What are typical/first generation/conventional/ classic antipsychotic drugs?
- Chlorpromazine is a phenothiazine. Need to be given at higher doses due to low potency. H1 antagonist–> relieve pruritus and preoperative
- Haloperidol is butyrophenones . Need to be given at low doses due to high potency . This drug is good at causing EPS and hyperprolacemia
- they both have similar side effects with exception to haloperidol not causing anticholernergic effects and orthostatsis
- difficult to find a dose that does not cause eps
What are positive, negative and cognitive symptoms?
Positive:
disorganized thought
Disorganized behavior
Delusions (unusual thought content) Hallucinations
Negative:
Affective flattening
Alogia
Anhedonia
Avolition
Cognitive:
Impaired attention
Impaired working memory
Impaired executive function
What are select atypical/ second generation/newer drugs?
- Clozapine(D2 antagonist): not retained for many weeks after cessation. Blocks H1, M1 and alpha adrenergic which causes agranulocytosis, seizure, myocarditis, weight gain. Use: treatment of refractory disease and to decrease risk of suicide
- Olanzapine(D2 antagonist): cause weight gain
- Risperidone(D2 antagonist): high risk for hyperlactemia and eps
- Ziprasidone (D2 antagonist)
- Aripiprazole (partial D2 agonist): only triggers a partial response in comparison to dopamine. This drug is a good dopamine ‘tuner’.
- atypicals are good dopamine tuners cause the act on both dopamine and serotonin . They block 5ht in nigrostriatal and mesocortical pathway which causes modulation of dopamine release. D2 + 5HT 2A antagonism = therapeutic efficacy, general lower risk of eps, td and hyperprolacemia
- apripiprazole and ZiprasIDONE has good side effect but have not been studied for too long
- cause weight gain
What does first and second generation treat?
Second generation treat negative and cognitive symptoms better than first generation.
*cognitive symptoms are least responsive to action of these drugs
About the different pathways
- nigrostriatal pathway (blocking D2= movement disorders): involved in voluntary movement- this pathway is normal in schizophrenia
- mesolimbic (blocking is good for relieving psychosis) and mesocortical pathway (blocking can cause psychosis): related to behavior and psychosis- there is high dopamine In mesolimbic which cause positive symptoms. In the mesocortical, there is low dopamine, which cause cognitive and negative symptoms
- tuberoinfundibular (blocking can cause increase prolactin secretion): it is normal pathway in schizophrenia
What are characteristics of first generation antipsychotics
- good at antagonizing d2 receptors and really good at preventing positive symptoms
.-binding affinity is high hence Cause of extra pyramidal side effects
What are characteristics of second generation drugs?
- new drugs have a higher affinity for serotonin 2A receptors than for D2 receptors
- tend to dissociate antipsychotics action from eps
- thought to improve negative symptoms and possibly even cognitive symptoms
- decrease positive symtoms
- low risk for Eps
About antipsychotics
Many experience first pass metabolism
Metabolizes by liver cytochrome p450 enzyme
Highly lipid solvable and protein bound so retained for many weeks after cessation (except for clozapine)
What are drug uses -psychiatric?
Primary indication- schizophrenia (except catatonic form)
Psychotic bipolar disorder
Psychotic depression
Treatment resistant depression
Schizoaffective disorders
Tourette syndrome
Off label aggression in patient w dementia
Irritability in autism spectrum disorder
*never use in anxiety
What are drug uses -nonpsychiatric?
- antiemetic effect due to dopamine receptor blockade
- relief pruritus or as preoperative
- neuroleptanesthesia
- uncontrollable hiccups
Why use typical and atypical drugs?
Typical: used previously w no side effects, cost less, extended release
Atypical: cost less, less pyramidal effects, injectable, work on cognitive and negative effects
Atypical is the first line of treatment
What did the CATIE study show ?
> CATIE study:
● Reported a typical agent was as effective as atypical antipsychotic drugs (with modest exception of olanzapine)
● Conclusion: based on their lower cost, typical antipsychotic drugs are the treatment of choice for schizophrenia
● Problems with the study design:
- Did not adequately consider the risk of tardive dyskinesia
- Did not adequately consider patient treatment history
Use of the typicals still occurs
Typicals vs atypicals
> In terms of positive symptoms, approximately 70% of patients with schizophrenia will experience equal efficacy of typical and atypical agents.
With the exception of clozapine and maybe olanzapine, thought that most antipsychotics are, across a broad group of patients, equally effective
What are the reasons for antipsychotics have side effects?
Known extension of the pharmacodynamics of antipsychotics
Some side effects are allergic in nature
Some are idiosyncratic
What does H1 antagonism cause?
Sedation
What does D2 antagonism in nigra striatal cause?
EPS (Parkinsonism, dystonias)
Super sensitive D2 receptors cause tardive dyskenisia
What does M1 antagonism cause?
Anticholernergic symptoms such as dry mouth, difficulty urinating, constipation
What does alpha 1 antagonism cause?
Orthostatic
What does 5HT 2C and H1 antagonism cause?
Weight gain
What is tardive dyskenisia caused by?
Cause by super sensitivity in long term use
What are rare but serious side effects?
Neuro plastic malignant syndrome- due to strong d2 blockade causes strong eps usually with 10days . Stop meds
Tardive dyskinesia- is a serous because it is not reversible once it occurs
* CATIE study didn’t take this into account
Some fact about tardive dyskinesia are?
- it is highest in typical drugs
- it is repetitive voluntary movement
- Cause super sensitivity in dopamine
- difficult to treat, need to switch medication to give dopamine time to reset
- patient with eps are thought to develop td later on
How to manage side effects?
Lower dose or switch drugs
Manage dosing- take sedative drugs at night
Parkinsonism and dystonias- antiparkinson but not levodopa
Akathisia propranolol or benzodiazepines
Treat symptoms
Behavioral modification such diet and exercise
What are some other issues w typical and atypical?
Typical: ocular deposits
Atypical and typical: abnormal ECgs, potential cardiac toxicity, sudden cardiac death, seizure
