Antipsychotics Flashcards
Psychoses
• Patients exhibit gross disturbances in their
comprehension of reality, as evidenced by
False perceptions (hallucinations) and False
beliefs (delusions).
Biological Basis: Dopamine hypothesis:
• Abnormalities in DA neurotransmission in mesolimbic and mesocortical
neuronal pathways
Supported by:
• Drugs which block D2 receptors improve disorder
• Affinity at D2 receptors correlated with clinical efficacy
• Drugs which increase DA release (amphetamine) or block reuptake
(cocaine) induce psychotic behavior.
Problems with hypothesis:
• Receptors blocked immediately, psychosis disappears slowly
Dopamine Tracts and Psychosis
1 Nigrostriatal: No Change: Extrapyramidal side effects
of antipsychotics
2 Mesolimbic Hyperactive – positive symptoms Typical antipsychotics
3 Mesocortical Hypoactive DLPFC – negative and cognitive symptoms VMPFC – negative and affective symptoms Atypical antipsychotics better
4 Tuberoinfundibular No change Prolactin related side
effects of antipsychotics
5 Others Unknown ?
Causes of Acute Psychosis
• Drug abuse and withdrawal – Phencyclidine/hallucinogens – Amphetamines, cocaine – Alcohol withdrawal – Sedative-hypnotic withdrawal
• Toxic Agents
– Heavy metals
– Digitalis toxicity
– L-Dopa
• Metabolic Causes – Hypoglycemia – Acute intermittent porphyria – Cushing’s syndrome – Hypo/hypercalcemia – Hypo/hyperthyroidism
• Nutritional causes
– Thiamine deficiency
– Niacin deficiency
– Vitamin B12 deficiency
• Neurological causes – Stroke – Brain tumor – Early Alzheimer’s or Pick’s disease – Hypoxic encephalopathy
Schizophrenia
Positive symptoms: • Probably result from excessive neuronal activity in mesolimbic neuronal pathways; respond well to neuroleptics (antipsychotic drugs)
Negative symptoms: • Probably result from insufficient activity in mesocortical neuronal pathways • More difficult to treat – Often persist after positive symptoms resolve and are associated with a poor prognosis – Do not respond as well to neuroleptics; atypical antipsychotics may be more effective
Drugs Used: Typicals
Phenothiazines: Chlorpromazine (Thorazine) - prototype Fluphenazine (Flufenan) Thioridazine (Mellaril) Trifluoperazine (Stelazine) Mesoridazine (Serentil) Perphenazine (Trilafon)
Thioxanthenes: Thiothixene (Navane) Chlorprothixene (Taractan) Butyrophenones: Haloperidol (Haldol) Spiperone
Azepines:
Loxapine (Loxitane)
Dihydroindolone:
Molindone (Moban)
Drugs Used: aTypicals
Azepines:
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Benzisoxazole:
Risperidone (Risperdal)
Aripiprazole (Abilify)
Benzisothiazolylpiperzine:
Ziprasidone (Geodon)
Mechanism of action:
– Competitive blockade of DA and 5-HT receptors.
• Typical Antipsychotics: Affinity: D2 >5-HT2 receptors:
• Atypical Antipsychotics: Affinity for 5-HT2 > D2
receptors:
• Selectivity for mesolimbic over nigro-striatal regions in their effects on
the DA system
• More likely to be effective in drug-refractory patients
• Likely to improve positive & negative symptoms
Adverse effects
attributed to blockade of the following receptors: • α1-adrenergic • Histamine H1 • Muscarinic
Class Pharmacokinetics
• Absorbed erratically from GI tract
• Parenteral administration of some
antipsychotics available
• Metabolized to active/inactive metabolites
in liver
• t1/2 = 20-40 hr
• Renal excretion of glucuronide conjugates
Antipsychotics CNS Actions
– Positive symptoms subside in 1-3 weeks
– Spontaneous movement and complex behavior
suppressed
– Less agitation
– Patient easily aroused, capable of answering
direct questions
– Intact intellectual function
– Withdrawn patients become more responsive
– Impulsive behavior decreases
– Hallucinations, delusions and incoherent
thoughts decrease
Antipsychotics: Motor
Improved Motor Effects
– No motor incoordination at USUAL doses
– Spontaneous activity diminished
– Catatonic signs relieved or rigidity reduced
Actions at Dopamine Receptors
• D2 receptors found pre/postsynaptically • D2 receptors coupled to Gi or Go • Blockade of D2 receptors results in: – ↑DA synthesis and release – ↑cAMP – ↓K+ currents
Dopaminergic Neurotransmission
• Presynaptic Effect
– Short Term Treatment: Activated neurons
– Long Term Treatment: Inactivated neurons
• Postsynaptic Effect
– Short Term Treatment: Receptor Blockade
– Long Term Treatment: Receptor
Supersensitivity
Time Course of Therapy Response
1-3 days ↓Agitation / hostility ↓Aggression / combativeness ↓Anxiety Normalization of eat / sleep patterns
1-2 weeks
↑Socialization
↑Self care habits
↑Mood
3-6 weeks
↑Thought disorder
↓Delusions / hallucinations
Appropriate conversations
