L7-8 Antipsychotics Flashcards
What is thought to cause the psychosis and positive symptoms in Schizophrenia?
Increased DA in the mesolimbic system
What is thought to cause the negative symptoms and cognitive dysfunction in patients with Schizophrenia?
Decreased DA in the hippocampus and prefrontal cortex
How do the classical antipsychotics work vs. the newer atypical antipsychotics?
Classic-block D2, treat positive symptoms, no help in negative symptoms
Newer, Atypical-block 5-HT2a, treat negative symptoms better
What are 5 mechanisms that can be theoretically used to treat Schizophrenia?
Block D2: classical antipsychotics
Block 5-HT2a: newer antipsychotics. Facilitates DA release in prefrontal cortex to treat negative symptoms
Stimulate NMDA receptors (glutamate): increases DA in mesocortical (combats negative symptoms) and decreases DA in mesolimbic (combats positive symptoms)
Increase GABA: decreased GABA synthesis has been reported in schizophrenia and bipolar perhaps as a result of decreased activity of NMDA receptors. Decrease in GABA leads to overstimulation of cortical neurons
Stimulate M4 receptors (in trial): improve cognitive disorders
What types of receptor blockade do most of the side effects come from with the antipsychotics?
muscarininc blockade
alpha-adrenergic blockade
histamine blockade
What are the low potency Phenothiazines?
How do they work?
What types of side effects do they cause?
Chlorpromazine and Thioridazine
Block D2, alpha, histamine
Very effective but require high doses
Considerable anti-cholinergic effects, less likely to cause extrapyramidal symptoms
More sedation and hypotension
What are the high potency Phenothiazines?
How do they work?
What types of side effects do they cause?
Fluphenazine and trifluoperazine
High potency, more selective for DA receptors
Less anti-cholinergic effects, more likely to cause extrapyramidal symptoms
Less sedation and hypotension
What are the side effects of the classical antipsychotics?
Extrapyramidal effects: due to blockage of DA receptors in nigrostriatal system (motor control, Parkinsonian sx), treated with anti-cholinergic drugs
Tardive Dyskinesia: uncontrollable movements of mouth, tongue, face, clozapine and olanzapine less likely to cause
Endocrine effects: weight gain, increarse prolactin release (DA inhibits prolactin), decrease release of sex hormones (decreased libido, infertility, amenorrhea, gynecomastia)
Autonomic effects: due to blockage of muscarininc (dry mouth, blurred vision, constipation, tahycardia), alpha (orthostatic hypotension, difficulty ejaculating), and histamine (sedation)
Seizures: slow frequency of EEG
Neuroleptic Malignant Syndrome: life-threatening-muscle rigidity, catatonia, increase temp, change BP and HR
Which antipsychotics are least likely to cause tardive dyskinesia?
clozapine and olanzapine
Which antipsychotics are seizures most likely to occur with?
What patients should not be given antipsychotics?
Clozapine, olanzapine, chlorpromazine
Used with caution in untreated epileptics and patients who are withdrawing from CNS depressants
What is neuroleptic malignant syndrome?
How do you treat it?
Life-threatening side effect of the classical antipsychotics: muscle rigidity, catatonia, increase in body temp, altered BP and HR
Tx: discontinue antipsychotic immediately, supportive care
Dantrolene, diazapan, and dopamine agonists may also be used
Name the Phenothiazines.
What are they used for?
Chlorpromazine, Thioridazine, Fluphenazine, Trifluoperazine, Prochlorperazine
Widely used to treat schizophrenia, used in psychotic episodes, manic episodes, hallucinations
Other uses: nausea, vomitting, pre-anesthetic sedation, premature ejaculation, relieves severe itching
Low potency drugs (chlor and thio): high anti-cholinergic activity-increases autonomic side effects, lower chance of extrapyramidal symptoms
What is important about the phamacokinetics of the phenothiazines?
Absorbed erratically when taken orally
Effective IM
24-48 hr half-life, very slow liver elimination
What are the side effects of Phenothiazines?
Anticholinergic: blurred vision, constipation, dry mouth, urinary retention, decreased GI motility
Alpha blockade: postural hypotension, inhibition of ejaculation
Negative inotropic action
Mild jaundice in 2nd to 4th week
Decrased seizure threshold (worse with chlorpromazine)
Thioridazine: retinal deposits
Haloperidol
Selective blocking of D2 receptors
Similar effects to phenothiazines: sedation, indifference, reduced initiative, decreased anxiety
Well absorbed orally
Often injected in acute situations
Concentration in brain can be much higher than in blood
Slow metabolism and excretion, blood levels stable for 3 days
Most likely of all antipsychotics to cause extrapyramidal symptoms
Pimozide
Similar to haloperidol, blocks D2
Can be used for motor and phonic tics in patients with Tourette’s
High extrapyramidal symptoms, moderate sedation, moderate anti-cholinergic
ECG changes, lengthen QT interval
Loxapine
Similar to phenothiazines
Used when other drugs have not worked
Lowers seizure threshold more than phenothiazines
Molindone
D2 blockade
Moderate sedation, increases motor activity, mild euphoria
Extrapyramidal effects, xerostomia, constipation, hypotension, syncope, tachycardia
Clozapine
Atypical antipsychotic, Improves negative symptoms
Binds D4 (mainly in limbic and cerebral cortex and not in striatum) causing lower incidence of extrapyramidal symptoms
Binds 5-HT2a: faciliatates DA release in prefrontal cortex
Inhibits muscarinic, alpha, and histamine receptors
Unlikely to cause tardive dyskinesia
Treat delusions in Parkinson’s disease
Use is reserved for patients who do not respond to conventional drugs
What are the side effects of Clozapine?
Sedation
Decreased seizure threshold
Hypotension, tachycardia
Increased salivation, dizziness
Weight gain
Agranulocytosis in 1%-serious!
Olanzapine
Similar to clozapine
Blocks D2, D4, 5-HT2a (more effective for negative symptoms)
anticholinergic, extrapyramidal rare
Can improve positive and negative symptoms
Also used to treat bipolar
Does not cause agranulocytosis, less toxicity than clozapine
What are the side effects of Olanzapine?
Weight gain-very common
Sedation and dizziness
Orthostatic hypotension
Akathisia (restlessness, anxiety, pacing)
Constipation
Increased incidence of hyperglycemia and type II diabetes
What antipsychotic is most likely to cause weight gain and a high incidence of hyperglycemia and type II diabetes?
Olanzapine
Risperidone
Atypical antipsychotic
Very effective at relieving positive AND negative symptoms
Used in combo with SSRIs to in treatment resistant depression and in autism
Inhibits D2 and especially 5-HT2a, blocks alpha receptors
Enhances DA in basal ganglia-few extrapyramidal
Low incidence of tardive dyskinesia
What is Paliperidone?
The active metabolite of risperidone (atypical antipsychotic)
Supplied as extended release product
What is significant about the pharmacokinetics of Risperidone?
Well absorbed orally
Highly protein bound
What are the side effects of Risperidone?
Alpha antagonist: postural hypotension
Agitation, anxiety, insomnia
Headache, nausea, weight gain
extrapyramidal at hihg doses
lengthens QT interval
Increased prolactin release may occur
Ziprasidone
Similar to risperidone
Blocks D2 and 5-HT2a
Some antidepressant activity
Used in Tourette’s and to treat acute mania
Not as likely to cause weight gain
Orally or IM
What are the side effects of Ziprasidone?
Prolongs QT interval: avoid in patients with cardiac conduction defects, recent MI, taking TCAs
Sedation and impairs cognitive and motor skills in initial days of tx
May cause hyperprolactinemia
Use in caution with seizure disorders or other drugs that decrease seizure threshold
Quetiapine
Similar to clozapine, no agranulocytosis
Improves positive and negative symptoms
Few extrapyramidal
Used as adjunct in depression tx
Helps sleep problems in patients with depression
Used as monotherapy in bipolar depression
Asenapine
Blocks multiple 5-HT receptors (2a and 2c)
Not a strong D2 blocker, but blocks D3
Histamine and alpha1 blocker
Small increase in QT
Less metabolic effects, less likely to cause weight gain
Used off label for tx of nightmares in patients with PTSD
Aripiprazole (Abilify)
First in a new class called “dopamine system stabilizers”
Activates DA receptors in DA tone is low and blocks DA receptors if tone is high
Partial D2 and 5-HT1a agonist
Antagonist at 5-HT2a
Histamine and alpha1 blocker
No effect on prolactin or QT interval
Unlikely to cause weight gain in adults
Tx of drug-resistant depression and antipsychotic effects
What are the side effects of Aripiprazole?
Orthostatic hypotension
Elevations in blood glucose: diabetes may develop or worsen
Seizures
Sedation
Decrases motility of esophagus: used in caution in elderly (risk of aspiration pneumonia)
Decreases ability to regulate body temp in hypothalamus
Low incidence of extrapyramidal effects
Iloperidone
Atypical antipsychotic
Blockade of D2 and 5-HT2a
alpha blockade, no muscarinic effect
Lurasidone
Atypical antipsychotic
Blocks D2 and 5-HT2a, partial agonist at 5-HT1a
NO antihistamine or antimuscarinic effect
Used in tx of depression associated with bipolar
Some incidence of agranulocytosis and neutropenia-monitor blood counts
What two things decrease antipsychotic concentration by inducing liver enzymes and increasing metabolism?
Carbamazepine and Smoking
What if given with an antipsychotic will cause increased sedation?
What will cause increased side effects such as dry mouth and urinary retention?
Sedative-hypnotics
Anti-cholinergics
What are the first line drugs for Schizophrenia and why?
When would you give Clozapine?
Risperidone, Quetiapine, Olanzapine
due to low incidence of extrapyramidal effects
Clozapine is reserved for paitens who fail to respond to at least two others, or who are disabled by tardive dyskinesia. Clozapine is expensive and needs frequent blood monitoring due to possibility of agranulocytosis
Which antipsychotics are most commonly used for Tourette’s syndrome?
Haloperidol and Pimozide
What is the recommendations for the use of antipsychotics in Alzheimer’s disease?
Risperidone has been used but increased mortality.
Use of antipsychotics is not recommended in elderly patients, especially with dementia.
What antipsychotic is frequently used as an antiemetic?
Prochlorperazine
What antipsychotics can be used as adjunct drugs for treatement-resistant depression?
Quetiapine, olanzapine, aripiprazole
How is Lithium used when treatment is started for bipolar disorder?
The onset of action of lithium is slow, so it is common to begin with antipsychotics and/or benzos until mania is controlled, and then maintain on lithium alone.
An antidepressant can be added in the depressive phase.
Maintainance with lithium can prevent both mania and depression and decrease suicide risk.
How is lithium excreted?
What is the optimal concentration range?
When is a steady state reached?
Excreted by kidney
Optimal concentrations range from 0.6-1.2 mEq/L
Steady-state is generally reached within 5-6 days of treatment
What 3 mechanisms can increase lithium concentration?
- Lithium is reabsorbed by the proximal tubule in the kidney and competes with sodium reabsorption
Decreases in sodium (decrease salt intake, hot weather, exercise) will increase lithium concentration
- Thiazide diuretics decrease the clearance of lithium
- NSAIDs also decrease lithium clearance
What drugs are most commonly used to treat bipolar disorder?
Lithium, Valproic acid, Carbamazepine
Lurasidone, Lamotrigine, and Olazapine are also used
What are the side effects of Lithium?
Tremor: one of the most common side effects
Nausea, diarrhea, anorexia, bloating, ususally transient
Headache, memory impairement, mental confusion
Decreased thyroid function: lithium blocks thyroxine synthesis and release, decreases sensitivity to TSH, possibly causing receptor uncoupling
Edema, weight gain
Can be used during pregnancy
What are the renal effects of Lithium?
Nephrogenic diabetes insipidus with polyuria and polydypsia, due to loss of ability of the collecting tubule to conserve water under the influence of ADH (Lithium blocks action of ADH)
Resistant to vassopressin, can be treated with amiloride (blocks entry of lithium into collecting duct)
Chronic insterstitial nephritis and nephrotic syndromes may also occur with long-term treatment, but renal failure does not generally result
What is considered mild v. severe Lithium toxicity?
How do you treat Lithium overdose?
Mild=plasma levels >2.0mEq/L
Severe=plasma levels > 2.5mEq/L
Treat with dialysis and saline
What two classes of drugs are generally safe to use in combination with Lithium?
Antipsychotics and Benzos
What is the significant about the drug interaction between Lithium and antidepressants?
Can increase mania in some people
What is the significant about the drug interaction between Lithium and Diuretics?
Drugs that alter sodium excretion will also affect Lithium, because Lithium and sodium compete for reabsorption.
Thiazide diuretics decrease clearance of Lithium (less lithium is getting excreted, because more sodium is getting excreted)
Amiloride, a K-sparing diuretic has been used to decrease polyuria and has little effect on lithium clearance.
What is the significant about the drug interaction between Lithium and NSAIDs?
Decrease Lithium clearance and increase plasma concentration
What is the significant about the drug interaction between Lithium and sodium?
Low sodium intake, sweating, exercise, hot weather–>decrease sodium and may therefore increase plasma lithium concentrations
Name the 5 anticonvulsants used in the treatment of bipolar disorder.
Valproic acid
Carbamazepine
Lamotrigine
Topiramate
Gabapentin
Valproic acid
Anticonvulsant that is widely used as a mood stabilizer.
Equal efficacy to Lithium.
Effective in some patients who do not respond to Lithium.
Rapid onset of action.
Few side effects-GI most common.
Cabamazepine (Tegretol)
Anticonvulsant that can be used in patients who do not respond to lithium or in combination with lithium
Mechanism of action may be related to membrane stabilization
Not recommended during pregnancy and lactation
Stevens Johnson syndrome-worst case side effect
What are the side effects of Carbamazepine?
GI
CNS toxicity (60%): drowsiness, dizziness, fatigue, clumsines, vertigo, ataxia
Hypersensitivity reactions, rashes
Idiosyncratic hematologic effects-watch for sore throat, fever, bruising
Stevens Johnson Syndrome: genetic testing for presence of HLA B1502 recommended for patients treated with carbamazepine
What drugs may increase the toxicity of Carbamazepine when given concurrently?
cimetidine, erythromycin, isoniazid, verapamil, diltiazem, propoxyphene, and fluoxetine
these decrease metabolism of carbamazepine
Lamotrigine
Anticonvulsant, as effective as lithium in tx of bipolar
Common side effects: nausea, ataxia, dizziness, double vision, sleepiness, headache, rash (SJS)
Does not cause weight gain
Topiramate (Topamax)
Effective as monotherapy in some patients with bipolar
Used as anticonvulsant, tx for alcoholism, to offset weight gain from SSRIs, reduce binge-eating, prevention of migraine
Causes weight loss
Gabapentin (Neurotonin)
Used as anticonvulsant and for neurologic pain
Not very effect long-term mood stabilizer
GABA analogue, may increase GABA release
Side effects: drowsiness and weight gain common, ataxia, blurred vision, hypertension, back pain
Not recommended in pregnancy
