6.1 Antipsychotic drugs Flashcards
What are the 3 main dopaminergic pathways and their origin + projections + function?
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
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
L-tyrosine ;
vesicular monoamine transporter (VMAT-2);
______________ gene: involved in synaptic development and plasticity, and effects on NMDA receptor (glutamate) expression
o Transgenic mice expressing the gene shows schizophrenic-like phenotype
Neuregulin-1
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
thalamus;
too little; too much;
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
- Deficient dopaminergic transmission in _________________:
• Causes negative symptoms (mediated via _______________)
mesolimbic and striatum;
D2 receptors;
prefrontal region;
D1 receptors
Glutamate: Normally exerts excitatory effects on ________________:
- Reduced glutamate concentration/receptor density:
• Observed in post-mortem schizophrenic brains
• NMDA receptor antagonists (e.g. phencyclidine, ketamine) produce psychotic symptoms
GABAergic striatal neurones
What are the atypical anti psychotic drugs?
Risperidone, Quetiapine, Olazapine, Clozapine, Aripiprazole
What are the typical anti psychotic drugs>
1) Phenothiazines
- Group 1: Chlorpromazine
- Group 2: Pericyazine
- Group 3: Fluphenazine, Trifluperazine
2) Thioxanthines
- flupenthixol
- zuclopenthixol
3) others
- haloperidol
- pimozide
- sulpride
Which receptors do atypical antipsychotics have strong relative affinities at?
α-adrenoceptors, H1 receptors and 5-HT2A receptors
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
dopamine or histamine;
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)
Parkinsonian features
drug withdrawal;
anticholinergics;
What are the endocrine side effects more common with atypical antipsychotics?
Blockade of D2 receptors in tuberoinfundibular system:
• Increased serum prolactin concentrations → breast swelling (in men and women) and sometimes lactation (in women)
What are the adrenergic side effects more common with atypical antipsychotics?
Blockade of α-adrenoceptors → orthostatic hypotension
What are the metabolic side effects more common with atypical antipsychotics?
Blockade of 5-HT receptors → weight gain
What are the muscarinic side effects more common with atypical antipsychotics?
Blockade of cholinergic muscarinic receptors → typical peripheral anti-muscarinic side effects (e.g. blurry vision, increased IOP, dry mouth, constipation, urinary retention)