A.27. 1st generation ("typical") antipsychotic agents Flashcards
definition of psychosis
collection of psychological symptoms resulting in a loss of contact with reality
positive symptoms for psychosis
thought disorders delusions hallucinations paranoia/ catatonia disorganized speech
negative symptoms for psychosis
amotivation
social withdrawal
poverty of speech (alogia)
anhedonia (inability to feel pleasure)
types of psychosis
- schizophrenia
- affective psychoses
- other: schizoaffective, drug-induced, psychosis from organic reasons (dementia, parkinson)
what are the hypothesizes of psychosis?
- dopamine
- serotonin
- dysregulation
what does the serotonin hypothesis say?
cause of the disease is excessive serotonergic stimulation in the cerebral cortex
what does the dysregulation hypothesis say?
psychosis is a multifactorial condition, affected by multiple pathways and neurotransmitter interactions (GABA, glutamate, 5-HT, dopamine)
what does the dopamine hypothesis say?
changes in dopamine function that cause psychosis: mesocortical pathways (↓ activity --> negative symptoms) mesolimbic pathways ( ↑ activity --> positive symptoms) nigrostriatal pathway ( extrapyramidal motor function) tuberoinfundibular pathways (control of prolactin release) chemoreceptor trigger zone (emesis)
when does psychosis start?
mostly in young adults ~20
what are the clinical uses of antipsychotic agents? name 3
- treatment of schizophrenia and other psychotic disorders–> symptomatic, allow them to be in society
- initial treatment of bipolar disorders (atypical)–> usually in combination with lithium
- management of toxic (acute) psychosis due to overdose by CNS stimulants
- Tourette’s syndrome
- Huntingtons disease
- Alzheimer and Parkinson (atypical)
- antiemetic activity
do typical agents have an effect on negative symptoms?
no
disorders are characterized as psychotic or on the schizophrenia spectrum when..
either positive and negative symptoms appear
pharmacokinetic properties of typical antipsychotic agents (1st generation)
good oral bioavailability
parenteral preparations for both rapid initiation of therapy and depot formulations
long T1/2–> once-daily dosing
hepatic P450 metabolism
↑ lipid solubility –> penetrates the CNS
what are the groups of typical antipsychotic agents (1st gen’)?
- phenothiazines- oldest
- butyrophenones
- thioxanthene
list the phenothiazines
chlorpromazine
thioridazine
fluphenazine
list the butyrophenones
haloperiodol
droperiodol
what is flupentixol?
it’s a thioxanthene
give the typical agents with low potency D₂ blockage?
chlorpromazine
thioridazine
give the typical agents with high potency D₂ blockage?
haloperidol
droperidol
flupentixol
give the typical agents with no 5-HT blocking?
haloperidol
give the typical agents with 5-HT and no muscarinic blocking?
droperiodol
flupentixol
give the typical agents with muscarinic blocking?
chlorpromazine
thioridazine
give the typical agents with 𝝰₁ blocking?
chlorpromazine
thioridazine
haloperidol
give the typical agents with no 𝝰₁ blocking?
droperidol
give the typical agents with histamine blocking and high sedation effect?
chlorpromazine
thioridazine
droperidol
give the typical agents without histamine blocking?
haloperidol
Flupentixol
give the typical agents with low sedation effect?
haloperidol
flupentixol
SE of chlorpromazine?
corneal depositions (high dose)
SE of thioridazine?
cardiotoxicity (prolonged QT, torsade)
retinal depositions
is Fluphenazine available as depot injection?
yes
for what is haloperidol used and what is the dose?
acute psychotic disorders (delirium), 5mg IM
what are the SE of haloperidol?
neuroleptic malignant syndrome (NMS) and TD
strong EPS
what is the use of droperidol?
- anti-emetic use
- used in neuroleptanalgesia (in combination with fentanyl)
- sedative effect- used in general anesthesia
adverse effects and toxicity of typical agents
extrapyramidal symptoms (EPS) akathisia tardive dyskinesia (TD) acute dyskinesia dysphoria hyperprolactinemia weight gain neuroleptic malignant syndrome (NMS) autonomic abnormalities
what is dysphoria and what is the mechanism?
worsens negative symp of schizophrenia
dopamine receptor blockade
what is the management of dysphoria?
dose reduction
what are extrapyramidal symptoms? EPS
Drug-induced parkinsonism
(weeks after the initiation of treatment ):
bradycardia
tremor (perioral–> ‘rabbit’s mouth)
rigidity (‘cogwheel rigidity’)
dystonia - involuntary, abnormal muscle spasm and posture
what is the mechanism of EPS?
dopamine receptor blockade
management of EPS
dose reduction antimuscarinic agents (biperiden)
what is akathisia?
can’t sit, state of agitation and restlessness
what is tardive dyskinesia (TD)
involuntary, repetitive movements
develops after months- years of antipsychotic therapy, usually irreversible
what is acute dyskinesia?
immediate-torticollis (neck muscles stuck down), oculogyric (eye is stuck up), tongue automatisms (repetitive movements)
mechanism of akathisia
tardive and acute dyskinesia
dopamine receptor hypersensitivity
treatment of akathisia
tardive and acute dyskinesia
antihistamines (diphenhydramine) atypical antipsychotics (tiapride)
mechanism of hyperprolactinemia?
dopamine receptor blockade
presentation of hyperprolactinemia
gynecomastia
amenorrhea- galactorrhea syndrome
impotence
infertility
reason of weight gain
H₁ and 5-HT blockade
presentation of thermo-regulation abnormalities (neuroleptic malignant syndrome–> NMS)
muscle rigidity, rhabdomyolysis extreme catatonia impairment of sweat malignant hyperthermia fever altered mental status autonomic instability
management of neuroleptic malignant syndrome–> NMS
Diazepam dantrolene (RYR inhibitor) bromocriptine (D₂ agonist) discontinue causative agent stabilize BP, cool the patient
what is the presentation of autonomic abnormalities?
loss of accommodation (blurred vision)
dry mouth
urinary retention, constipation
orthostatic hypotension
what is the mechanism of autonomic abnormalities?
muscarinic and 𝝰- adrenergic blockade
