Clinical Pharmacokinetics

, Volume 28, Issue 6, pp 494–504

Emergency Treatment of Psychotic Symptoms

Pharmacokinetic Considerations for Antipsychotic Drugs
  • Grace V. Milton
  • Michael W. Jann
Review Article Pharmacokinetics-Therapeutics

Summary

Psychotic symptoms related to mental and medical disorders can pose a medical emergency. Selecting an appropriate antipsychotic medication to treat this emergency is based on the clinical situation, preferred route of administration, pharmacokinetic profile of the antipsychotic and the medications currently being taken by the patient. Intramuscular preparations are usually preferred over oral medication when the patients are not co-operative and require drugs with a faster onset of action and good bioavailability.

High potency antipsychotics such as haloperidol and fluphenazine are effective in stabilising patients with psychotic symptoms quickly. Loxapine is an alternative when sedation is necessary and molindone is useful if a short-acting antipsychotic is required. Rapid neuroleptisation with intramuscular preparations of antipsychotic achieves therapeutic drug concentrations more rapidly, and also provides optimal control of psychotic symptoms. If the patient is cooperative, liquid oral preparations can be used; they are as effective as intramuscular formulations.

If long term treatment with an antipsychotic is necessary and the patients are stabilised, they can be switched from intramuscular to oral preparations. The oral dose is usually 1.5 to 5 times the total intramuscular dose per day, based on the bioavailability of the antipsychotic medication. If the patient is currently taking antipsychotic medication when the emergency situation occurs, it is usually adequate to increase the dose of antipsychotic drug.

Appropriate dose adjustment or antipsychotic selection is necessary when drug interactions are expected. An in-depth knowledge of the pharmacokinetic profile and drug interaction profile of antipsychotic is necessary for the selection of the appropriate antipsychotic for any given emergency situation.

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References

  1. 1.
    Javaid JI. Clinical pharmacokinetics of antipsychotics. J Clin Pharmacol 1994; 34: 286–95PubMedGoogle Scholar
  2. 2.
    Eisendrath SJ, Link N. Mental changes in the ICU: detection and management. Drug Ther 1983; 18: 16–21Google Scholar
  3. 3.
    Boston collaborative drug surveillance program: psychiatric side effects of non-psychiatric drugs. Semin Psychiatry 1976; 3: 406Google Scholar
  4. 4.
    Caranasos GJ, Stewart RB, Cluff LE. Drug-induced illness leading to hospitalization. JAMA 1974; 228: 713–7PubMedCrossRefGoogle Scholar
  5. 5.
    Dubin WR, Weiss KJ, Dorn JM. Pharmacotherapy of psychiatric emergencies. J Clin Psychopharmacol 1986; 6: 210–22PubMedCrossRefGoogle Scholar
  6. 6.
    Weiner HD. Drug abuse emergencies. In: Dubin WR, Hanke N, Nickens HW, editors. Clinics in emergency medicine: psychiatric emergencies. New York: Churchill Livingstone, 1984; 4Google Scholar
  7. 7.
    Ellinwood, EH. Amphetamine psychosis: description of individuals and process. J Nerv Ment Dis 1967; 144: 273–83CrossRefGoogle Scholar
  8. 8.
    Disclafani A, Hall RCW, Garderner ER. Drug-induced psychosis: emergency diagnosis and management. Psychosomatics 1981; 22: 845–55PubMedGoogle Scholar
  9. 9.
    Rappolt RT, Gay GR. Emergency management of acute phencyclidine intoxication. J Am Coll Emerg Phys 1979; 8: 68–76CrossRefGoogle Scholar
  10. 10.
    Weiss KJ. Phencyclidine intoxication and abuse. In: Akhtar S, editors. New psychiatric syndromes: DSM III and beyond. New York: Jason Aronson, 1983Google Scholar
  11. 11.
    Tinkleberg JR, Berger PA. Treatment of abusers of non-addictive drugs. In: Barchas JD, Berger PA, Ciaranello RD et al., editors. Psychopharmacology from theory to practice. New York: Oxford University Press, 1977: 386–403Google Scholar
  12. 12.
    Jann MW, Richards AL. Selection of antipsychotic drugs in emergency situations. US Pharmacist 1985; H1–H12Google Scholar
  13. 13.
    Hodding GC, Jann MW, Ackerman I. Drug withdrawal syndrome: a literature review. West J Med 1980; 133: 383–91PubMedGoogle Scholar
  14. 14.
    Rivera-Calimlim L, Nasrallah H, Strauss J, et al. Clinical response and plasma levels: effect of dose, dosage, and drug interaction on plasma chlorpromazine levels. Am J Psychiatry 1976; 133: 646–52PubMedGoogle Scholar
  15. 15.
    Curry SH, Davis JM, Janowsky DS, et al. Some factors affecting chlorpromazine plasma levels in psychiatric patients. Arch Gen Psychiatry 1970; 22: 209–15PubMedCrossRefGoogle Scholar
  16. 16.
    Hollister LE, Curry SH, Derr JE, et al. Plasma levels and urinary excretion of four different dosage forms of chlorpromazine. Clin Pharmacol Ther 1970; 11: 49–59PubMedGoogle Scholar
  17. 17.
    Curry SH. Chlorpromazine: concentrations in plasma, excretion in urine and duration of effect. Proc R Soc Med 1971; 64: 285–9PubMedGoogle Scholar
  18. 18.
    Whitfield LR, Kaul PN, Clark ML. Chlorpromazine metabolism. IX. Pharmacokinetics of chlorpromazine following oral administration in man. J Pharmacokinet Biopharm 1978; 6: 187–96PubMedGoogle Scholar
  19. 19.
    Dahl SG, Strandjord RE. Pharmacokinetics of chlorpromazine after single and chronic dosage. Clin Pharmacol Ther 1977; 21: 437–48PubMedGoogle Scholar
  20. 20.
    Curry SH. Antipsychotic agents. Chlorpromazine: pharmacokinetics, plasma levels and clinical response. In: Burrows GD, Norman TR, editors. Psychotropic drugs. Plasma concentration and clinical response. New York: Marcel Decker, 1981: 243–86Google Scholar
  21. 21.
    Rivera-Calimlim L, Hershey L. Neuroleptic concentrations and clinical response. Annu Rev Pharmacol Toxicol 1984; 23: 451–5Google Scholar
  22. 22.
    Rivera-Calimlim L, Nasrallah H, Strauss J, et al. Clinical response and plasma levels: effect of dose, dosage schedule and drug interactions on plasma chlorpromazine levels. Am J Psychiatry 1976; 133: 646–52PubMedGoogle Scholar
  23. 23.
    Forsman A, Ohman R. Applied pharmacokinetics of haloperidol in man. Curr Ther Res 1977; 21: 396–411Google Scholar
  24. 24.
    Cressman WA, Bianche JR, Slotnick VB, et al. Plasma profile of haloperidol in man following intramuscular administration. Eur J Clin Pharmacol 1974; 7: 99–103PubMedCrossRefGoogle Scholar
  25. 25.
    Forsman A, Ohman, R. Pharmacokinetic studies on haloperidol in man. Curr Ther Res Clin Exp 1976; 20: 319–36PubMedGoogle Scholar
  26. 26.
    Holley FO, Maggliozzi JR, Stanski DR, et al. Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther 1983; 33: 477–84PubMedCrossRefGoogle Scholar
  27. 27.
    Schaeffer CB, Shahid A, Javaid JI, et al. Bioavailability of intramuscular versus oral haloperidol in schizophrenic patients. J Clin Pharmacol 1982; 2: 274–6Google Scholar
  28. 28.
    Khot V, DeVane L, Korpi ER, et al. The assessment and clinical implications of haloperidol acute-dose, steady-state, and withdrawal kinetics. J Clin Pharmacol 1993; 13: 120–7Google Scholar
  29. 29.
    Mason AS, Granacher RP. Basic principles of rapid neuroleptization. Dis Nerv Sys 1976; 37: 547–51Google Scholar
  30. 30.
    Forsman A, Folsch G, Larsson M, et al. On the metabolism of haloperidol in man. Curr Ther Res 1977; 21: 606–17Google Scholar
  31. 31.
    Inaba T, Kovacs J. Haloperidol reductase in human and guinea pig livers. Drug Metab Dispos 1989; 17: 330–3PubMedGoogle Scholar
  32. 32.
    Midha KK, Hawes EM, Hubbard JW, et al. Interconversion between haloperidol and reduced haloperidol. J Clin Psychopharmacol 1987; 7: 362–3PubMedCrossRefGoogle Scholar
  33. 33.
    Jann MW, Huang HF, Lin SK, et al. Formation of reduced haloperidol after intramuscular haloperidol administration in schizophrenic patients. Drug Invest 1994; 7: 13–20CrossRefGoogle Scholar
  34. 34.
    Chang WH, Lam YWF, Jann MW, et al. Pharmacokinetics of haloperidol and reduced haloperidol in Chinese schizophrenic patients after intravenous and oral administration of haloperidol. Psychopharmacology 1992; 106: 517–22PubMedCrossRefGoogle Scholar
  35. 35.
    Jann MW, Lam YWF, Chang WH. Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients. Psychopharmacology 1990; 101: 107–11PubMedCrossRefGoogle Scholar
  36. 36.
    Volavka J, Cooper TB. Review of haloperidol blood level and clinical response: looking through the window. J Clin Psychopharmacol 1987; 7: 25–30PubMedCrossRefGoogle Scholar
  37. 37.
    Chang WH, Lin SK, Jann MW, et al. Pharmacodynamics and pharmacokinetics of haloperidol in schizophrenic patients. Biol Psychiatry 1989; 26: 239–49PubMedCrossRefGoogle Scholar
  38. 38.
    Perry PJ, Miller DD, Arndt SV, et al. Haloperidol dosing requirements: the contribution of smoking and non-linear pharmacokinetics. J Clin Psychopharmacol 1993; 13: 46–51PubMedCrossRefGoogle Scholar
  39. 39.
    Jann MW, Saklad SR, Ereshefsky L, et al. Effect of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology 1986; 90: 468–70PubMedCrossRefGoogle Scholar
  40. 40.
    Dysken MW, Javaid JI, Chang SS, et al. Fluphenazine pharmacokinetics and therapeutic response. Psychopharmacology 1981; 73: 205–10PubMedCrossRefGoogle Scholar
  41. 41.
    Midha KK, McKay G, Edon R, et al. Kinetics of oral fluphenazine disposition in humans by GC-MS. Eur J Clin Pharmacol 1983; 25: 709–11PubMedCrossRefGoogle Scholar
  42. 42.
    Ereshefksy L, Jann MW, Saklad SR, et al. Bioavailability of psychotropic drugs: historical perspective and pharmacokinetic overview. J Clin Psychiatry 1986; 47 Suppl. 9: 6–15Google Scholar
  43. 43.
    Midha KK, Hawes EM, Hubbard JW, et al. Variation in the single dose pharmacokinetics of fluphenazine in psychiatric patients. Psychopharmacology 1988; 96: 206–11PubMedCrossRefGoogle Scholar
  44. 44.
    Mavroidis ML, Garver DL, Kanter DR, et al. Therapeutic blood levels of fluphenazine: plasma or RBC determinations? Psychopharmacol Bull 1984; 20: 168–70PubMedGoogle Scholar
  45. 45.
    Mavroidis ML, Garver DL, Kanter DR, et al. Fluphenazine plasma levels and clinical response. J Clin Psychiatry 1984; 45: 370–3PubMedGoogle Scholar
  46. 46.
    Levinson DF, Simpson GM, Singh H, et al. Fluphenazine dose, clinical response and extrapyramidal symptoms during acute treatment. Arch Gen Psychiatry 1990; 47: 761–8PubMedCrossRefGoogle Scholar
  47. 47.
    Bolvig Hansen L, Larsen N-E. Plasma levels of perphenazine related to clinical effect and extrapyramidal side effects. In: Gram LF, Usdin E, Dahl SG, et al., editors. Clinical pharmacology in psychiatry bridging the experimental-therapeutic gap. London: Macmillan, 1983: 175–81Google Scholar
  48. 48.
    Balant-Gorgia AE, Balant LP, Andreoli A. Pharmacokinetic optimisation of the treatment of psychosis. Clin Pharmacokinet 1993; 25: 217–36PubMedCrossRefGoogle Scholar
  49. 49.
    Bolvig Hansen L, Larsen N-E. Plasma concentrations of perphenazine and its sulphoxide metabolite during continuous oral treatment. Psychopharmacology 1977; 53: 127–30CrossRefGoogle Scholar
  50. 50.
    Hansen CE, Christensen TR, Elley J, et al. Clinical pharmacokinetic studies of perphenazine. Br J Clin Pharmacol 1976; 3: 915–20CrossRefGoogle Scholar
  51. 51.
    Hals PA, Dahl SG. Dopaminergic D2 receptor binding of phenothiazine drugs and their metabolites. Nordisk Psychiatrisk Tidsskrift 1984; 10 Suppl.: 17–20CrossRefGoogle Scholar
  52. 52.
    Dahl-Puustinen ML, Liden A, Alm C, et al. Disposition of perphenazine is related to polymorphic debrisoquine hydroxylation in humans. Clin Pharmacol Ther 1989; 84: 99–102Google Scholar
  53. 53.
    Physicians Desk Reference 47th edition. Montvale, NJ: Medical Economics Data (a division of Medical Economics Company Inc.), 1993; 1241–2Google Scholar
  54. 54.
    Simpson GM, Cooper TB, Lee JH, et al. Clinical and plasma level characteristics of intramuscular and oral loxapine. Psychopharmacology (Berl) 1978; 56: 225–32CrossRefGoogle Scholar
  55. 55.
    Cooper TB, Kelly RG. GLC analysis of loxapine, amoxapine and their metabolites in the serum and urine. J Pharm Sci 1979; 68: 216–9PubMedCrossRefGoogle Scholar
  56. 56.
    Zetin M, Cramer M, Garber D, et al. Bioavailability of oral and intramuscular molindone hydrochloride in schizophrenic patients. Clin Ther 1985; 7: 50–6Google Scholar
  57. 57.
    Fann WE, Moreira AF. Neuroleptic bioequivalency: tablet versus concentrate. J Clin Pharmcol 1985; 25: 305–6Google Scholar
  58. 58.
    Mavroidis ML, Garver DL, Kanter DR, et al. Clinical relevance of thiothixene plasma levels. J Clin Psychopharmacol 1984; 4: 155–7PubMedCrossRefGoogle Scholar
  59. 59.
    Hobbs DC, Welch WM, Short MJ, et al. Pharmacokinetics of thiothixene in man. Clin Pharmacol Ther 1974; 16: 473–8PubMedGoogle Scholar
  60. 60.
    Van Putten T, May PRA, Marder SR, et al. Plasma levels of thiothixene by radioreceptor assay: clinical usefulness. Psychopharmacology 1983; 79: 40–4PubMedCrossRefGoogle Scholar
  61. 61.
    Midha KK, Hawes EM, Hubbard JW, et al. Kinetics of oral trifluoperazine. Br J Clin Pharmacol 1983; 15: 380–2PubMedCrossRefGoogle Scholar
  62. 62.
    Midha KK, Korchinski ED, Veebeeck RK, et al. A pharmacokinetic study of trifluoperazine in two ethnic populations. Psychopharmacology 1988; 95: 333–8PubMedCrossRefGoogle Scholar
  63. 63.
    Ayd Jr FJ. Guidelines for using short-acting intramuscular neuroleptics for rapid neuroleptization. Int Drug Ther News 1977; Feb–Mar: 5–12Google Scholar
  64. 64.
    Reschke RW. Parenteral haloperidol for rapid control of severe disruptive symptoms of acute schizophrenia. Dis Nerv Sys 1974; 35: 112–5Google Scholar
  65. 65.
    Dubin WR, Weiss KJ. Rapid tranquilization: a comparison of thiothixene and loxapine. J Clin Psychiatry 1986; 47: 294–7PubMedGoogle Scholar
  66. 66.
    Stotsky BA. Relative efficacy of parenteral haloperidol and thiothixene for emergency treatment of acutely excited and agitated patients. Dis Nerv Sys 1977; 38: 967–73Google Scholar
  67. 67.
    Ereshefsky L, Jann MW, Saklad SR, et al. Bioavailability of psychotropic drugs: historical perspective and pharmacokinetic overview. J Clin Psychiatry 1986; 47: 6–15PubMedGoogle Scholar
  68. 68.
    Fruensgaard K, Korsgaard S, Jorgensen H, et al. Loxapine versus haloperidol parenterally in acute psychosis with agitation. Acta Psychiat Scand 1977; 56: 256–64PubMedCrossRefGoogle Scholar
  69. 69.
    Loga S, Curry S, Lader M. Interactions of chlorpromazine and nortriptyline in patients with schizophrenia. Clin Pharmacokinet 1981; 6: 454–62PubMedCrossRefGoogle Scholar
  70. 70.
    Goff DC, Midha, KK, Brotman AW, et al. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine. Am J Psychiatry 1991; 148: 790–2PubMedGoogle Scholar
  71. 71.
    Douyon R, Angrist B, Preselow E, et al. Neuroleptic augmentation with alprazolam: clinical effects and pharmacokinetic correlates. Am J Psychiatry 1989; 146: 231–4PubMedGoogle Scholar
  72. 72.
    Goff DC, Midha KK, Brotman AW, et al. An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychopharmacol 1991; 11: 193–7PubMedGoogle Scholar
  73. 73.
    Arana GW, Goff DC, Freidman H, et al. Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry 1986; 143: 650–1PubMedGoogle Scholar
  74. 74.
    Kidron R, Averbuch I, Klein E, et al. Carbamazepine-induced reduction of blood levels of haloperidol in chronic schizophrenia. Biol Psychiatry 1985; 20: 219–22PubMedCrossRefGoogle Scholar
  75. 75.
    Jann MW, Ereshefsky L, Saklad SR, et al. Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol 1985; 5: 106–9PubMedCrossRefGoogle Scholar
  76. 76.
    Linnoila M, Viukari M, Vaisanen K, et al. Effect of anticonvulsants on plasma haloperidol and thioridiazine levels. Am J Psychiatry 1980; 137: 819–21PubMedGoogle Scholar
  77. 77.
    Loga S, Curry S, Lader M. Interactions of orphenadrine and phenobarbitone with chlorpromazine: plasma concentrations and effects in man. Br J Clin Pharmacol 1975; 2: 197–208PubMedCrossRefGoogle Scholar
  78. 78.
    Ishizaki T, Chiba K, Saito M, et al. The effects of neuroleptics (haloperidol and chlorpromazine) on the pharmacokinetics of valproic acid in schizophrenic patients. J Clin Psychopharmacol 1984; 4: 254–62PubMedCrossRefGoogle Scholar
  79. 79.
    Wolf M, Mosnaim AD. Lithium and molindone interaction: pharmacokinetic studies. Res Commun Psychol 1986; 11: 23–8Google Scholar
  80. 80.
    Rivera-Calimlim L, Nasrallah H, Strass J, et al. Effect of dose, dosage schedules and drug interactions on plasma chlorpromazine levels. Am J Psychiatry 1976; 133: 646–52PubMedGoogle Scholar
  81. 81.
    Howes CA, Puller T, Sourindhrin I, et al. Reduced steady-state plasma concentrations of chlorpromazine and indomethacin in patients receiving cimetidine. Eur J Clin Pharmacol 1983; 24: 99–102PubMedCrossRefGoogle Scholar
  82. 82.
    Verghese C, Kessel JB, Simpson GM. Pharmacokinetics of neuroleptics. Psychopharmacol Bull 1991; 27: 551–63PubMedGoogle Scholar
  83. 83.
    Ereshefsky L, Jann MW, Saklad SR, et al. Effects of smoking on fluphenazine clearance in psychiatric patients. Biol Psychiatry 1985; 20: 329–52PubMedCrossRefGoogle Scholar
  84. 84.
    Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; 2: 584–6PubMedCrossRefGoogle Scholar
  85. 85.
    von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Cytochromes in psychopharmacology. J Clin Psychopharmacol 1994; 14: 1–4Google Scholar
  86. 86.
    Gram LF, Fredricson-Overo K. Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. BMJ 1972; 1: 463–5PubMedCrossRefGoogle Scholar
  87. 87.
    Smith DA, Jones BC. Speculations on the substrate structure activity relationship (SSAR) of cytochrome P450 enzymes. Biochem Pharmacol 1992; 44: 2089–98PubMedCrossRefGoogle Scholar
  88. 88.
    Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985; 38: 402–8PubMedCrossRefGoogle Scholar
  89. 89.
    Bertilsson L, Lou Y-Q, Du Y-L, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97PubMedCrossRefGoogle Scholar
  90. 90.
    Dahl-Puustinen M-L, Liden A, Alm C, et al. Disposition of perphenazine is related to polymorphic debrisoquine hydroxylation in human beings. Clin Pharmacol Ther 1989; 46: 78–81PubMedCrossRefGoogle Scholar
  91. 91.
    LLerena A, Alm C, Dahl M-L, et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype. Ther Drug Monit 1992; 14: 92–7PubMedCrossRefGoogle Scholar
  92. 92.
    LLerena A, Dahl M-L, Ekqvist B, et al. Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of reduced metabolite in poor metabolizes. Ther Drug Monit 1992; 14: 261–4PubMedCrossRefGoogle Scholar
  93. 93.
    Spina E, Martines C, Caputi AP, et al. Debrisoquine oxidation phenotype during neuroleptic monotherapy. Eur J Clin Pharmacol 1991; 41: 467–70PubMedCrossRefGoogle Scholar
  94. 94.
    Llerena A, Alm C, Dahl ML, et al. Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther Drug Monitor 1992; 14: 92–7CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Grace V. Milton
    • 1
    • 2
  • Michael W. Jann
    • 1
  1. 1.Southern School of PharmacyMercer UniversityAtlantaUSA
  2. 2.Dialysis Clinic Inc.AtlantaUSA

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