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Pharmacology III > Antipsychotics & Mood Stabilizers > Flashcards

Antipsychotics & Mood Stabilizers Flashcards

1
Q

“Classical” Antipsychotics

A
  • “Neuroleptics”
  • Block DA D2 receptors
  • Target the mesolimbic system
  • Alleviate the positive symptoms

Chlorpromazine (Thorazine®)
Haloperidol (Haldol®)

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2
Q

“Atypical” Antipsychotics

A
  • Block 5-HT2A and DA receptors
  • Target the mesocortical (and mesolimbic) system
  • Alleviate both negative and positive symptoms
Clozapine (Clozaril®)
Olanzapine (Zyprexa®)
Risperidone (Risperdal®)
Ziprasidone (Geodon®)
Quetiapine (Seroquel®)
Aripiprazole (Abilify®)
Lurasidone (Latuda®)
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3
Q

Distribution of DA Receptors in CNS

A

 DA D2 receptors predominate the mesolimbic region

 DA D4 receptors distributed in mesocortical region

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4
Q

Antipsychotic Drug Interactions

A

 Anticholinergics: more side effects (dry mouth,
urinary retention, constipation, etc)
 Sedative-hypnotics: will increase sedation
 TCAs - seizures and cardiac effects
 Drugs that induce CYP450s (carbamazepine;
cimetidine)
 Smoking – induces CYP450s
 Unpredictable w/ antihypertensives (alpha-blockade)

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5
Q

Antipsychotic Side Effects

A

 Very common; generally not pleasant and
compliance is poor
 Decreased seizure threshold
 Endocrine-weight gain, increased prolactin secretion
 Autonomic
• Anticholinergic - dry mouth, blurred vision,
tachycardia, constipation
• α-adrenergic - postural hypotension
• Histamine - sedation
 Dental – xerostomia and bruxism

  • Extrapyramidal Symptoms (EPS)
  • Tardive Dyskinesia
  • Neuroleptic Malignant Syndrome
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6
Q

Neuroleptic Malignant Syndrome

A
  • Life threatening
     Muscle rigidity, hyperpyrexia, changes in BP and
    heart rate
     Block of DA D2 receptors in the striatum and
    hypothalamus
     Treated with dantrolene (Dantrium®)
     DA agonists (bromocriptine) used to stimulate DA
    receptors
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7
Q

Tardive Dyskinesia

A

 Choreiform; uncontrollable, jerky movements of face
and limbs
 Occurs late in disease following long-term treatment
 Difficult to treat, often irreversible - Discontinue drug
 Clozapine and olanzapine least likely to cause TD

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8
Q

Extrapyramidal Symptoms (EPS)

A

 DA receptor antagonists also block DA receptors in
the nigrostriatal pathway
 Parkinson’s like - tremor, rigidity, dyskinesias, rocking
(akathisia), pacing, restlessness, anxiety, dystonia
 Imbalance of striatal DA and ACh
 Treat with anticholinergics such as benztropine
(Cogentin) to restore ACh/DA balance
 Degree of EPS is based on the anticholinergic
activity of the drug (chlorpromazine vs. haloperidol)
 Classical antipsychotics tend to cause more EPS
than atypicals

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9
Q

Classical Antipsychotics - MoA

A

 Block DA D2receptors

 Requires ~60% receptor occupancy

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10
Q

Classical Antipsychotics - Pharmacokinetics

A

 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 (2D6 and 3A4)

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11
Q

Chlorpromazine (Thorazine®) - Uses

A

Psychosis associated with mania and drugs of abuse

Antiemetic (Prochlorperazine)

Pre-anesthetic

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12
Q

Chlorpromazine (Thorazine®) - MoA

A

Blocks DA D2 receptors; also has alpha-adrenergic actions

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13
Q

Chlorpromazine (Thorazine®) - Side Effects

A

 TD, and neuroleptic malignant syndrome may occur  High anticholinergic effects thus low incidence of
EPS
 Sedation, postural hypotension, blurred vision,
constipation, decreased GI motility, inhibition of
ejaculation, jaundice, decreases seizure threshold
 May cause retinal deposits; “browning of vision”

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14
Q

Haloperidol (Haldol®)

A 
 “Vitamin H”
 Potent blocker of DA D2 receptors
 Also has affinity for DA D1, 5-HT2, and H1 receptors
 Used frequently in acute situations
 May be injected 
 Long half life
 No anticholinergic activity
 Extrapyramidal symptoms; especially when used 
    chronically
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15
Q

Fluphenazine (Prolixin®)

A

similar to chlorpromazine; selective for DA D2 receptors; less anticholinergic activity and more EPS

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16
Q

Atypical Antipsychotics - MoA

A

 Block 5-HT2A receptors but also block DA D2 (and
D4) receptors
 Alleviate both the “negative” and “positive”
symptoms

17
Q

Clozapine (Clozaril®)

A

 Blocks 5-HT2A and DA D4 receptors; some affinity
for DA D2
 EPS and tardive dyskinesia are very rare
 Side effects – Hypersalivation, sedation, dizziness,
postural hypotension, tachycardia,
weight gain
 Decreased seizure threshold
 Rapid relapse if discontinued abruptly
 Drug of last choice due to agranulocytosis
 Blood must be monitored

18
Q

Olanzapine (Zyprexa®)

A

Similar to clozapine but no agranulocytosis
 Improves “positive” and “negative” symptoms
 Blocks 5-HT2A receptors; also blocks DA D4 and D2
receptors
 Some anticholinergic activity
 Extrapyramidal symptoms rare
 Side effects - sedation, orthostatic hypotension,
weight gain
• Hyperglycemia, type II diabetes (“Zyprexia
diabetes”)
 Also used for bipolar disorder

19
Q

Risperidone (Risperdal®)

A

 “First-line drug” for psychosis
 Blocks and 5-HT2A and DA D2 receptors
 Improves both positive and negative symptoms
 No significant effect on DA neuro-transmission in
nigrostriatal pathway
 Extrapyramidal symptoms and tardive dyskinesia are
rare
 Side effects - hypotension, weight gain, insomnia,
anxiety, some cardiac effects (lengthens QT interval)

20
Q

Ziprasidone (Geodon®)

A

 Blocks DA D2 and 5-HT2A receptors
 Some antidepressant activity (5-HT1A receptor agonist, inhibition of 5-HT reuptake)
 Uses: Tourette’s syndrome; acute mania
 Given orally or injected IM; Metabolized by CYP3A4
 Side Effects
• Prolongs QT interval
• Causes sedation, impairs cognitive and motor skills
• May cause hyperprolactinemia
• Used with caution in patients with history of seizure
disorders or with drugs that decrease seizure
threshold

21
Q

Quetiapine (Seroquel®)

A

 Similar to clozapine
 No agranulocytosis
 Blocks 5-HT2A and DA D2 receptors
 Used to promote sleep onset and maintenance
 Few extrapyramidal symptoms
 Side effects - very sedating, dizziness, constipation,
xerostomia, orthostatic hypotension, weight gain
 Does not elevate prolactin

22
Q

Aripiprazole (Abilify®)

A

“Dopamine system stabilizer”
• Dopaminergic tone is low– DA receptors are activated
• Dopaminergic tone is high– DA receptors are blocked
 Partial agonist for DA D2 and 5-HT1A; Antagonist for
5-HT2A
 Low incidence of EPS
 Metabolized by CYP3A4 and 2D6
 Also blocks α1 and histamine receptors
 No increase in prolactin; Does not lengthen QT
interval
 Side effects - hyperglycemia, seizures, sedation,
increased glucose, orthostatic hypotension,
decreases esophageal motility

23
Q

Lurasidone (Latuda®)

A

 Blocks D2 and 5-HT2A receptors
 Partial agonist at 5-HT1A
 No antihistamine or antimuscarinic effect
 Used in treatment of depression associated with
bipolar disorder
 Some incidence of agranulocytosis and neutropenia,
blood counts should be monitored.
 Side effects similar to other atypical antipsychotics

24
Q

Bipolar Disorder Treatment

A
  • Lithium (Eskalith)
  • Anticonvulsants

 Patients with bipolar disorder are often treated with
combinations of these drugs and antipsychotics such
as olanzapine (Zyprexa®).

25
Q

Lithium (Li) - MoA

A

Suppress 2nd messengers (IP3)

• May increase ACh, NE, and DA

26
Q

Lithium (Li) - Uses

A

 Calming effect in manic patients

27
Q

Lithium Absorption

A

 Lithium is reabsorbed by the proximal tubule in the
kidney
 Competes with sodium (Na+) for re-absorption
• Na+ decreases -> Li absorption increases -> Toxicity
• Na+ increases -> Li absorption decreases; excretion
increases
• Li increases -> Na+absorption decreases ->
hyponatremia

28
Q

Lithium Side Effects and Toxicity

A

Small therapeutic window - (Optimal plasma concentrations range from 0.6-1.2 mEq/L)
• Plasma levels > 2 mEq/L - Nausea, diarrhea, anorexia,
muscle weakness, headache, tremor, confusion,
memory impairment
• Plasma levels > 2.5 mEq/L - Confusion, slurred
speech, sedation, nystagmus, seizures, renal failure,
cardiac arrhythmias, coma, death
 Thyroid function reduced (Hypothyroidism)
 Diabetes insipidus
• Li inhibits ADH; collecting tubule cannot conserve
water
• Increased thirst and urine output
• Treat with amiloride (blocks entry of Li into collecting duct)
 Not recommended in pregnancy

29
Q

Lithium Drug Interactions

A

 Antidepressants: mania may increase
 Benzodiazepines & antipsychotics: safe
 Diuretics (alter sodium excretion) can alter Li
clearance
 NSAIDS
• Increase Li toxicity - decrease clearance, increase Li
uptake
 Sodium
• Reduces Li concentration
• Li may lead to decreased Na+ re-absorption and
hyponatremia

30
Q

Anticonvulsants: Alternative to Lithium

A

Valproic Acid (Depakene®)
Gabapentin (Neurontin®)
Lamotrigine (Lamictal®)
Carbamazepine (Tegretol®)

31
Q

Valproic Acid (Depakene®)

A

 Rapid cycling manic/depressive phases
 Effective in some patients who do not respond to
lithium
 Efficacy is equal to or greater than lithium; rapid
onset of action
 Mechanism: Unknown (inhibition of ion channels,
increased GABA)
 Side Effects: GI upset, sedation, liver enzyme
induction, weight gain, surgical bleeding (dental)
 Teratogenic - Anticonvulsants are generally not safe
in pregnancy

32
Q

Gabapentin (Neurontin®)

A

used for rapid cycling

33
Q

Carbamazepine (Tegretol®)

A

 Refractory bipolar disorder; used in combination with
lithium
 Side Effects - GI upset, sedation, CNS toxicity,
hypersensitivity, rashes, hematologic reactions
 Drug interactions - competes for metabolism with
cimetidine, isoniazid, fluoxetine, erythromycin;
increases toxicity
 Stevens Johnson Syndrome
• Toxic epidermal necrolysis
• Testing for the human antigen is now required

34
Q

Lamotrigine (Lamictal®)

A

Approved for:

  • Prevention of relapse
  • Depressive state following mania
  • Acute mania
35
Q

“Positive” symptoms

A

• Hallucinations (auditory and visual) & delusions
• Catatonic behavior, disorganized speech & thinking
• Over-active dopamine pathways in limbic system
(Mesolimbic)

36
Q

“Negative” symptoms

A

• Affective behavior, apathetic, withdrawn, anti-social,
lack of motivation, depressed
• Under-active dopamine pathways in frontal cortex
(Mesocortical)

Pharmacology III (10 decks)

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