpha synuclein and thought to be defensive mechanism to protect against toxic altered proteins
What percentage of dopaminergic neurones and stratal dopamine has to be depleted before symptoms appear?
Lose 80-85% of dopaminergic neurones and deplete 70% of striatal dopamine
What prevents appearance of symptoms in Parkinson’s?
Compensatory mechanisms such as neurone overactivity and up regulation of DA receptors
What is L-DOPA?
Dopamine replacement therapy
What is the difference between DOPA and L-DOPA?
L-DOPA can cross BBB
What does L-DOPA require to allow L-DOPA to cross BBB be centrally converted to dopamine?
Dopa-decarboxylase inhibitor
What is L-DOPA used for
Hypokinesia, rigidity and tremor
What are the acute side effects of L-DOPA?
Nausea- prevented by doperidone
Hypotension
Psychological effects- schizophrenia like
What are the chronic side effects of L-DOPA?
Dyskinesia- abnormal movement of limbs and face
On-off effects- rapid fluctuation in clinical state
What do DA-agonists target?
The receptors directly, principally the D2 receptors
Give examples of DA agonists
Bromocriptine, pergolide and ropinerol
How do DA agonists compare to L-DOPA?
Longer duration of action so smoother and more sustained response- less dyskinesia
What are the adverse effects of DA agonists?
Common- confusion, dizziness, nausea/vomiting and hallucinations
Rare- Constipation, headache, dyskinesias
What is monoamine oxidase involved in?
Breakdown of DA- stored in synaptic vesicles and will be released into synaptic cleft
What is deprenyl (selegiline)
Selective inhibitor for MAO-B- predominates in dopaminergic areas of CNS, no peripheral side effects
What are the side effects of deprenyl?
They are rare- hypotension, nausea/vomiting, confusion and agitation
How does resagiline have neuroprotective properties?
It inhibits apoptosis
Where is catechise-O-methyl transferase present?
In the CNS and periphery
What does COMT do in the CNS?
Prevents breakdown of dopamine in the brain
What does COMT do in the periphery?
It converts L-DOPA to 3-0-methyl-DOPA- they compete for the same transport system into the brain so less L_DOPA will cross BBB and there will be a smaller effect
What do COMT inhibitors e.g. Tolocapone do?
They stop 3-OMD formation thus increasing the bioavailability of L-DOPA so more is converted to dopamine in CNS and it allows you to reduce L-DOPA dosage
Unfortunately they have marked side effect profile including CVS effects
What percentage of the population is affected by schizophrenia?
1%
What are the clinical features of schizophrenia?
Positive- Delusions, hallucinations, thought disorders
Negative- withdrawal, flattening of emotional responses
What is the aetiology of schizophrenia strongly linked to?
It has a strong hereditary tendency with first degree relatives suffering in 10% and monozygotic twin risk rises to 50%
What is the onset of schizophrenia like?
It is in adolescence following one of two types:
Relapsing and remitting (most common)
Chronic progressive
What causes the positive and negative symptoms in schizophrenia?
Excessive dopamine transmission in the mesolimbic and stratal region lead to positive symptoms- mediated through D2 receptors
Whilst dopamine deficit in pre-frontal region, mediate by D1 receptors leads to negative symptoms
What is the evidence to support the mechanism of schizophrenia?
Dopamine agonists e.g. bromocriptine can induce psychotic reactions
Typical anti-schizophrenic drugs are dopamine receptor antagonists
What do typical neuroleptics include and what are they like?
They include chlorpromazine and are potent antagonists at many receptors therefore have big side effect profile
What do atypical receptors include and why are they not preferable?
They include clozapine and aren’t preferable as they have smaller antagonist activity at other receptors
What is he mechanism of all neuroleptic drugs?
They are antagonists at dopamine D2 like receptors. Most block other receptors e.g. 5-HT which accounts for side effects
Why is clozapine effective at treating schizophrenia?
It is relatively non-selective between D1 and D2 but has high affinity for D4 receptors which are increased in schizophrenia
What do drugs treat in schizophrenia?
The positive symptoms but not negative
Why do neuroleptics have delayed effects?
Neuroleptics initially induce an increase in DA synthesis and neuronal activity i.e. compensatory mechanism to increase DA to overcome blockade (declines with time
What other actions of neuroleptics are there?
Anti-emetic effect (blocks receptors in CTZ)
Blocking action at histamine receptors
Effective at controlling motion sickness
Endocrine effects- DA is involved in tuberoinfundibular system that regulates prolactin secretion. They increase serum prolactin concentrations which can lead to breast swelling and sometimes lactation in women
Blockade of cholinergic muscarinic receptors- typical peripheral anti-muscarinic side effects
What are the side effects of neuroleptics?
Extrapyramidal side effects- Blockade of dopamine receptors in nigrostriatal system can induce Parkinson like side effects
Acute dyskinesias- related to blockade of dopamine receptors in striatum which leads to increased cholinergic function
Tardive dyskinesia- involuntary movements often involving face and tongue
