E1: Antipsychotics: Flashcards
What is the dopamine hypothesis of schizophrenia?
- DA receptors may be greater in schizophrenics
- drugs that increase DA neurotransmission can induced psychosis
What is the serotoninc hypothesis of schizophrenia?
-Serotonin receptors are altered in schizophrenics and serotonin receptors mediate DA transmission
What are the positive symptoms of schizophrenia and what causes them?
- Hallucinations, delusions, catatonic behavior, disorganized speech
- Caused by overactive dopamine pathways in the limbic systemic
What are negative symptoms in schizophrenia and what causes them?
- Affective behaviior, apathetic, withdrawn, antisocial
- Caused by underactive dopamine pathways in the frontal cortex
What are the 4 dopamine pathways in the brain?
1) mesolimbic: VTA to limbic system
2) Mesocortical: VTA to frontal cortex
3) Nigrostriatal: SN to Striatum
4) Tuberoinfundibular: Hypothalamus to pituitary
What are the “classic” antipsychotics?
- “neuroleptics” that block DA D2 receptors and target the mesolimbic system
- Alleviates the positive symptoms
What are the “atypical” antipsychotics?
- Blocks 5-HT2A and DA receptors and targets the mesocortical and mesolimbic system
- Alleviates both negative and positive symptoms
What two antipsychotics have the highest affinity for D2 receptors?
Haldol and Aripiprazole
What type of dopamine receptors predominate the mesolimbic system?
D2
What type of dopamine receptors predominate the mesocortical region?
D4
What are the general effects of antipsychotics?
- delayed onset (6weeks)
- decreased aggression, restlessness, anxiety
- psychomotor function is slowed
- reduce spontaneous movements
- sedation
What are the common side effects of antipsychotics?
- decreased seizure threshold
- weight gain, increased prolactin secretion
- anticholinergics: dry mouth, blurred vision
- Alpha adrenergic: postural hypotension
- Histamine: sedation
- Extrapyramidal symptoms
- Tardive dyskinesia
- Neuroleptic malignant syndrome
What are extrapyramidal symptoms and what causes them?
- Parkinsons like symptoms: tremor, rigidity, dyskinesias rocking, pacing, restlessness, anxiety
- caused because DA receptor antagonists also block DA receptors in the nigrostriatal pathway, causing an imbalance in striata DA and ACh
How are extrapyrimidal symptoms treated?
-treat with anticholinergics such as Benztropine (cogentin) to restore ACh/DA balance
Which kind of antipsychotics tend to cause more EPS symptoms?
Classical antipsychotics
-degree of EPS is based on the anticholinergic activity of the drug
What is tardive dyskinesia?
Uncontrollable, jerky movements of the face and limbs, occurs late in disease following long term treatment
Which antipsychotics are least likely to cause TD?
Clozapine and Olanzapine
What is neuroleptic malignant syndrome?
A life threatening side effect
-muscle rigidity, hyperpyrexia, changes in BP and HR
How is neuroleptic malignant syndrome treated?
Dantrolene
What are the 4 classical antipsychotics?
- Chlorpromazine
- Prochlorperazine
- Fluphenazine
- Haloperidol
What are the atypical antipsychotics?
- Clozapine
- Olanzapine
- Quetiapine
- Aripiprazole
- Risperdone
- Ziprisadone
- Lurasidone
What are the uses of Chlorpromazine?
Psychosis associated with mania and drugs of abuse, antiemetic (prochlorperazine), pre anesthetic
What are the side effects of Chlorpromazine?
- Decreases seizure threshold
- may cause retinal deposits “browning of vision”
- sedation, postural hypotension, blurred vision
How is Fluphenazine different from Chlorpromazine?
Fluphenazine is similar, it is selective for DA D2 receptors. It does have less anticholinergic activity and more EPS
Does Haldol have anticholinergic activity? What does this mean for its side effects?
- no anticholinergic activity
- high incidence of EPS
What is the MOA of Clozapine?
Blocks 5-HT2A and DA D4 receptors, EPS and TD are rare
What are the side effects of clozapine?
- Hypersalivation, sedation, dizziness, postural hypotension, tachycardia, weight gain
- decreased seizure threshold
- rapid relapse if discontinued abruptly
Why is Clozapine a drug of last choice?
Risk of agranulocytosis
What are the side effects Olanzapine?
- Hyperglycemia type II DM (Zyprexa DM)
- sedation, orthostatic hypotension, weight gain
What are the uses of olanzapine?
- Positive and negative symptoms
- Bipolar
What is the first line drug for psychosis?
Risperdone
Why is risperdone the first line drug for psychosis?
-no significant effect on DA neurotransmission in nigrostriatal pathway, EPS and TD are rare
What are the uses of Ziprasidone?
- Some antidepressant activity
- Tourette’s
- acute mania
What are the side effects of Ziprasidone?
- Prolonged QT
- Sedation
- Hyperprolactinemia
- decreases seizure threshold
What are the side effects of Quetiapine?
- Very sedating, dizziness, constipation, weight gain
- Does not elevate prolactin
- few EPS
What is the MOA of Aripiprazole?
- Dopamine system stabilizer (if dopaminergic tone is low, DA receptors are activated. If dopaminergic tone is high, DA receptors are blocked)
- Partial agonist for DA D2 and 5-HT1A.
- Antagonist for 5-HT2A
What are the side effects of Aripiprazole?
-Decreases esophageal motility, hyperglycemia, sedation, seizures, increased glucose
What is the use of Lurasidone?
Used in the treatment of depression associated with bipolar
What are the side effects of Lurasidone?
- Some incidence of agranulocytosis and neutropenia
- side effects similar to other atypicals
- no antihistamine or anti muscarinic effect
What is the treatment of bipolar disorder?
- lithium
- anticonvulsants
**patient are often treated with these drugs and antipsychotics such as olanzapine
What causes Bipolar?
Lack of GABAergic activity
How is lithium metabolized?
It is not metabolized, it is excreted by the kidneys in its original form
-Therefore has minimal drug interactions
What is the MOA of lithium?
Supress 2nd messengers (IP3)
Why do you need to monitor salt intake when taking lithium?
- Lithium is reabsorbed by the proximal tubule in the kidney and competes with sodium for re-absorption
- if Na+ decreases, Lithium absorption increases, leading to toxic doses and vice versa
What are the side effects of lithium?
- VERY small therapeutic window
- DI (lithium inhibits ADH, leading to increased thirst and urine output)
- Thyroid function reduced
- not recommended with pregnancy
How can you treat DI induced by lithium
Amiloride- blocks lithium from entering into the collecting duct
What medications cannot be combined with lithium?
- NSAIDs
- Antidepressants (mania may increase)
- Sodium (reduces Li concentration)
What happens when NSAIDs and Lithium are combined?
Increases Li toxicity by decreasing clearance and increasing Li uptake
What are the anticonvulsants that can be used in the treatment of bipolar?
- Valproic acid
- Gabapentin
- Carbamzepine
- Lamotrigine
What is Valproic acid indicated for in bipolar?
Rapid cycling of manic and depressive phases
-effective in some who dont response to lithium
What are the side effects of Valproic acid?
- Surgical bleeding, GI upset, weight gain
- Teratogenic
What is the use of Carbamazepine in bipolar disorder?
-Refractory bipolar, used in combo with lithium
What are the potential side effect of Carbamazepine?
- GI upset, sedation, CNS toxicity, hypersensitivity
- SJS/toxic epidermal necrosis is
What drugs cannot be combined with Carbamazepine?
Carbamazepine competes for metabolism with Cimetidine, isoniazid, fluoxetine, and erythromycin so toxicity is increased
What is the used of Lamotrigine in bipolar disorder?
Approved for prevention of relapse, depressive state following mania, and acute mania
