6 Antipsychotics and Mood Stabilizers Flashcards
What are some hypotheses for the causes of schizophrenia?
Dopamine
• DA receptors may be greater in schizophrenics
• Drugs that increase DA neurotransmission can induce psychosis
• Most antipsychotics block DA receptors
Serotonin (LSD, mescaline)
• 5HT receptors are altered in schizophrenics
• 5HT receptors mediate DA transmission
Glutamate (PCP, ketamine)
What are the “positive” symptoms of schizophrenia?
Hallucinations (auditory and visual) and delusions
Catatonic behavior, disorganized speech and thinking
Over-active dopamine pathways in limbic system (mesolimbic)
What are the “negative” symptoms of schizophrenia?
Affective behavior, apathetic, withdrawn, anti-social, lack of motivation, depressed
Under-active dopamine pathways in frontal cortex (mesocortical)
What happens to schizophrenics cognitively?
Distracted, disorganized thought, memory loss
What are the four dopamine pathways?
- Mesolimbic - VTA to limbic system (EMOTION)
- Mesocortical - VTA to frontal cortex (Cognition, emotion)
- Nigrostriatal - SN to striatum (Motor control)
- Tuberoinfundibular - Hypothalamus to pituitary (Prolactin)
MOA for “classical” antipsychotics
“Neuroleptics”
Block DA D2 receptors
Target the mesolimbic system
Alleviate the POSITIVE symptoms
MOA for “atypical” antipsychotics
Block 5HT-2a and DA receptors
Target the mesocortical and mesolimbic system
Alleviate both negative and positive symptoms
_______ receptors predominate in the mesolimbic region
DA D2
______ receptors are distributed in the mesocortical region
DA D4
DA D2 receptors predominate the ________ region while DA D4 receptors are distributed in the _________ region
Mesolimbic
Mesocortical
General effects of antipsychotics
Delayed onset - 6 weeks
Decrease aggression, restlessness, anxiety
Psychomotor function is slowed, initiative/motivation decrease
Reduce spontaneous movements
Sedation
Antiemetic (Prochlorperazine)
Most antipsychotics also block _______, _________, and ________ receptors in the brain and periphery
Muscarinic
Alpha-adrenergic
Histamine
Why is compliance usually poor with antipsychotics
Very common, not very pleasant side effects
Side effects of antipsychotics
Decreased seizure threshold
Endocrine - weight gain, increased prolactin secretion
Autonomic - anticholinergic sx, postural hypotension, sedation
Dental - xerostomia and bruxism (grinding teeth)
What are Extrapyramidal Symptoms (EPS)?
DA receptor antagonists also block DA receptors in the nigrostriatal pathway —> Parkinson’s like tremor, rigidity, dyskinesias, rocking, pacing, restlessness, anxiety, dystopia
Due to imbalance of striata DA and ACh
How do you treat Extrapyramidal Symptoms?
Anticholinergics such as benztropine (Cogentin) to restore ACh/DA balance
Degree of EPS a patient experiences is based on…
The anticholinergic activity of the antipsychotic drug (chlorpromazine vs. haloperidol)
Classical antipsychotics tend to cause more EPS than atypicals
Choreiform, uncontrollable, jerky movements of face and limbs, occurring in late disease following long term treatment
Tardive dyskinesia (15-25% of patients)
Difficult to treat, often irreversible - d/c drug
Which drugs are most likely to cause tardive dyskinesia?
Clozapine and Olanzapine
Life threatening side effect of antipsychotics —> muscle rigidity, hyperpyrexia, changes in BP and HR
Neuroleptic Malignant Syndrome
Block of DA D2 receptors in the striatum and hypothalamus
How do you treat Neuroleptic Malignant Syndrome?
Dantrolene (Dantrium)
Can also use DA agonists (bromocriptine) to stimulate DA receptors
What happens if you mix antipsychotics with anticholinergics?
Just more of the same side effects (dry mouth, urinary retention, constipation etc)
What happens if you mix sedative-hypnotics with antipsychotics?
Will increase sedation
What happens if you mix TCAs with antipsychotics?
Seizures and cardiac effects
What does smoking do if you’re on antipsychotics?
Induces CYP450s - so the antipsychotics don’t work as well
MOA for classical antipsychotics
Block DA D2 receptors
Requires ~60% receptor occupancy
Pharmacokinetics of classical antipsychotics
Readily absorbed from gut following oral administration
Most have high first pass metabolism
Half lives range from 20 to 35 hours
Effects persist for weeks after last administration
Metabolized by CYP450s
How is Chlorpromazine (Thorazine) used?
Psychosis associated with mania and drugs of abuse
Also an antiemetic (prochlorperazine) and a pre-anesthetic
May cause TD and neuroleptic malignant syndrome
High anticholinergic effects so low incidence of EPS
Side effects of Chlorpromazine (Thorazine)
Sedation, postural hypotension, blurred vision, constipation, decreased GI motility, inhibition of ejaculation, jaundice
Decreases seizure threshold
May cause retinal deposits*** —> “browning” of vision
Fluphenazine (Prolixin) is similar to chlorpromazine but…
Selective for DA D2 receptors —> less anticholinergic activity and more EPS
Potent blocker of DA D2 receptors that is used frequently in acute situations
Haloperidol (“Vitamin H”)
Also has affinity for DA D1, 5HT-2, and H1 receptors
Haloperidol has no __________ but does have __________
No anticholinergic activity
Extrapyramidal symptoms, esp when used chronically
MOA for atypical antipsychotics
Block 5HT-2A receptors but also DA D2 and D4 receptors
Alleviate both the negative and positive symptoms
Which antipsychotic is the drug of last choice due to agranulocytosis?
Clozapine (Clozaril)
Blood must be monitored
What is Clozapine (Clozaril)?
Atypical antipsychotic that blocks 5HT-2A and DA D4
EPS and tardive dyskinesia very rare
Side effects - hypersalivation, sedation, dizziness, postural hypotension, tachycardia, weight gain
Decreased seizure threshold
Relapse if d/c abruptly
Olanzapine (Zyprexa) is similar to clozapine but…
No agranulocytosis
Improves both positive and negative symptoms
Some anticholinergic activity
EPS symptoms rare
Which antipsychotic can cause T2DM?
Olanzapine (Zyprexa)
“Zyprexa Diabetes” - hyperglycemia and weight gain are major side effects
But it’s also used for bipolar disorder
First line drug for psychosis
Risperidone (Risperdal)
Blocks 5HT-2A and DA D2 receptors to improve both positive and negative symptoms
No significant effect on DA neurotransmission in nigrostriatal pathway so EPS and TD rare
What are the side effects of Risperidone (Risperdal)
Hypotension, weight gain, insomnia anxiety
Some cardiac effects - Lenghtens QT INTERVAL
What drug is used for Tourette’s syndrome and acute mania?
Ziprasidone (Geodon)
Blocks DA D2 and 5HT-2A receptors
Some antidepressant activity
Side effects of Ziprasidone (Geodon)
Prolongs QT interval
Causes sedation, impair cognitive and motor skills
May cause hyperprolactinemia
Used with caution in patients with history of seizure disorders or with drugs that decrease seizure threshold
Quetiapine (Seroquel) is similar to clozapine but…
No agranulocytosis and does not elevate prolactin
Used to promote sleep onset and maintenance
Few EPS but VERY sedating
What is Aripiprazole (Abilify)
“Dopamine system stabilizer”
• When dopaminergic tone is low - DA receptors activated
• When dopaminergic tone is high - DA receptors blocked
Low incidence of EPS
Major side effect of Aripiprazole (Abilify)
Decreases esophageal motility
What is Lurasidone (Latuda)
Blocks D2 and 5HT-2A receptors, and partial agonist at 5HT-1A
No antihistamine or antimuscarinc effect
Used to treat depression associated with bipolar disorder
Some incidence of agranulocytosis and neutropenia, so monitor CBC
What is thought to cause bipolar disorder?
A lack of GABAergic activity
What are the two main treatments for bipolar disorder?
Lithium (Eskalith)
Anticonvulsants
Often treated with combos of these drugs and antipsychotics such as olanzapine (Zyprexa)
What are the pharmacokinetics of Lithium (Li)
Readily absorbed from the gut
Distributed throughout the body (half-life 24 hours)
NO METABOLISM - excreted by the kidneys
MOA for Lithium
Suppresses 2nd messengers (IP3), which may increase ACh, NE, and DA
Effective in about 60% of bipolar patients
Calming effect in manic patients
Poor compliance - extremely toxic in overdose
Where is lithium absorbed?
By the proximal tubule in the kidney
Competes with sodium (Na+) for re-absorption
• If Na+ decreases —> Li absorption increases —> toxicity*
• If Na+ increases —> Li absorption decreases —> excretion increases
• If Li increases —> Na+ absorption decreases —> Hyponatremai*
What are the main side effects of lithium
Small therapeutic window (optimal plasma concentration range 0.6-1.2 mEq/L)
• >2 mEqL - N/D, weakness, HA, tremor, confusion, etc
• >2.5 mEq/L = confusion, sedation, nystagmus, seizures, renal failure, arrhythmias, coma, DEATH
Thyroid function reduced
Diabetes Insipidus (b/c Li inhibits ADH) - treat with amiloride
Not recommended in pregnancy
Is it a good idea to mix lithium with antidepressants?
Nope - may increase mania
Is it ok to mix benzos or antipsychotics with lithium?
Sure - pretty safe
What happens if you take diuretics with your lithium?
Alters sodium excretion —> can also alter Li clearance
What happens if you take NSAIDs with your lithium?
Increased Li toxicity - decreased clearance, increased Li uptake
What are the alternatives to Lithium for bipolar patients?
Valproic Acid (Depakene) - good for rapid cycling manic/depressive phases but causes surgical bleeding and TERATOGENIC
Gabapentin (Neurontin) - also good for rapid cycling
Carbamazepine (Tegretol) - good for refractory BD in combo with Li - inc chance of SJS
Lamotrigine (Lamictal) - approved for prevention of relapse, depressive state following mania, acute mania
