Antipsychotic Drugs and Side Effects

Antipsychotic Drugs and Side Effects

Side Effects of antipsychotic drugs

D– Acute dystonia=usually appears first (hours to days), most often unilateral, neck and above

  • Treatment= Anticholinergic Drug (Benztropine (Cogentin), trihexyphenidyl (Artane), procyclidine (Kemadrin), Benadryl
  • Do not use antipsychotic drugs in elderly, glaucoma, BPH = use VALIUM for first choice (muscle relaxer)

A- Akathisias= motor internal restlessness; will commit suicide from Akathisias

  • Pay close attention to patient; some doctors up the dose and patient will get worse
  • Treatment=Antianxiety

TTardive Dyskinesia= Can be irreversible

  • With long-term potent drug therapy, dopaminergic receptors in the brain become sensitive and they lose control of motor movement
  • Higher in females; patient usually unaware
  • Can mask TD with increasing dose of medication but when TD comes’s worse
  • Treatment is prevention…NO CURE


E- Extrapyramidal side effects Think pseudo-Parkinson’s (drug-induced Parkinson’s disease)

  • Bradykinesia is from drug-induced Parkinson’s because biochemical reason for Parkinson’s is an imbalance between dopamine and acetylcholine
  • We supply dopamine to adjust the balance of underlining pathophysiology of schizophrenia. As a result, if there is too much dopamine we bring down dopamine; but if we bring it down too far or fast you will see manifestations of Parkinson’s (PSEUDO PARKINSON’S)
  • See shuffling gait, mask-like appearance, cognitive rigidity, tremors
  • Treatment= make adjustment on dose or change to less potent agent



Neuroleptic Malignant Syndrome (NMS)

  • Pt has been on a drug that blocks dopamine (antipsychotic, Reglan/metoclopramide, Compazine/prochlorperazine, Phenergan/promethazine, and Inapsine/ droperidol) causing decreased dopamine receptor activation.
  • The dopamine has been blocked and results in a LOSS of CONTROL in the CNS and patient will manifest some of the s/s as in serotonergic syndrome
  • Hyperthermia is a big component of neuroleptic malignant syndrome, the main thing that needs to be treated during the neuroleptic malignant syndrome flare up is the body temperature with drugs like Dantrium/dantrolene.
  • Aggressive hydration of the body may be required to help prevent kidney damage due to the high CPK levels in the blood stream by increasing the ratio of water to CPK proteins.


 Biochemical basis of Schizophrenia

  • Seems to involve excessive levels, activity or effect of dopamine (DA) in certain parts of the brain that control emotions, thoughts, and behavior because:
    • Drugs that block DA receptors or ↓ DA levels there ↓ S/S of schizophrenia
    • Drugs that stimulate DA receptors or ↑DA levels in the dopaminergic synapses there cause or worsen S/S of schizophrenia
  • Put a patient on levodopa or Carbidopa if they have mental changes and start hallucinating (↑ DA levels)
  • In Schizophrenia there is cognitive impairment with positive/negative symptoms
  • New drugs (2nd generation) antipsychotic are better for treating the negative symptoms (the most debilitating part of schizophrenia)
  • No cure: relapse is common because compliance is very hard
  • Very important that you make the proper diagnosis, pick the right drug, and monitor therapy


Hallucination APATHY
Paranoia ABULIA (lack of motivation)
Hyperactivity ALGEDONIC (lack of pleasure)
Hearing voices ALOGIA (short of speech)
  AUTISIUM (don’t have a good thought process)



Antipsychotic Drugs

  • Used mainly for schizophrenia, acute or long-term
  • Are sometimes called “neuroleptic drugs”
  • Are adjuncts to, not substitutes for, psychotherapy and other treatment modalities
  • Critical elements of treatment
    • proper diagnosis
    • picking the right drug out of many
    • monitoring therapy
    • proper, effective, support interventions
    • patients must be motivated to follow-through with tx


Class of Antipsychotic

  • According to potency*:potency refers to size of dose, not to efficacy
    • low potency (e.g., chlorpromazine)
    • high potency (e.g., haloperidol)
  • According to chemical class
    • Phenothiazine (e.g. Chlorpromazine)
    • Butyrophenones (e.g. Haloperidol)


 Major actions of Antipsychotic

  • Block dopamine, Ach (muscarinic), histamine (H1) and adrenergic (alpha) receptors in CNS and in periphery
  • Antipsychotic effects
    • Are primarily from central dopamine receptor blockade
    • Initial symptoms control may occur after a few days of therapy, but “good” control (normalization of thought processes, mood behavior) may take a month or so of continued therapy.
    • These drugs aren’t permanent “cures”


Sedation from Antipsychotic

  • Depends on which drug is selected and dose
  • May/may not be desirable (depends on the Pt’s needs)
  • ↑ potency of other drugs with CNS depressant activity


Old Drugs

Special Properties/Uses of Some Phenothiazine’s

  • Mostly used for nausea vomiting; because stimulation of N/V center is precipitated by DA—block DA block N/V
  • Low potent and weak in controlling schizophrenic
  • They block DA, ACE, and Alpha-adrenergic blocker capability
  • Cause sedation
  • Compazine, Thorazine, promethazine,
  • Phenergan (promethazine)
    • useful antihistaminic (H-1 blocking),antipruritic, and antitussive (cough suppressant) effects
    • used for allergy s/s, esp. when sedation is desirable
  • Compazine(prochlorperazine)
    • useful antiemetic effects, e.g., in the setting of chemotherapy, surgery, other cases of uncontrollable vomiting
    • cough suppressing effects


Other Effects of Phenothiazine’s

  • Shared by all drugs in class, but…
  • Some of the phenothiazine…
    • have a greater ability than others to → certain rather unique effects
    • Have special uses in nonpsychotic pts. because of these special properties/effects: antihistamine (H-1 blocking) activity; antitussive effects; antiemetic effects


Side-effects, Contraindications, Adverse Reactions of Most Antipsychotics

  • Incidence, severity, vary from drug to drug and are usually dose-dependent
  • Autonomic
    • atropine-like→ “anti-SLUDGE”
    • alpha-adrenergic blockade→hypotension
  • Other
    • gynecomastia, altered menses , increase fertility, galactorrhea (secretion of milk), weakness of bone (interferes with the regulation of prolactin release=block DA and DA is the prolactin inhibitory factor)
    • ↓temperature perception,→ ↑susceptibility to hyperthermia (heat stroke) or hypothermia (body cannot adapt to temperature changes…like a reptile)
    • ↓seizure threshold→↑risk of seizures (esp. a problem for, but not limited to, people with epilepsy)
    • allergic or hypersensitivity rxn (esp. blood ,skin ;sometimes severe)
    • EKG changes, risk of potentially serious/life-threatening ventricular arrhythmias(some phenothiazine’s, not all)


Adverse Effects of Antipsychotics-I Extrapyramidal Reactions (EPS)

  • Brain’s extrapyramidal system is responsible for maintaining normal voluntary control of skeletal muscle activity
  • Extrapyramidal side effects(EPS) of antipsychotics probably due to creating excessive imbalance between DA and Ach in brain as a result of blocking DA receptors


Early-Developing EPS
(days, weeks, months)

  • Acute dystonia can occur within hours or a few days after starting therapy
    • severe spasmodic movements of tongue, neck, back, extremities
    • oculogyric crisis, opisthotonus
    • may be a medical emergency
    • Managed with centrally-acting antimuscarinics (e.g., diphenhydramine)
  • Parkinsonism tends to develop within a month or so
    • including skeletal muscle tremor, rigidity, and consequences thereof
    • managed with central-acting antimuscarinics
  • Akathisias usually develop by about a month
    • Often intense subjective feeling of jitteriness, restlessness, leading to pacing about, squirming
    • signs/symptoms can be confused with worsening schizophrenia


Extrapyramidal Side Effects(EPS) of Phenothiazine’s

  • Resemble Parkinson’s Disease s/s
    • bradykinesia
    • akinesias
    • dyskinesia
    • Akathisias
  • Caused by excessive↓ of DA effects in brain areas (extrapyramidal system) that regulate voluntary/involuntary control of skeletal muscle
  • severity, vary among the individual drugs
  • S/S tend to develop gradually (month, years) with the “ low potency” antipsychotics, can occur in days with “high potency” agents
  • May disappear w/continued tx., usually tend to worsen
  • May progress to→ tardive dyskinesia (irreversible)


 Tardive Dyskinesia’s: Late-Developing EPS

  • Affects 15-20% of all patients on long-term treatment
  • Risks: high potency antipsychotics>low potency>>> atypical agents (lowest potential)
  • Typically occurs after many months, to several years, after the start of therapy
  • Initial s/s include choreoathetotic movements (mainly tongue and face, eventually progresses to involve extremities, trunk)
  • S/S probably involve central DA receptor supersensitivity
  • S/S irreversible, so best approach is prevention (e.g., limit antipsychotic tx. duration and dose to a minimum that is feasible)


EPS: What to Do When We Start Seeing S/S of It?

  • ↓dose (or stop) current drugs (which will likely restore s/s of schizophrenia),or
  • Switch to another antipsychotic with less risk of EPS, or
  • “Treat” with Antiparkinson drugs, which will…
    • mask/obscure mild EPS S/S but…
    • won’t prevent underlying brain biochemical changes that ultimately develops to tardive dyskinesia if administration of the offending antipsychotic continues


Other Adverse Reactions

  • Reduction of brain’s “seizure threshold”→↑risk of seizures, esp. in patients with history of epilepsy
  • Neuroleptic malignant syndrome
  • Hyperprolactinemia: DA receptor blockade prevents normal inhibition of hypothalamic-pituitary prolactin release. Main consequences are; gynecomastia, galactorrhea, irregular menses
  • Avoid in women with prolactin-dependent breast cancer


What is the seizure threshold

  • Think of it as the amount of extra or abnormal brain electrical activity needed to “destabilize” normal neurons to start a seizure/convulsion. Exceed that “threshold”→ a seizure will develop
  • Phenothiazine, most other antipsychotics, and several other drugs (quite different drug classes)↓the threshold (the amount of extra or abnormal electrical activity) necessary to→ seizures, making it easier for seizures to develop
  • The seizure risk applies to all patients receiving phenothiazine’s, but obviously, it is of greater concern for patients who already have a seizure disorder (i.e., epilepsy)


Neuroleptic Malignant Syndrome:
A Serious and Rather Common Adverse Response

  • Sudden, unpredictable, rapidly worsening onset of…
    • Fever
    • muscle tremor→→severe muscle rigidity
    • autonomic hyperactivity
    • catatonia(a detached, trance-like state)
  • May occur after 1st few doses or after months of’s unpredictable
  • Overall incidence about 1 in 5 patients, fatal about 5% of the time overall
  • Close assessment, early and correct intervention essential to↓ chance of serious outcomes


Neuroleptic Malignant Syndrome
(NMS) Treatment

  • ↓Body temperature promptly with physical means and cautious use of antipyretics(ASA,APAP)
  • Ensure adequate hydration
  • Normalize BP and cardiac responses(HTN, tachycardia often occur)
  • Control anxiety {(e.g., IV benzodiazepines(BZDS)}
  • Muscle-relaxants (BZDs, dantrolene)
  • Block central DA receptors (with Bromocriptine)…will discuss further in Parkinson’s disease lecture


Adverse Effects of Most Antipsychotics in the Periphery

  • Anticholinergic side effects (muscarinic receptor blockade) may be significant
  • Orthostatic hypotension (alpha- adrenergic blockade)
  • Dermatitis, abnormal skin pigmentation, photosensitivity (skin sensitized to UV light→↑risk of sunburn)
  • Agranulocytosis
  • Severe cardiac arrhythmias (with some, not all phenothiazines)


Nonphenothiazine Antipsychotics

Older Antipsychotics

  •  Major example is Haldol (haloperidol)– butyrophenone class, a “high potency” antipsychotic
  • Fast onset (< 30 min with parenteral administration),short acting
  • Main antipsychotic for acute S/Sx (given parenterally): it’s what you’re most likely to give in the ER for acute psychosis
  • Other psychiatric uses besides schizophrenia (e.g., Tourette syndrome)
  • Compared w/chlorpromazine (Thorazine)
    • Greater risk and faster onset of EPS
    • Fewer/milder autonomic SEs
    • Lowers seizure threshold
  • Thorazine, Compazine, Haldol and Irretractable hiccups


Newer Agents of Antipsychotics

Aripiprazole (Abilify)

Olanzapine (Zyprexa)

Clozapine (Clozaril)

Ziprasidone (Geodon)

Quetiapine (Seroquel)


  • These agents block dopamine and serotonin; and greater chance to block serotonin than they do DA= they tend less DATE and NMS side effects
  • Older drugs have greater chance to have DATE
  • Now see metabolic syndrome X = DKA (will present in ER)
    • Most common in the following drugs (Don’t have a COW)
    • Clozapine (Clozaril)
    • Olanzapine (Zyprexa)
    • Weight coming up as a result of = Quetiapine (Seroquel)
    • Monitor blood sugar, blood pressure,daily weight, triglycerides and lipids on regular basis


Clozaril (clozapine)

  • ONLY USED FOR VERY RESISTANT SCHIZO B/C one of most dangerous SE is agranulocytosis
  • Antipsychotic action mainly from CNS blockade of 5-HT (serotonin) receptors
  • Very weak DA receptor blockade accounts for very low incidence of EPS (DATE)
  • Few significant peripheral autonomic side effects
  • May also cause:
    • Very high Anticholinergic profile (Increase spit and bedwetting)
    • hyperglycemia (→prediabetic or true diabetic state)
    • high incident to increase seizures threshold more than other antipsychotics
    • myocarditis
    • significant weight gain (appetite stimulation) (esp.; Clozaril, Zyprexa)
  • Main and most serious adverse response (Clozaril):↓↓WBC count, risk of serious infection, and potential agranulocytosis(fatal)-requires normal WBC counts (blood test )before each prescription can be refilled
  • PAY CLOSE ATTENTION TO WBC AND ANC absolute neutrophil count
  • The ANC refers to the total number of neutrophil granulocytes present in the blood.
    • Normal value: 1500 cells/mm3.
    • Mild neutropenia: 1000 – <1500/mm3.
    • Moderate neutropenia: 500 – <1000/mm3.
    • Severe neutropenia: < 500/mm3.
  • Neutrophils= major WBC that play resistance to disease state
  • Make sure someone can bring pt to get lab work

Ziprasidone Geodon

  • High incidence of propagation of QTc interval= torsade’s
  • Pay close attention to rhythm


Aripiprazole (Abilify)

  • Used to treat pt with tics, or addition to antidepressant



Olanzapine/Zyprexa and fluoxetine/Prozac

  • Combination drug antidepressant with an antipsychotic




Edmunds, M. W., & Mayhew, M. S. (2014). Pharmacology for the primary care provider (4th ed.). St. Louis, MO: Elsevier Mosby.

Harvey, R. A., Clark, M. A., Finkel, R., Rey, J. A., & Whalen, K. (2012). Drugs affecting the