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.
Describe the dyskinesia and ‘on-off’ symptoms associated with long-term use of L-DOPA
Dyskinesias – Abnormal movements which affect the face & limbs. Generally occur within two years of starting L-DOPA therapy. Dyskinesias disappear if the dose of the drug is reduced but clinical symptoms of PD reappear.
“On-Off” Effects – rapid fluctuations in clinical state, where hypokinesia and rigidity may suddenly worsen. These “off” periods may last from a few minutes to hours, with sudden improvement in the clinical state. Occurs more with L-DOPA
Why do we see dyskinesia and ‘on-off symtpoms’ with L-DOPA
As with the dyskinesias, the problem seems to reflect the fluctuating plasma concentration of levodopa, and it is suggested that as the disease advances, the ability of neurons to store dopamine is lost, so the therapeutic benefit of levodopa depends increasingly on the continuous formation of extraneuronal dopamine, which requires a continuous supply of levodopa.
Describe how we change the dose of L-DOPA over time
Start the patient off on a low dose of the drug and gradually increase the dose until the maximum benefit is observed without major side effects. The majority of patients respond well to LDOPA, with some patients being restored to normal function. As the disease progresses the effectiveness of L-DOPA declines and the dose of L-DOPA needs to be increased which leads to the development of major side effects. Therapeutic window gradually narrows.
Summarise the adjuncts that we can give with L-DOPA to improve its effectiveness
DOPA decarboxylase inhibitors: Carbidopa & Benserazide
*Do not cross BBB prevent peripheral breakdown of levodopa
Reduce required levodopa dosage
COMT inhibitors: Entacapone & Tolcapone
amount of levodopa in the brain
Describe how we can reduce the onset of ‘on-off’ symptoms in patients taking L-DOPA
The use of sustained-release preparations(intestinal gel), or co-administration of COMT inhibitors such as entacapone, may be used to counteract the fluctuations in plasma concentration of levodopa.
Essentially, trying to mimic the natural release of dopamine.
State two common preparations of L-DOPA
Preparations: Sinamet: (L-DOPA + Carbidopa) or Madopar ( LDOPA + Benserazide)
Describe the different types of dopamine receptors
Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors
What is important to remember about the dopamine receptor agonists
Dopamine receptor agonists: do not require intact presynaptic neurones unlike levodopa
Since, L-DOPA requires intact neurones to convert the L-DOPA to dopamine, as the disease progresses there are fewer and fewer neurones to convert the drug. Hence, dopamine agonists were developed to act directly on the target sites
What are the benefits of dopamine agonists over L-DOPA
Longer duration of action (but still need to give 3 times daily)
Smoother and more sustained response
Actions independent of dopaminergic neurones
Incidence of dyskinesias is less
NOTE: L-DOPA is still the gold standard
Summarise the two different types of dopamine agonists
Ergot derivatives: Bromocriptine & Pergolide
Act as potent agonists of D2 receptors
Associated with cardiac fibrosis
Non-ergot derivatives: Ropinirole & Rotigotine
Ropinirole also available as extended-release formulation
Rotigotine also available as a patch
What are the adverse effects of dopamine agonists
Common – confusion, dizziness, nausea/vomiting, hallucinations
Rare – constipation, headache, dyskinesia
Describe the clinical use of dopamine agonists clinically
Fewer patients can be treated with the dopamine agonists as a mono-therapy with many patients being withdrawn from treatment due to major adverse side effects.
Can be used in combination with L-DOPA. When L-DOPA is becoming less effective, dopamine agonists can be used in combination with L-DOPA.
Describe the key difference between the ergot and non-ergot dopamine agonists
o Ergot structures (ring structures in drugs) can be found which can cause problems with the heart valves.
o Non-ergot structure drugs can cause addictive behaviours.
Ergot- natural
Non-ergot- synthetic
Summarise the MAOB inhibitors
Selegiline (deprenyl) & Rasagiline
Reduce the dosage of L-DOPA required
Can increase the amount of time before levodopa treatment is required
Describe Selegiline
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%)
State the side effects of Selegiline
RARE
Hypotension
Nausea/vomiting
Confusion and agitation
Describe 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
Summarise COMT inhibitors
Tolocapone (CNS + PNS)
Entacapone (PNS)
Associated with cardiovascular complications.
Describe the central effects of COMT inhibitors
Prevents breakdown of dopamine in the brain
Describe the peripheral effects of COMT inhibitors
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
Summarise the epidemiology of schizophrenia
Affects 1% of population (higher than incidence of Parkinson’s and Alzheimer’s disease). & has genetic influence
Onset of symptoms: between 15-35 years
Higher incidence in ethnic minorities (eg Afro-Caribbean immigrants)
Patients’ life expectancy - 20-30 years lower than average
Describe the genetics of schizophrenia
Monozygotic twin studies have shown that if one twin has schizophrenia- then the other twin has a 50% risk of developing schizophrenia too.
Obviously, there is an environmental component too.
The disease shows a strong, but incomplete, hereditary tendency. In first-degree relatives, the risk is about 10%,
Summarise the positive symptoms of schizophrenia
Increased Mesolimbic dopaminergic activity
Hallucinations: Auditory & visual
Delusions: Paranoia
Thought disorder: Denial about oneself
Summarise the negative symptoms of schizophrenia
Decreased Mesocortical dopaminergic activity
Affective flattening: lack of emotion
Alogia: lack of speech
Avolition/ apathy: loss of motivation
Describe the cognitive defects associated with schizophrenia
· Memory
· Attention
· Planning
· Decision making
What are the four main outcomes for patients with schizophrenia
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
Summarise the aetiology of Schizophrenia
Unknown, but several hypotheses including, may be due to a slow viral infection possibly linked with an auto-immune process. Alternately, may be due to a developmental abnormality ~ anatomical changes in the temporal lobes (entorhinal cortex, hippocampus) and amygdala – Mesolimbic system.
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)
Describe the evidence that supports the involvement of dopamine in schizophrenia
Dopamine agonists can induce various psychotic reactions
Typical antipsychotics are dopamine receptor antagonists (blocking D2 receptors)
In drug naïve patients PET scans show increased dopamine receptor number
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
Summarise the neuroleptics
Drugs tend to treat the positive symptoms of the disease but not the negative ones!
Because neuroleptics are D2 antagonists correcting the over activity of dopamine in the mesolimbic system and striatum but have no effect on the forebrain dopamine deficits where the negative symptoms are produced.
Neuroleptics have a delayed effect, take weeks to work. This may be due to the fact that initially neuroleptics induce an increase in dopamine synthesis and neuronal activity, and an increase in
dopamine receptors on the target cells. However this declines with time.
Name two first generation (typical) anti-psychotics
Chlorpromazine
Haloperidol
Describe chlorpromazine
Discovered whilst developing new antihistamines
Primary mechanism of action – possibly D2 receptor antagonism
Side effects
High incidence - anti-cholinergic, especially sedation
Low incidence - extrapyramidal side-effects (EPS)
Describe haloperidol
Very potent D2 antagonist (~ 50x more potent than chlorpromazine)
Therapeutic effects develop over 6-8 weeks
Little impact on negative symptoms
Side effects
High incidence - EPS
Greatest affinity for D2, but also reduced affinities for D3,4 and alpha 1
Name three second generation (atypical) anti-psychotics
Clozapine
Risperidone
Quetiapine
Describe clozapine
Most effective antipsychotic
Very potent antagonist of 5-HT2A receptors
Only drug to show efficacy in treatment resistant schizophrenia & negative symptoms
Side effects
Can cause potentially fatal neutropenia, agranulocytosis, myocarditis & weight gain
Describe the affinity of clozapine for different receptors
Greatest affinity for M1 receptor
Equal affinity for 5HT2A, H1 and alpha 1
5HT2A- Gq linked
PIP2- IP3 (–Ca2+) + DAG (–PKC)
Describe risperidone
Very potent antagonist of 5-HT2A & D2 receptors
Side effects
More EPS & hyperprolactinaemia than other atypical antipsychotics
Equal affinity for D2 and 5HT2A, reduced affinity for D4 and a1
Describe quetiapine
Very potent antagonist of H1 receptors
Side effects
Lower incidence of EPS than other antipsychotics
High affinity for H1 and A1, reduced affinity for D2
Describe aripiprazole
Partial agonist of D2 & 5-HT1A receptors
No more efficacious than typical antipsychotics
Side effects
Reduced incidences of hyperprolactinaemia & weight gain than other antipsychotics
Equal affinity for D2,3 reduced affinity for 5HT2A
Explain the importance of aripirazole being a partial agonist
Will act as an agonist when activity is low (I,e improve negative symptoms), will act as an antagonist when activity is high (i.e improve positive symptoms).
Why do anti-psychotics cause extra-pyramidal side effects
Blockade of dopamine receptors in the nigrostriatal system can induce Parkinson-like side effects
Give two examples of 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
Describe some other unwanted effects of anti-psychotics
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
Anti-emetic
Because they block dopamine receptors in the chemotactic trigger zone
Phenothiazine is a neuroleptic that is really good at preventing nausea/vomiting caused by drugs
NOTE: many neuroleptics also block histamine receptors – this is effective at controlling motion sickness
Describe the genetic aetiology of schizophrenia
§ Hereditary tendency – no identifiable gene though (there are risk genes).
§ Features many polymorphisms with weak associations.
o Neuroregulin-1 gene – synaptic development and plasticity (effects on NMDA-R expression).
o 8 other susceptibility genes discovered associated with glutamate or DA.
