Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Flashcards Preview

Y2 LCRS 1 - Pharmacology and Therapeutics - Laz COPY > Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia > Flashcards

Flashcards in Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and Schizophrenia Deck (58)
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1
Q

Describe dopamine synthesis

A

*

2
Q

Describe how dopamine is metabolised from the synapse (how it is removed from the synapse and subsequently broken down)

A
  • Dopamine transporter (DAT) and Noradrenaline transporter (NET) both are reuptake transporters that reuptake dopamine from the synapse back into the presynaptic neurone and once here they are metabolised / degraded
  • 3 enzymes are involved in the metabolism / degradation:
  1. Monoamine oxidase A (MAO-A): metabolises DA, NE, 5-HT
  2. Monoamine oxidase B (MAO-B): metabolises DA
  3. Catechol-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
3
Q

What are the three main dopaminergic pathways in the brain?

A
  1. Nigrostriatal
  2. Mesolimbic
  3. Tuberoinfundibular system
4
Q

Where are each of these pathways found?

A

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

5
Q

What are the roles of these pathways?

A

Nigrostriatal – control of movement Mesolimbic – involved in emotion Tuburoinfundibular system – regulate hormone secretion

6
Q

What are the two families of dopamine receptors and which receptors fall into each of these families?

A

D1 family – D1 + D5 D2 family – D2, D3 + D4

7
Q

Is Parkinson’s disease more common in males or females?

A

Males – 4:1

8
Q

What percentage of all cases of Parkinson’s disease is accounted for by familial Parkinson’s disease?

A

8% The rest are idiopathic

9
Q

What are the possible causes of idiopathic Parkinson’s disease?

A

Possibly a combination of environmental, oxidative stress, altered protein metabolism and risk genes

10
Q

What are the cardinal signs of Parkinson’ disease?

A

Resting tremor (pill-rolling tremor) Rigidity (stiffness – limbs feel weak and heavy) Bradykinesia (slowness of movement) Postural abnormality

11
Q

What are the presenting symptoms of Parkinson’s disease?

A

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

12
Q

Describe the initial distribution of symptoms across the body.

A

Unilateral onset Symptoms spread to both sides Generally symptoms worsen with some patients becoming severely disabled

13
Q

What are some non-motor symptoms of Parkinson’s disease?

A

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

14
Q

What is the main area of the brain that is affected by Parkinson’s disease?

A

Substantia nigra Other brain areas affected: locus coeruleus, dorsal vagus nucleus, nucleus basalis of Mynert

15
Q

Describe the neuropathology of Parkinson’s disease.

A

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

16
Q

What are the stages of Parkinson’s disease?

A

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

17
Q

What is the main biochemical change seen in Parkinson’s disease?

A

Marked reduction in the caudate nucleus/putamen dopamine content

18
Q

What proportion of dopaminergic neurones of the nigrostriatal dopaminergic pathway must be lost before symptoms occur?

A

80-85% of dopaminergic neurones and 70% of striatal dopamine must be depleted before symptoms appear

19
Q

What is the reason for this?

A

There are compensatory mechanisms e.g. neurone overactivity and increase in dopamine receptors

20
Q

What other type of drug has to be given with L-DOPA in dopamine replacement therapy and why?

A

Peripheral DOPA decarboxylase inhibitor This prevents the conversion of L-DOPA to dopamine by peripheral DOPA decarboxylase (this can cause nausea and vomiting)

21
Q

State two different preparation of dopamine replacement therapy.

A

Sinamet = Carbodopa + L-DOPA Madopar = Benserazide + L-DOPA

22
Q

What does L-DOPA treat?

A

Hypokinesia Tremor Rigidity

23
Q

Describe how the dosage of L-DOPA is changed with continued treatment.

A

It is started low and increased until maximum benefit of drug is achieved without side effects Effectiveness of L-DOPA declines with time

24
Q

What are the acute side effects of L-DOPA?

A

Nausea (prevented by domperidone) Hypotension Psychological effects (schizophrenia like syndrome with dellusions, hallucinations, confusion, disorientation and nightmares)

25
Q

What are the chronic side effects of L-DOPA?

A

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

26
Q

Name three dopamine agonists.

A

Bromocriptine Ropinerol Pergolide

27
Q

Which receptors do they act on?

A

D2 receptor

28
Q

What are the benefits of dopamine agonists over L-DOPA?

A

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

29
Q

What are the adverse effects of dopamine agonists?

A

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

30
Q

What structure used to be present in older dopamine agonists that caused quite serious clinical problems?

A

Ergot ring This caused problems with heart valves

31
Q

What has been the consequence of the removal of this structure within dopamine agonists?

A

Development of addictive behaviour e.g. gambling

32
Q

Name two MAO inhibitors.

A

Deprenyl (selegiline) Rasagiline

33
Q

What are the effects of Deprenyl?

A

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%)

34
Q

What are the side effects of Deprenyl?

A

RARE Hypotension Nausea/vomiting Confusion and agitation

35
Q

What are the effects of Rasagiline?

A

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

36
Q

Name two COMT inhibitors.

A

Tolocapone (CNS + PNS) Entacapone (PNS)

37
Q

What are the effects of COMT inhibition in the CNS?

A

Prevents breakdown of dopamine in the brain

38
Q

What are the effects of COMT inhibition in the peripheral nervous system?

A

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

39
Q

What are the side effects of COMT inhibitors?

A

Cardiovascular complications

40
Q

What percentage of the general population is affected by schizophrenia?

A

1%

41
Q

What are the symptoms of schizophrenia?

A

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

42
Q

What appears to have quite a strong contribution to the development of schizophrenia?

A

Genetics

43
Q

Once schizophrenia has been diagnosed, what are the four main outcomes for patients?

A

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

44
Q

Describe the involvement of dopamine in schizophrenia.

A

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)

45
Q

What evidence has arisen that supports this hypothesis?

A

Dopamine agonists can induce various psychotic reactions Typical antipsychotics are dopamine receptor antagonists (blocking D2 receptors)

46
Q

Describe the involvement of glutamate in schizophrenia.

A

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

47
Q

What is the most robust gene associated with schizophrenia?

A

Neuregulin-1

48
Q

What are all the susceptibility genes for schizophrenia associatedwith?

A

Dopamine and glutamate neurotransmission

49
Q

What type of drug are all neuroleptics?

A

Dopamine receptor antagonists (D2 receptors) NOTE: most neuroleptics block other receptors

50
Q

Which symptoms do neuroleptic drugs treat?

A

Positive symptoms ONLY

51
Q

What are the initial effects of neuroleptic drugs?

A

Initial increase in dopamine synthesis and neuronal activity – this declines with time

52
Q

What is meant by an atypical antipsychotic?

A

Newer antipsychotics are given this term – they have fewer extrapyramidal side effects

53
Q

Name an atypical antipsychotic.

A

Clozapine

54
Q

Name a typical antipsychotic.

A

Haloperidol

55
Q

What is an important other action of neuroleptics?

A

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

56
Q

What are the extrapyramidal side effects of antipsychotics caused by?

A

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

57
Q

What are the two main extra-pyramidal side effects? Acute Dystonia

A

 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

58
Q

What are the unwanted effects of antipsychotics?

A

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