Anti-Parkisonian drugs and neuroleptics

Question 1

What are neuroleptics used to treat

Answer 1

Schizophrenia

Question 2

Outline the synthesis of dopamine in the pre-synaptic membrane of the dopaminergic neurone

Answer 2

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.

Question 3

Summarise the metabolism of dopamine (once it has exerted its effect on the post-synaptic membrane)

Answer 3

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

Question 4

Where are DAT and NET expressed

Answer 4

DAT- pre-synaptic membrane and surrounding glial cell

NET- pre-synaptic membrane

Question 5

Where are MAO-A and MAO-B expressed

Answer 5

MAO-A- mitochondrial membrane of the pre-synaptic cell and the glial cell
MAO-B- mitochondrial membrane of the pre-synaptic cell

Question 6

Where is COMT expressed

Answer 6

Post-synaptic membrane

Cytoplasm of glial cell

Question 7

State the 4 main dopaminergic pathways in the brain

Answer 7

Nigrostriatal
Mesolimbic
Mesocortical
Tuberoinfundibular

Question 8

Describe the nigrostriatal pathway

Answer 8

susbstantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders (involved in the pathophysiology of Parkinson’s).

Question 9

Describe the mesolimbic pathway

Answer 9

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

Question 10

Describe the mesocortical pathway

Answer 10

VTA to the cerebrum. Important in executive functions & complex behavioural patterns.
Involved in the pathophysiology of schizophrenia

Question 11

Describe the tuberoinfundibular pathway

Answer 11

arcuate nucleus (of the hypothalamus) to the median eminence and pituitary gland . Inhibition results in hyperprolactinaemia  
Involved in the regulation of hormone secretion

Question 12

Summarise the epidemiology of Parkinson’s Disease

Answer 12

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

Question 13

Summarise the pathophysiology of Parkinson’s Disease

Answer 13

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.

Question 14

Describe the link between alpha-synuclein and Parkinson’s

Answer 14

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.

Question 15

What is the principal affected area in the pathophysiology of Parkinson’s

Answer 15

§ 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.

Question 16

What is the main biochemical change seen in Parkinson’s

Answer 16

Marked reduction in the caudate nucleus/putamen dopamine content

Question 17

What is the function of the nigro-striatal pathway

Answer 17

§ 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.

Question 18

Summarise the clinical presentation of a patient with Parkinson’s

Answer 18

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

Question 19

Describe the clinical signs of the motor symptoms of P.D

Answer 19

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.

Question 20

Describe the bradykinesia

Answer 20

•
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;

Question 21

Describe the onset features of the motor symptoms of P.D

Answer 21

§ 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.

Question 22

What proportion of dopaminergic neurones must be lost before the onset of symptoms

Answer 22

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

Question 23

What are the presenting symptoms of P.D

Answer 23

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

Question 24

What are some of the non-motor symptoms of P.D

Answer 24

Depression 
Pain 
Taste/smell disturbances 
Cognitive decline/dementia 
Autonomic dysfunction (constipation, postural hypotension, urinary frequency/urgency, impotence, increased sweating)

Question 25

Summarise and describe Braak's staging for P.D

Answer 25

``` 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.

Question 26

What is important to remember about the brain of a patient with Parkinson's in terms of the pharmacology

Answer 26

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

Question 27

Describe L-DOPA as a treatment for P.D

Answer 27

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.

Question 28

Summarise the long-term side effects of L-DOPA

Answer 28

Long-term side-effects: dyskinesias & ‘on-off’ effects. NOT disease-modifying - so life expectancy not increased- underlying pathology of the disease is not targeted.

Question 29

Describe the acute side-effects of L-DOPA

Answer 29

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.

Question 30

Describe the dyskinesia and 'on-off' symptoms associated with long-term use of L-DOPA

Answer 30

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

Question 31

Why do we see dyskinesia and 'on-off symtpoms' with L-DOPA

Answer 31

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.

Question 32

Describe how we change the dose of L-DOPA over time

Answer 32

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.

Question 33

Summarise the adjuncts that we can give with L-DOPA to improve its effectiveness

Answer 33

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

Question 34

Describe how we can reduce the onset of 'on-off' symptoms in patients taking L-DOPA

Answer 34

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.

Question 35

State two common preparations of L-DOPA

Answer 35

Preparations: Sinamet: (L-DOPA + Carbidopa) or Madopar ( LDOPA + Benserazide)

Question 36

Describe the different types of dopamine receptors

Answer 36

Dopamine (DA) can act on D1,5(Gs linked) or D2-4 (Gi-linked) receptors

Question 37

What is important to remember about the dopamine receptor agonists

Answer 37

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

Question 38

What are the benefits of dopamine agonists over L-DOPA

Answer 38

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

Question 39

Summarise the two different types of dopamine agonists

Answer 39

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

Question 40

What are the adverse effects of dopamine agonists

Answer 40

Common – confusion, dizziness, nausea/vomiting, hallucinations Rare – constipation, headache, dyskinesia

Question 41

Describe the clinical use of dopamine agonists clinically

Answer 41

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.

Question 42

Describe the key difference between the ergot and non-ergot dopamine agonists

Answer 42

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

Question 43

Summarise the MAOB inhibitors

Answer 43

Selegiline (deprenyl) & Rasagiline Reduce the dosage of L-DOPA required Can increase the amount of time before levodopa treatment is required

Question 44

Describe Selegiline

Answer 44

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%)

Question 45

State the side effects of Selegiline

Answer 45

RARE Hypotension Nausea/vomiting Confusion and agitation

Question 46

Describe Rasagiline

Answer 46

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

Question 47

Summarise COMT inhibitors

Answer 47

Tolocapone (CNS + PNS) Entacapone (PNS) Associated with cardiovascular complications.

Question 48

Describe the central effects of COMT inhibitors

Answer 48

Prevents breakdown of dopamine in the brain

Question 49

Describe the peripheral effects of COMT inhibitors

Answer 49

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

Question 50

Summarise the epidemiology of schizophrenia

Answer 50

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

Question 51

Describe the genetics of schizophrenia

Answer 51

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%,

Question 52

Summarise the positive symptoms of schizophrenia

Answer 52

Increased  Mesolimbic dopaminergic activity Hallucinations: Auditory & visual Delusions: Paranoia Thought disorder: Denial about oneself

Question 53

Summarise the negative symptoms of schizophrenia

Answer 53

Decreased Mesocortical dopaminergic activity Affective flattening: lack of emotion Alogia: lack of speech Avolition/ apathy: loss of motivation

Question 54

Describe the cognitive defects associated with schizophrenia

Answer 54

· Memory · Attention · Planning · Decision making

Question 55

What are the four main outcomes for patients with schizophrenia

Answer 55

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

Question 56

Summarise the aetiology of Schizophrenia

Answer 56

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.

Question 57

Describe the involvement of dopamine in schizophrenia

Answer 57

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)

Question 58

Describe the evidence that supports the involvement of dopamine in schizophrenia

Answer 58

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

Question 59

describe the involvement of glutamate in schizophrenia

Answer 59

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

Question 60

Summarise the neuroleptics

Answer 60

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.

Question 61

Name two first generation (typical) anti-psychotics

Answer 61

Chlorpromazine | Haloperidol

Question 62

Describe chlorpromazine

Answer 62

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)

Question 63

Describe haloperidol

Answer 63

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

Question 64

Name three second generation (atypical) anti-psychotics

Answer 64

Clozapine Risperidone Quetiapine

Question 65

Describe clozapine

Answer 65

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

Question 66

Describe the affinity of clozapine for different receptors

Answer 66

Greatest affinity for M1 receptor Equal affinity for 5HT2A, H1 and alpha 1 5HT2A- Gq linked PIP2- IP3 (--Ca2+) + DAG (--PKC)

Question 67

Describe risperidone

Answer 67

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

Question 68

Describe quetiapine

Answer 68

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

Question 69

Describe aripiprazole

Answer 69

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

Question 70

Explain the importance of aripirazole being a partial agonist

Answer 70

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).

Question 71

Why do anti-psychotics cause extra-pyramidal side effects

Answer 71

Blockade of dopamine receptors in the nigrostriatal system can induce Parkinson-like side effects

Question 72

Give two examples of extra-pyramidal side effects

Answer 72

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

Question 73

Describe some other unwanted effects of anti-psychotics

Answer 73

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

Question 74

Describe the genetic aetiology of schizophrenia

Answer 74

§ 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.