Anti-Parkisonian drugs and neuroleptics Flashcards
What are neuroleptics used to treat
Schizophrenia
Outline the synthesis of dopamine in the pre-synaptic membrane of the dopaminergic neurone
L-tyrosine — L-DOPA (tyrosine hydroxylase)
L-DOPA – DOPA (DOPA decarboxylase)
The first step is the rate limiting step and thus is dependent on the amount of tyrosine hydroxylase (if you only have 100 units of tyrosine hydroxylase)- you will only get 100 units of L-DOPA synthesised.
Summarise the metabolism of dopamine (once it has exerted its effect on the post-synaptic membrane)
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
Where are DAT and NET expressed
DAT- pre-synaptic membrane and surrounding glial cell
NET- pre-synaptic membrane
Where are MAO-A and MAO-B expressed
MAO-A- mitochondrial membrane of the pre-synaptic cell and the glial cell
MAO-B- mitochondrial membrane of the pre-synaptic cell
Where is COMT expressed
Post-synaptic membrane
Cytoplasm of glial cell
State the 4 main dopaminergic pathways in the brain
Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular
Describe the nigrostriatal pathway
susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders (involved in the pathophysiology of Parkinson’s).
Describe the mesolimbic pathway
Mesolimbic – projecting from the ventral tegmental area to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercle
Involved in the regulation of emotion and the reward system of the brain.
Involved in the pathophysiology of schizophrenia
Describe the mesocortical pathway
VTA to the cerebrum. Important in executive functions & complex behavioural patterns.
Involved in the pathophysiology of schizophrenia
Describe the tuberoinfundibular pathway
arcuate nucleus (of the hypothalamus) to the median eminence and pituitary gland . Inhibition results in hyperprolactinaemia Involved in the regulation of hormone secretion
Summarise the epidemiology of Parkinson’s Disease
1-2% of individuals over 60 years old- main risk factor is age
Around 5% of cases are due to mutations in certain genes (e.g. SNCA, LRRK2, PINK) - responsible for early onset Parkinson’s
Summarise the pathophysiology of Parkinson’s Disease
Severe loss of dopaminergic projection cells in SNc
Lewy bodies & neurites Found respectively within neuronal cell bodies & axons- drugs don’t target these
Consist of abnormally phosphorylated neurofilaments, ubiquitin & -synuclein
Essentially, lewy bodies are aggregates of protein.
Describe the link between alpha-synuclein and Parkinson’s
It is possible (see Lotharius & Brundin, 2002) that the normal function of α-synuclein is related to synaptic vesicle recycling, and that the misfolded form loses this functionality, with the result that vesicular storage of dopamine is impaired. This may lead to an increase in cytosolic dopamine, degradation of which produces ROS and hence neurotoxicity. Consistent with the α-synuclein hypothesis, another mutation associated with PD (parkin) also involves a protein that participates in the intracellular degradation of rogue proteins.
What is the principal affected area in the pathophysiology of Parkinson’s
§ Principal affected area – Substantia nigra (pars compacta).
o Projects into the Caudate and the Putamen.
o SNpc contains neuro-melanin pigment which we don’t know the function of – there is a loss of this pigment in PD.
o This SNpc degeneration accounts for the MOTOR features.
§ Other affected areas – Locus Coeruleus (LC), dorsal vagus nucleus, Nucleus Basalis of Mynert.
What is the main biochemical change seen in Parkinson’s
Marked reduction in the caudate nucleus/putamen dopamine content
What is the function of the nigro-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.
Summarise the clinical presentation of a patient with Parkinson’s
Motor symptoms resting tremor, bradykinesia, rigidity, postural instability (cardinal symptoms)
Autonomic nervous system effects olfactory deficits, orthostatic hypotension, constipation
Neuropsychiatric sleep disorders, memory deficits, depression, irritability
Describe the clinical signs of the motor symptoms of P.D
o Resting tremor – shaking of the limbs when relaxed (opposite of intention tremor). - EARLY -starts in the hands (rolling-pin) tremor- tends to diminish during voluntary activity
o Rigidity – stiffness, limbs feel heavy/weak. - LATE- detectable by an increased resistance in passive limb movements
o Bradykinesia – slowness of movement.
o Postural abnormalities.
Describe the bradykinesia
•
suppression of voluntary movements (bradykinesia), due partly to muscle rigidity and partly to an inherent inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate;
Describe the onset features of the motor symptoms of P.D
§ Onset features:
o Unilateral and spreads to both sides of the body.
o Current drugs can only treat symptoms and DON’T slow the degenerative process.
What proportion of dopaminergic neurones must be lost before the onset of symptoms
80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear
There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors
What are the presenting symptoms of P.D
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
What are some of the non-motor symptoms of P.D
Depression Pain Taste/smell disturbances Cognitive decline/dementia Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)
Summarise and describe Braak’s staging for P.D
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
Non-motor symptoms (loss of smell, sleep disorders and constipation) may precede motor symptoms
Important, can detect P.D as early as possible to improve the prognosis.
What is important to remember about the brain of a patient with Parkinson’s in terms of the pharmacology
Although the dopaminergic neurones are lost- the post-synapatic receptors containing dopamine receptors still exist, and hence we can target this in our pharmacology.
This is particularly important for L-DOPA which needs to get into the cytoplasm of dopaminergic neurones.
It is not certain whether the effect depends on an increased release of dopamine from the few surviving dopaminergic neurons or on a ‘flooding’ of the synapse with dopamine formed elsewhere
Describe L-DOPA as a treatment for P.D
First line treatment
§ Cannot give DA itself as it won’t cross the BBB (bar CTZ). - so leads to nausea and vomiting.
§ L-DOPA does cross the BBB so can use this
Rapidly converted by DOPA-decarboxylase to DOPA.
Summarise the long-term side effects of L-DOPA
Long-term side-effects: dyskinesias & ‘on-off’ effects. NOT disease-modifying - so life expectancy not increased- underlying pathology of the disease is not targeted.
Describe the acute side-effects of L-DOPA
Nausea – Can be prevented by using Domperidone, a peripherally acting dopamine (D2) antagonist.
Hypotension
Psychological effects – Schizophrenia like syndrome with delusions and hallucinations, 20% of patients also exhibit confusion, disorientation, insomnia and nightmares.
