Psychotropic drug therapy in patients in the intensive care unit – usage, adverse effects, and drug interactions: a review

Figures & data

Table 1 Pharmacodynamic and pharmacokinetic parameters of benzodiazepines

Medication	Equivalent potency (mg)	Metabolism	Elimination half-life (hours)	Onset after oral dose consumption (hours)	Commentsa
Chlordiazepoxide	50	Oxidation by CYP3A4 to active metabolites (desmethyldiazepam)	30–100	1	Special attention should be paid to elderly patients, those with liver disease, persons taking other drugs interfering with BZD metabolism, or those who are poor metabolizers
Oxazepam	30	Non-CYP glucuronidation in liver to non-active metabolites	5–15	1–2	Preferred in patients with liver disease and in the elderly
Flurazepam	30	Oxidation by CYP3A4 to active metabolites (desalkylflurazepam, hydroxyethylflurazepam)	40–114 (120–160 in older adults)	0.5–1	–
Temazepam	30	Primarily non-CYP glucuronidation in liver to minimally active metabolite	8–20	0.5–1	Preferred in patients with liver disease and in the elderly
Clorazepate	15	Oxidation by CYP3A4 to active metabolites (desmethyldiazepam)	30–200	0.5–1	–
Quazepam	15	Oxidation by CYP3A4 and non- CYP metabolism in liver to active metabolites (2-Oxoquazepam, Ndesalkyl-2-oxoquazepam)	28–100 (190 in older adults)	1	–
Diazepam	10	Oxidation by CYP2C19 and CYP3A4 to active metabolites (desmethyldiazepam)	50–100 (prolonged in older adults and renal or hepatic impairment)	0.25–0.5	Special attention should be paid to elderly patients, those with liver disease, persons taking other drugs interfering with benzodiazepine metabolism, or those who are poor metabolizers
Lorazepam	1.5–2	Non-CYP glucuronidation in liver to non-active metabolites	10–20	0.5–1	Preferred in patients with liver disease and in the elderly
Alprazolam	1	Oxidation by CYP3A4 to minimally active metabolites	11–15 (16 in older adults, 20 in hepatic impairment, 22 in obesity)	1	–
Clonazepam	0.5	Oxidation and reduction by CYP3A4	18–50	0.5–1	–
Estazolam	0.3	Oxidation by CYP3A4 to minimally active metabolites	10–24	0.5–1	–
Triazolam	0.25	Oxidation by CYP3A4 to minimally active metabolites	1.5–5	0.25–0.5	–
Midazolam	–	Oxidation by CYP3A4 to non- active metabolites	1–4	0.1–0.3	–

Notes:

a The drugs in this category have interactions with other CNS depressants such as alcohol and barbiturates and their concurrent use can lead to CNS and respiratory depression. Another significant drug interaction includes inhibitors (azole antifungals) or inducers of CYP3A4 especially in the case of diazepam and chlordiazepoxide.

Abbreviations: BZD, benzodiazepine; CNS, central nervous system.

Table 2 Characteristics and properties of antipsychotics

Medication	Equivalent dose (mg)	Metabolism	Elimination half-life (hours)	Onset after oral dose consumption	Commentsa
FGAs
Low potency
Chlorpromazine	100	Mainly CYP2D6; also, other CYPs and UGT glucuronidation to active and inactive metabolites	24–30	30–60 minutes	Variable oral absorption; high sedation, anticholinergic side effects, and orthostatic hypotension especially in older adults and mechanically ill patients
Thioridazine	100	Mainly CYP2D6; also, other CYPs to active (mesoridazine) and inactive metabolites	Parent drug: 4–10 Active metabolites: 21–25		Dose-dependent retinitis pigmentosa; very high risk of QTc prolongation; prolactin elevation; high sedation, anticholinergic side effects, and orthostatic hypotension
Mild potency
Loxapine	10	CYP1A2, CYP2D6, and CYP3A4 and UGT glucuronidation to active and inactive metabolites	Parent drug: 6–8 Active metabolites: 12	Within 0.5 hours	–
Perphenazine	8–10	Mainly CYP2D6; also, CYP3A4 and other CYPs to active and inactive metabolites	Parent drug: 9–12 Active metabolites: 10–19	2–4 weeks	Variable bioavailability (60%–80%); similar tolerability and efficacy to some SGAs in higher daily doses
Trifluperazine	5	Mainly CYP1A2; also, other CYPs to active and inactive metabolites	Parent drug: 3–12 Active metabolites: 22	2–4 weeks (control of agitation, aggression, hostility) Within 1 week (control of psychotic symptoms)	Variable bioavailability; high EPS and TD
Thiothixene	4	CYP1A2 and other CYPs	34	–	Variable oral absorption, high EPS and TD
Fluphenazine	2	CYP2D6	14–33	24–72 hours for decanoate	Highly variable oral absorption, high EPS and TD
Haloperidol	2	Mainly CYP2D6; also, CYP3A4 and UGT glucuronidation; some metabolites potentially active or toxic	18–20	–	High EPS and TD; prolactin elevation; QTc prolongation
Pimozide	1	CYP1A2, CYP2D6, CYP3A4, and others	55; 150 in CYP2D6 poor metabolizers	Within 1 week	Variable bioavailability due to extensive hepatic first-pass metabolism; high EPS and TD
SGAs
Quetiapine	75	CYP3A4	6–12	–	Least likely to induce drug-induced parkinsonism; QTc prolongation; monitor patients routinely for glucose dysregulation, weight gain, and hyperlipidemia; increased likelihood of CVAs and TIAs in elderly patients
Ziprasidone	60	CYP3A4	7	5–5.5 hours in children; 6–8 hours in adults	High risk of QTc prolongation
Clozapine	50	CYP1A2, CYP3A4, other CYPs, and UGT glucuronidation	8–12	Within 1 week (sedation); 6–12 weeks (antipsychotic effects)	Potent muscarinic receptor antagonists; the most frequent dose limiting factor is hypotension; one of the most metabolically problematic agents (glucose dysregulation, weight gain, and hyperlipidemia); dose-related tachycardia; sialorrhea; black box warnings: agranulocytosis, seizures, myocarditis, other adverse cardiovascular and respiratory effects, and increased mortality in elderly patients with dementia-related psychosis
Aripiprazole	7.5	CYP2D6 and CYP3A4 to active and inactive metabolites	75–94	1–3 weeks	Partial D2 receptor agonist; so, better to take in the morning as it may be activating in some patients; decreases serum prolactin and triglycerides; low risk of weight gain, dyslipidemia, and QTc prolongation; partial D3 agonist and may induce an increase in risky, reward-based behaviors, such as gambling
Olanzapine	5	CYP1A2, CYP2D6, and UGT glucuronidation	21–54	Within 1–2 weeks (control of aggression, agitation, insomnia); 3–6 weeks (control of mania and positive psychotic symptoms)	Potent muscarinic receptor antagonists; high risk of glucose dysregulation, weight gain, and hyperlipidemia
Paliperidone	3	Mainly excreted unchanged in urine; also, limited CYP2D6 and CYP3A4	23	–	Dose reduction in renal insufficiency is necessary
Risperidone	2	CYP2D6 to active (paliperidone) and inactive metabolites; P-gp substrate	3–20	–	Prolactin elevation; weight gain; orthostatic hypotension; high EPS and TD
Asenapine	–	CYP1A2 and UGT glucuronidation	24	–	–
Lurasidone	–	CYP3A4 to active and inactive metabolites	18–37	–	Absorption increases when taken with a meal
Iloperidone	–	CYP2D6, CYP3A4, and other CYPs to active and inactive metabolites	18–33	–	Significant orthostatic hypotension

Notes:

a Most antipsychotics are metabolized by CYP450 isoenzymes, so the inhibitors (fluvoxamine, fluoxetine, paroxetine, bupropion, and ciprofloxacin) or inducers of these isoenzymes (carbamazepine, phenytoin, and cigarette smoke) can change the antipsychotic serum levels. These interactions are more significant for agents such as clozapine. Also administering medications with overlapping side effects such as cardiac, sedative, anticholinergic, or metabolic risks should be avoided.

Abbreviations: FGA, first-generation antipsychotic; UGT, UDP-glucuronosyltransferase; SGA, second-generation antipsychotic; EPS, extrapyramidal symptoms; TD, tardive dyskinesia; CVAs, cerebrovascular accidents; TIAs, transient ischemic attacks; P-gp, P-glycoprotein; QTc, corrected QT interval.

Table 3 Different characteristics and properties of antidepressants

Medication	Metabolism	Elimination half-life (hours)	Onset after oral dose consumption	Commentsa
SSRIs
Citalopram	CYP3A4, CYP2D6, and CYP2C19 to weakly active metabolites (desmethylcitalopram, didesmethylcitalopram)	33–35	1–4 weeks	The highest protein binding among SSRIs; dose-related QTc prolongation
Escitalopram	CYP3A4, CYP2D6, and CYP2C19 to weakly active metabolites (S-desmethylcitalopram, S-didesmethylcitalopram)	27–32	Within a week	The least protein binding among SSRIs (56%)
Fluoxetine	CYP3A4, CYP2D6, and CYP2C9 to active metabolites (norfluoxetine)	Parent drug: 24–144; active metabolite: 96–384	Within a week	Causes a decrease in appetite; activating agent; longest half-life among SSRIs
Paroxetine	CYP2D6 to non-active metabolites	21–24	Within a week	A weak anticholinergic agent; very high risk of sexual dysfunction; weight gain
Sertraline	CYP3A4, CYP2D6, and CYP2C19 to weakly active metabolites (desmethylsertraline)	26	Within a week	More GI disturbances including diarrhea than other SSRIs; variable oral bioavailability
SNRIs
Duloxetine	CYP1A2 and CYP2D6 to inactive metabolites	12 (8–17)	–	Should not be used in patients with substantial alcohol use or evidence of chronic liver disease due to an increase in LFTs
Venlafaxine	CYP2D6 to active metabolite (O-desmethylvenlafaxine) and inactive metabolites (N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine)	Parent drug: 4; active metabolite: 11	–	Dose-related increase in BP and heart rate
Desvenlafaxine	Mainly via hepatic conjugation; also, oxidation by CYP3A4	10–11	–	–
Levomilnacipran	Hepatic to inactive metabolites	12	–	More potent effects on NE as compared to its 5-HT reuptake; the greatest risk of increasing BP among SNRIs

Notes:

a Most SSRIs are inhibitors of the CYP/CYP450 isoenzymes and can alter the blood levels of other medications. Among them, sertraline, citalopram, and escitalopram have the minimal effect on CYP450 enzyme system. Fluoxetine and paroxetine have the highest impact on CYP2D6 (interaction with tamoxifen), and fluvoxamine is potent inhibitor of CYP1A2. Among SNRIs, only duloxetine is a moderately potent inhibitor of CYP2D6 and the others do not have significant effect on CYP/CYP450 isoenzymes. SNRIs should not be used in patients who have received MAOIs in previous 2 weeks due to the risk of serotonin syndrome.

Abbreviations: SSRI, selective serotonin reuptake inhibitor; GI, gastrointestinal; SNRI, serotonin–norepinephrine reuptake inhibitor; LFT, liver function test; BP, blood pressure; QTc, corrected QT interval; NE, norepinephrine; MAOIs, monoamine oxidase inhibitors; HT, hydroxytryptamine.

Table 4 The characteristics and properties of alpha2 agonists

Medication	Metabolism	Elimination half-life	Onset of action after consumption (minutes)	Commentsa
Dexmedetomidine	CYP2A6 and glucoronidation	3 hours (prolonged in hepatic impairment)	5–15 (5–10 and 15 with and without loading dose administration)	Potentially significant hypotension and bradycardia or hypertension that do not resolve quickly upon abrupt discontinuation which occur more commonly in patients with cardiovascular instability or hypovolemia; rapid administration of loading dose may be associated with cardiovascular instability, tachycardia, bradycardia, or heart-block; does not induce the deep sedation needed for neuromuscular blockade
Clonidine	Hepatic metabolism to inactive metabolites	12–16 hours (41 hours in renal impairment)	10	Causes bradycardia, hypotension, and xerostomia; use with caution in patients with cardiovascular and cerebrovascular diseases; CNS depressant

Notes:

a Drugs that alter the blood pressure level can affect hypertensive or hypotensive effect of alpha2 agonists. Tricyclic antidepressants can desensitize alpha2 adrenoreceptors and should be stopped 3 weeks prior to use of these two drugs.

Abbreviation: CNS, central nervous system.

Table 5 Pharmacodynamic and pharmacokinetic properties of propofol and ketamine

Medication	Metabolism	Elimination half-life (hours)	Onset after oral dose consumption	Commentsa
Propofol	Hepatic mainly via CYP2B6 to water-soluble sulfate and glucuronide conjugates; also, via CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4	4–7	1–2 minutes	Cardiovascular and respiratory depression (propofol-related infusion syndrome); hypotensive agent; contraindicated in patients with egg allergy
Ketamine	Hepatic via CYP2B6, CYP2C9, and CYP3A4 to active (norketamine) and non-active metabolites; also, via hepatic conjugation	1–2	30 seconds IV; 3–4 minutes IM	Increased airway secretions and laryngospasm; elevated IOP and ICP; emergence reactions, CNS depressant, sympathetic stimulator (increases HR and BP); psychotomimetic effects (hallucinations and nightmares)

Notes:

a Special care should be taken when administering propofol with alfentanil (due to risk of opisthotonus and/or grand mal seizures), CNS, and respiratory depressants (opioid narcotics, sedatives). Ketamine can worsen cardiovascular toxicity of cocaine and TCAs.

Abbreviations: IV, intravenous; IM, intramuscular; IOP, intraocular pressure; ICP, intracranial pressure; HR, heart rate; BP, blood pressure; CNS, central nervous system.