6.1 Antipsychotic drugs Flashcards

1
Q

What are the 3 main dopaminergic pathways and their origin + projections + function?

A

1) NIgrostriatal
- origin: SNc
- projections: striatum
- function: control and regulation of movement

2) Mesolimbic
- origin: ventral tegmental area
- projections: Nucleus accumbens, frontal cortex, limbic cortex, olfactory tubercle
- function: Emotion, sensing the environment, reward pathways

3) Tubero-infundibular:
- origin: hypothalamic arcuate nucleus (short neurones)
- projections: Medial eminence of hypothalamus, pituitary gland
- function: Regulation of hormonal secretion

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2
Q

Dopamine is synthesised from ____________ in the presynaptic knob
• Packaged into neurotransmitter vesicles by the ____________________ uptake protein as a free molecule (protected from breakdown enzymes)
• Released into the synaptic cleft and binds to dopamine receptors (D1/D2 families)
• After dopamine serves its functions, it is deactivated by reuptake systems into the nerve endings (via VMAT-1) and into adjacent astrocytes for breakdown

A

L-tyrosine ;

vesicular monoamine transporter (VMAT-2);

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3
Q

______________ gene: involved in synaptic development and plasticity, and effects on NMDA receptor (glutamate) expression
o Transgenic mice expressing the gene shows schizophrenic-like phenotype

A

Neuregulin-1

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4
Q

The pathogenesis of schizophrenia is linked to dopamine and glutamate and their relationship with GABAergic striatal neurones:
• GABAergic striatal neurones project to the _______ (serves as sensory gate) → ____________ glutamate/ __________ dopamine disables the gate → uninhibited sensory input to cerebral cortex → overinterpretation of external environment

A

thalamus;

too little; too much;

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5
Q

Dopamine: Normally exerts inhibitory effects on GABAergic striatal neurones
1. Excessive dopaminergic transmission in _________________:
• Causes positive symptoms (mediated via ______________ → mainly found on the presynaptic neurone)
• Dopamine agonists (e.g. bromocriptine) and amphetamines can induce various psychotic reactions
• Typical anti-schizophrenic drugs are dopamine receptor antagonists → strong correlation with D2 blocking activity

  1. Deficient dopaminergic transmission in _________________:
    • Causes negative symptoms (mediated via _______________)
A

mesolimbic and striatum;

D2 receptors;

prefrontal region;

D1 receptors

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6
Q

Glutamate: Normally exerts excitatory effects on ________________:

  1. Reduced glutamate concentration/receptor density:
    • Observed in post-mortem schizophrenic brains
    • NMDA receptor antagonists (e.g. phencyclidine, ketamine) produce psychotic symptoms
A

GABAergic striatal neurones

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7
Q

What are the atypical anti psychotic drugs?

A

Risperidone, Quetiapine, Olazapine, Clozapine, Aripiprazole

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8
Q

What are the typical anti psychotic drugs>

A

1) Phenothiazines
- Group 1: Chlorpromazine
- Group 2: Pericyazine
- Group 3: Fluphenazine, Trifluperazine

2) Thioxanthines
- flupenthixol
- zuclopenthixol

3) others
- haloperidol
- pimozide
- sulpride

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9
Q

Which receptors do atypical antipsychotics have strong relative affinities at?

A

α-adrenoceptors, H1 receptors and 5-HT2A receptors

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10
Q

Antipsychotics also exert an anti-emetic effect by blocking ______________ receptors in the chemoreceptor trigger zone (CTZ):
• Phenothiazine (neuroleptic) is effective at controlling nausea and vomiting caused by _________________ and _____________
• Histamine receptor blockade helps to control motion sickness
• Newer atypical antipsychotics target 5-HT receptors to control nausea and vomiting

A

dopamine or histamine;

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11
Q

Extrapyramidal side effects (more common with typical antipsychotics)

Acute dystonia: involuntary movements (e.g. muscle spasms, protruding tongue, fixed upward gaze, neck spasm) + _______________ (e.g. bradykinesia)
• Occurs in first few weeks (then decline with ongoing therapy)
• Reversible on ____________ (but risk of schizophrenia relapse) or use of _________________

Tardive dyskinesias: involuntary movements often involving the face and tongue (limb and trunk may be affected)
• Occur late in treatment (~20% of patients after several months or years) → may be related to proliferation of presynaptic D2 receptors or glutamate excitotoxic striatal neurodegeneration
• Aggravated by drug withdrawal or anticholinergics
• Improved by increasing dose (causes vicious cycle)

A

Parkinsonian features

drug withdrawal;

anticholinergics;

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12
Q

What are the endocrine side effects more common with atypical antipsychotics?

A

Blockade of D2 receptors in tuberoinfundibular system:

• Increased serum prolactin concentrations → breast swelling (in men and women) and sometimes lactation (in women)

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13
Q

What are the adrenergic side effects more common with atypical antipsychotics?

A

Blockade of α-adrenoceptors → orthostatic hypotension

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14
Q

What are the metabolic side effects more common with atypical antipsychotics?

A

Blockade of 5-HT receptors → weight gain

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15
Q

What are the muscarinic side effects more common with atypical antipsychotics?

A

Blockade of cholinergic muscarinic receptors → typical peripheral anti-muscarinic side effects (e.g. blurry vision, increased IOP, dry mouth, constipation, urinary retention)

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16
Q

What is the side effect that occurs with both typical and atypical antipsychotics which is the most life threatening adverse effect?

A

Neuroleptic malignant syndrome (NMS): Deranged dopaminergic function → precise physiology unknown • Most life-threatening adverse effect of antipsychotic use (20% mortality if not treated immediately)
• Presents with hyperthermia, muscle rigidity, autonomic instability, fluctuating unconsciousness
• Appears from a few days to weeks after beginning treatment

17
Q

Huntington’s disease (HD):
movement disorder affecting the bas al ganglia (increased _________ concentration in putamen; deficient _____________ –> reduced inhibition on nigrostriatal
system –> dopaminergic hyperactivity
• Hyperkinetic disorder (associated with excessive abnormal movements) –> movements are______________ (affecting different muscle groups in face, trunk,
• Hereditary disorder (onset during adult life) + associated with progressive dementia
• May be controlled to some extent using antipsychotics (by blockade of dopamine
receptors in the nigrostriatal pathway)

A

DA;

GABA and ACh;

involuntary, irregular , jerky