Psych pharm – Antipsychotics

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HY points followed by a quiz at the end

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Antipsychotics are either typical (1st gen) or atypical (2nd gen).

All of the antipsychotics, regardless of class, antagonize dopamine 2 (D2) receptors.

The 1st gen are considered to generate their antipsychotic effect exclusively via antagonizing the D2 receptors; the second generations are considered to have a slightly greater fractional effect at other types of receptors as well, including D4 and serotonin. But regardless, both 1st and 2nd gen primarily antagonize D2.

Antagonism of D2 –> treatment for psychosis (and can inadvertently induce Parkinsonism).

Agonism of D2 –> treatment for Parkinsonism (and can inadvertently induce psychosis).

Clear yourself of the myth that typicals help more with positive Sx of schizophrenia, whereas atypicals more with negative Sx –> literature doesn’t support this conclusively anymore, nor does USMLE assess things this way.

You’re expected to know the names of essentially all of the antipsychotic drugs for the Step, so the listing of drugs here beyond just one or two examples for each class is not superfluous.

1st gen (typicals)

Haloperidol

• Classic; highest yield.
• Haloperidol decanoate is HY on 2CK Psych shelf for patients who have poor compliance with oral antipsychotics; given as a once/month depo injection.
• Low-dose haloperidol is effective for Tourette (also on NBME where they ask Tx for Tourette; clonidine [alpha-2 agonist can be used for Tourette as well]).
• Used in theory for patients who are delirious and at risk of harm to themselves and others, however it is almost always a wrong answer on the USMLE in this context – e.g., if the Q says some guy is on drugs and combative in the emergency room, the answer is “observe in the emergency department,” not “administer haloperidol and observe.”

Trifluoperazine, Fluphenazine

• Nothing special about these. You just need to be familiar with their names.

Prochlorperazine

• Can be used as an anti-emetic / -nausea agent.
• You might see this in a patient’s chart and say, “Wait wtf, this patient has schizophrenia?” No, it’s just for nausea.

Chlorpromazine

• Can cause Corneal deposits.

Thioridazine

• Can cause reTinal deposits.

2nd gen (Atypicals)

“Old Closets Quietly Risper (Whisper) from A to Z.” –> Olanzapine, Clozapine, Quetiapine, Risperidone, Aripiprazole, Ziprasidone

Used first-line in the Tx of schizophrenia (choose one of these over the typicals if both are listed). As mentioned earlier, haloperidol decanoate is correct, however, if the patient has poor compliance.

Olanzapine

• Can cause weight gain / obesity.
• If patient is overweight and/or diabetic, use aripiprazole or ziprasidone instead.
• Can be added to valproic acid or lithium as adjuvant therapy in the Tx of bipolar and schizoaffective disorders.

Clozapine

• Can cause weight gain / obesity.
• Can cause agranulocytosis (neutropenia) –> one of the highest yield adverse drug effects on USMLE.
  • Can present as mouth ulcers, fever, and/or sore throat. The Q can also just simply tell you the patient was started on clozapine and now has a WBC count of 500/uL (NR 4-11,000), where neutrophils are 0 –> answer = drug-induced neutropenia (agranulocytosis).
  • If patient has neutropenia while on clozapine, the Tx is stop the drug immediately and give IV antibiotics for neutropenic fever (febrile neutropenia). Then give GM-CSF.

Quetipine

• Can be added to valproic acid or lithium as adjuvant therapy in the Tx of bipolar and schizoaffective disorders.

Risperidone

• Classically used as a first-line agent for schizophrenia.

Aripiprazole, Ziprasidone

• Used in patients who are overweight or have diabetes.

Important side-effects of the antipsychotics:

• Can cause QT prolongation (↑ risk of torsades arrhythmia).
• Neuroleptic malignant syndrome –> muscle rigidity + fever in someone who just commenced an antipsychotic –> fever is usually 103.5+.
  • Mechanism –> ryanodine channel becomes constitutively open –> calcium is released non-stop from sarcoplasmic reticulum into the cytosol –> cell uses lots of ATP in order to get calcium back into the sarcoplasmic reticulum –> generates heat.
  • Treat with dantrolene (inhibits ryanodine channel); rarely bromocriptine (D2 agonist) can treat (choose if dantrolene not listed).
• Hyperprolactinemia (impotence in men; galactorrhea and amenorrhea in women).
  • D2 agonism normally inhibits prolactin secretion. Therefore D2 antagonism causes increased prolactin.
• “Rule of 4s” –> After a patient is started on an antipsychotic, a general trend is seen in terms of the onset of particular Sx. The time frame is not strict/rigid; use it as a general trend – i.e., acute dystonia wouldn’t just start at 4 months; tardive dyskinesia wouldn’t occur as early as 2 weeks.
  • Acute dystonia at 4 hours –> torticollis, oculogyric crisis, muscle rigidity without fever.
    • Torticollis = stiff / crooked neck.
    • Oculogyric crisis = weird eye movements (don’t confuse with tongue movements of tardive dyskinesia).
    • Muscle rigidity without fever = acute dystonia. Muscle rigidity with fever = neuroleptic malignant syndrome.
    • Treat acute dystonia with benztropine (muscarinic receptor antagonist –> decreases muscle tone) or a 1st generation H1 blocker (diphenhydramine or chlorpheniramine). The latter have nasty anticholinergic (anti-muscarinic) side-effects that are actually what we want when we’re treating acute dystonia. Maybe 2/3 of acute dystonia Tx Qs will have benztropine as the answer; ~1/3 will have one of the 1st gen H1 blockers as correct.
      • 38F + started on trifluoperazine + now has diffuse muscle rigidity; temperature is 98.6F; treatment? –> answer = benztropine, diphenhydramine, or chlorpheniramine; Dx is acute dystonia, not NMS.
      • 38F + started on trifluoperazine + now has diffuse muscle rigidity; temperature is 103.8F; treatment? –> dantrolene (or rarely bromocriptine).
  • Akathisia at 4 days –> restlessness.
    • Treat with propranolol (beta-blockade).
  • Parkinsonism at 4 weeks –> akinesia / bradykinesia.
    • Treat with amantadine.
  • Tardive dyskinesia at 4 months –> abnormal facial movements (notably tongue).
    • Risk is greater with typicals compared to atypicals, but TD can be seen in the latter on NBME.
    • Treatment is stop the typical and give an atypical.
    • Couple of weird Psych NBME Qs on this:
      • Patient on atypical + gets TD; Tx? –> stop the atypical and give another atypical. (Just stop the drug and switch to yet another atypical.)
      • Patient on typical for 15 years and has no problems whatsoever (i.e., does not have TD); patient asks the psychiatrist what can be done to decrease his risk of developing TD; the correct answer is “stop the typical and give an atypical”; wrong answer is “maintain current drug regimen.” Apparently even if the patient has been on a typical long term without an issue, switching to an atypical still confers a reduction of risk of TD.
• The “triad” –> anti-cholinergic (anti-muscarinic), anti-alpha 1, anti-H1.
  • If an agent is cholinergic, it will cause DUMBBELSS signs/symptoms –> Diarrhea, Urination, Miosis, Bradycardia, Bronchoconstriction, neuromuscular Excitation, Lacrimation, Salivation, Sweating. Since antipsychotics are anti-cholinergic, they cause the opposite of they will cause the opposite of DUMBBELSS –> Constipation, Urinary retention, Mydriasis, Tachycardia, Not bronchodilation (β2 agonism, but not M antagonism, will bronchodilate), Skeletal muscle relaxation, Dry eye, Dry mouth, Anhydrosis.
    • 23M + started on aripiprazole for schizophrenia + now is hot, red, and dry; which of the following receptor effects is most likely responsible for this patient’s condition? –> answer = anti-cholinergic (anti-muscarinic).
  • Anti-alpha 1 –> orthostatic hypotension + fainting (alpha 1 agonism normally constricts peripheral arterioles, maintaining BP and cerebral perfusion).
  • Anti-H1 –> sedation.
  • The “triad” is seen with antipsychotics, TCA anti-depressants (e.g., amitriptyline), and 1st gen H1 blockers (e.g., diphenydramine).

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