pharm exam 2 - antipsychotic drugs

what are antipsychotic drugs useful for

treating schizophrenia, psychotic disorders (mood disorders, paranoid disorders), drug induced psychosis

also anxiety, autism, antiemetic, refactory hiccups

what is schizophrenia

thought disorder characterized by distorted or non-existent sense of reality

• experience hallucinations, delusions, disorganized speech, disorganized or agitated behavior

• genetic

schizophrenia peak age of onset

20s

schizophrenia medication duration

needed for all of patients life because it is not curing; only treats symptoms

schizophrenia as a genetic disorder

108 loci associated with a risk of schizophrenia, strong link between having higher levels gene C4A expression leads to greater risk

schizophrenia positive symptoms

hallucinations, delusions, disorganized speech and thoughts

schizophrenia negative symptoms

anhedonia (inability to feel joy), avolition (isolation), blunted affect

schizophrenia cognitive manifestations

memory issues, inability to process social cues, impaired sensory perception

dopamine nigrostriatal pathway

neural pathway in the brain that is involved in the coordination of movement

dopamine mesolimbic pathway

neural pathway in the brain associated with reward, emotion, and cognitive functions

increased dopamine causes positive symptoms of schizophrenia

dopamine mesocortical pathway

neural pathway in the brain that plays a role in cognitive functions, emotion regulation, and executive functions

decrease in dopamine causes negative and cognitive symptoms of schizophrenia

dopamine tuberoinfundibular pathway

neural pathway in the brain that regulates the release of prolactin from the pituitary gland.

serotonin-dopamine interaction

Interaction between systems that influences mood, behavior, and psychotic symptoms. This balance is crucial in the treatment of schizophrenia and other mood disorders.

serotonin acts as a break on dopamine

serotonin interacts with receptors (5-HT2A) at postsynaptic level and inhibits the release of dopamine

• 5-HT2A antagonists cause more release of DA

traditional antipsychotics (typicals) (old)- MOA

their main therapeutic effects stems from blockade of dopamine D2 receptors

atypical antipsychotics (new) - MOA

target serotonin sites as well as dopamine

• absence of extrapyramidal motor disturbances

• they reduce the symptoms of schizophrenia for those who dont respond to typicals

• better at reducing the negative symptoms

• absence of hyperprolactinemia

pharmacokinetics of antipsychotics

high rapid oral absorption, highly lipophilic, excreted in urine/bile

how long do therapeutic effects take from antipsychotics

often take several days to six weeks to emerge; however side effects emerge immediately

typical antipsychotics

phenothiazines and butyrophenones

typical antipsychotics and mesolimbic pathway

blockade of D2 receptors, resulting in reduced positive symptoms of schizophrenia

typical antipsychotics and mesocortical pathway

blockade of D2 receptors which causes cognitive symptoms or worsen negative symptoms

typical antipsychotics and nigrostriatal pathway

blockade of D2 receptors and produces EPS such as motor abnormalities, tardive dyskinesia or hyperkinetic movement disorder

typical antipsychotics and tuberoinfundibular pathway

blockade of D2 receptors causes hyperprolactinemia

atypical antipsychotic drugs

aripiprazole (partial agonist), clozapine (partial agonist), olanzapine, quetiapine, risperidone, ziprasidone

atypical antipsychotics and the mesolimbic pathway

the action of the D2 receptor blockade of antipsychotics is more robust than 5-HT2A, they help reduce positive symptoms

atypical antipsychotics and the mesocortical pathway

there are more 5-HT2A (serotonin) receptors than D2 (dopamine) receptors in this pathway, so 5-HT antagonists are better at blocking in this pathway, helps to improve negative symptoms

atypical antipsychotics in the nigrostriatal pathway

serotonin (5-HT2A) atagonists bind to the 5-HT2A receptors disinhibiting the dopaminergic neuron and thus cause more DA to be released to reduce extrapyramidal symptoms.

atypical antipscyhotics and tuberoinfudibular pathway

DA blocks the release of prolactin, whereas 5HT2A causes release of prolactin. antagonistic properties of atypical antipsychotics cancel DA and 5HT2A action on prolactin release

aripiprazole overview

antagonist at 5HT2A receptors and partial agonist at D2 receptors

low incidence of extrapyramidal adverse effects

75 hour half life

aripiprazole boxed warning

elderly patients with dementia-related psychosis treated with antiosychotic drugs are at an increased risk of death.

increased risk of SUICIDAL THOUGHTS AND BEHAVIORS in pediatric and young adult patients taking antidepressants

aripiprazole MOA as partial agonist

instead of turning dopamine completely on or completely off, it balances it out by acting as a partial.

It replaces dopamine with its own much weaker signal, acting as a functional antagonist (blocker)

aripiprazole MOA as an antagonist

complete blocker at the 5-HT2A (serotonin) receptor. Blocking 5-HT2A helps improve overall mood, cuts down on negative psychiatric symptoms, and reduces the risk of physical side effects like muscle stiffness.

aripiprazole partial agonist effects at mesolimbic pathway

completes with dopamine as an inhibitor to bring DOWN to normal levels and reduce positive symptoms leading to schizophrenia

aripiprazole partial agonist effects at mesocortical pathway

acts as a dopamine agonist to bring dopamine levels back up to normal levels when a deficit is causing negative and cognitive symptoms of schizophrenia

clozapine overview

first atypical antipsychotic, has few extrapyramidal effects

affinity for D2 dopamine (partial agonist) and 5-HT2A serotonin receptor antagonist

12 hour half life

clinical advantages of clozapine

robust efficacy in treatment resistant patients and positive and negative symptoms

improved outcome for partial responders

improved disorganized behavior

improved aspects of cognitice deficits

ONLY FDA APPROVED AGENT TO LOWER SUICIDE RISK

diminished aggressive behavior

no tardive dyskinesia

no increase in serum prolactin

improved compliance

clozapine warnings

life threatening agranulocytosis: lowered white blood cell count requires frequent blood tests

high risk of onset diabetes and diabetes ketoacidosis

reserved fro refractory patients only

antipsychotic adverse effects

Extrapyramidal symptoms

Tardive dyskinesia (TD)

Sedation

weight gain

metabolic abnormalities

extrapyramidal side effects - 4 classes

parkison-like

akathisia

acute dystonias

tardive dyskinesia

extrapyramidal side effects - parkinson like

bradykinesia, ridigity, variable tremor, masked facial expression, shuffling gait

extrapyramidal side effects - akathisia

motor restlessness

extrapyramidal side effects - acute dystonias

spasms of msucle tounge, face, neck, back

treat with benztropine or reduce dose/change antipsychotic drug

extrapyramidal side effects - tardive diskinesia

uncontrolled, involuntary, and erratic muscle movements of oral-facial or widespread

neuroleptic malignant syndrome MOA

muscle ridgitiy, stupor, hyperthermia, unstable blood pressure, myoglobinemia contirbuted by rapid antagonism of dopamine

neuroleptic malignant syndrome treatment

stop the neuroleptic immediately, dantrolene or diazepam as muscle relaxants or bromocriptine (D2 receptor agonist)

endocrine side effects of antipsychotics

D2 receptor blockade in tuberoinfundibular pathway causing increased prolactin

gynaecomastia (men)

galactorrhoea

amenorrhea (women)

SD or infertility (men)

cardiac side effects of antipsychotics

blockage of cardiac K+ channels cause prolonged QT in the ECG leading to ventricular arrythmia and sudden cardiac death

anticholinergic effects of typical antipsychotics

constipation, urinary retention, blurred and dry eye, dry mouth, hot, tachycardia, orthostatic hypotension, dizziness, confusion, hallucinations