Drug-induced delirium is a more common pharmacogenic disorder and is more common in patients with susceptibility factors (e.g., advanced age, neurological disorders, surgical procedures, and critical illness). Pharmacogenic delirium is mainly associated with neurological disorders caused by drugs affecting the synthesis, release and metabolism of neurotransmitters. Reports of pharmacogenic delirium are common in the combination of drugs, especially in critically ill patients with multiple underlying diseases and in elderly patients. The combination of multiple drugs affecting neurotransmitter function is more likely to induce delirium due to the superposition of pharmacological effects. Rational use of drugs can avoid the occurrence of pharmacogenic delirium, and early recognition of delirium symptoms and timely management are particularly important.
This paper reviews the common drugs that induce delirium, in order to promote the correct clinical identification, prevention and treatment.
I. Anticholinergic drugs
Anticholinergic drugs are mostly used clinically for antispasmodic, inhibition of glandular secretion, regulation of ciliary muscle paralysis, etc. The therapeutic amount has no obvious effect on the central nervous system, but as the dose increases, it will produce central inhibition, which is the most common drug causing delirium, such as atropine, scopolamine, scopolamine, solifenacin, etc.
Second, the treatment of central neurodegenerative drugs
1.Anti-Parkinson’s disease drugs
The dopamine-like drugs amantadine and levodopa, the dopamine agonists bromocriptine, carmeglumine and pramipexole, the cholinergic receptor blocker biperiden, and the selective monoamine oxidase B inhibitor sregiline may induce delirium, hallucinations, paranoia and other hydroxyl symptoms, especially the selective monoamine oxidase inhibitor may cause toxic delirium with excessive doses.
2.Anti-Alzheimer’s disease drugs
Cholinergic neuron degeneration is one of the important factors causing cognitive impairment in Alzheimer’s disease, and currently the more clinically used therapeutic drugs are acetylcholinesterase inhibitors. Donepezil and tacrine in this class of drugs have been reported to cause delirium.
Third, antihistamines
Antihistamines are often used to treat allergic reactions. 2nd generation antihistamines do not easily cross the blood-brain barrier, have high selectivity for H1 receptors, and have weak central sedative effects, but high doses can cause calcium channel blockade and induce delirium. There have been reports of delirium caused by severe poisoning with diphenhydramine and delirium caused by promethazine and cycloheximide.
Fourth, the digestive system drugs
Cimetidine, ranitidine and famotidine are H2 receptor blocking drugs, which can cross the blood-brain barrier and have some neurotoxicity. When used to treat gastrointestinal complications in alcoholics, delirium tremens can occur, with symptoms similar to those of withdrawal syndrome. The antiemetic metoclopramide causes delirium associated with its blockade of dopamine receptors. Gastrointestinal mucosal protective agent bismuth can cause encephalopathy in long course or overdose, and delirium can occur in severe poisoning.
V. Treatment of psychiatric disorders
1.Sedative-hypnotic and anxiolytic drugs
The serious adverse effects of benzodiazepines lorazepam, triazolam, zolpidem, etc. are delirium, especially when combined with antidepressants, the incidence of delirium increases significantly. Benzodiazepines such as alprazolam are drug dependent and delirium can occur with sudden discontinuation of the drug. The application of midazolam, propofol and dexmedetomidine for sedation and analgesia in seriously ill patients should be gradually reduced.
2.Antipsychotics
Clozapine can block D1, D2, D3, D4, 5-HT receptors and histamine H1 and other receptors, which has a high probability of inducing delirium, which can occur at low doses and is not easily recovered after discontinuation.
3.Antidepressants
Amitriptyline, nortriptyline and other tricyclic antidepressants with weak anticholinergic effects can induce delirium in elderly patients, especially when the dose is suddenly increased. Clomipramine, desipramine, and mianserin have all been reported to trigger delirium. Amitriptyline and its metabolite desoxyptyline have a higher risk of delirium at blood levels above 450 ng/ml, and clinical monitoring of blood levels can be used to avoid adverse reactions. The incidence of delirium is 0.10-10~1% as indicated in the instructions of mirtazapine.
4.Anti-manic drugs
Lithium carbonate treatment of mania should control the blood lithium concentration, the blood lithium concentration is 0.8-1.5 mmol/L under the treatment dose, lithium accumulation poisoning in the body can cause delirium and other encephalopathy syndrome, once it appears, the drug should be immediately stopped and measures should be taken to promote lithium excretion. In addition, lithium carbonate and thioridazine, clozapine, risperidone and other antipsychotics in combination can cause delirium and aggravate extrapyramidal reactions. Lithium salts should be avoided in patients with neuropathy.
5. Anti-epileptic and anticonvulsant drugs
Phenytoin sodium increases the negative value of the resting potential of cells by inhibiting the inward flow of sodium, raises the excitation threshold of brain cells, and stabilizes the membrane potential. Mild toxicity of carbamazepine can also cause delirium.
Six, analgesics
The adverse effects of opioids include hallucinations, confusion and delirium. An open long-term survey by Wallace et al. showed that the incidence of severe delirium was 0. 8% in 644 outpatients treated with intrathecal ziconotide (maximum dose 240 pLg/d) for chronic pain. The combination of the analgesic tramadol with the selective 5-HT3 receptor antagonist ondansetron may increase the risk of postoperative delirium.
VII. Antipyretic and anti-inflammatory drugs
Aspirin overdose can trigger salicylic acid toxicity, which can progress to delirium and agitation. Chronic salicylic acid poisoning often occurs in patients who apply salicylic acid drugs in large doses for a long time, especially in elderly patients. After symptoms of poisoning appear, the drug should be stopped immediately, and sodium bicarbonate should be administered orally or intravenously to alkalize the urine, reduce salicylate reabsorption and accelerate its excretion, and take corresponding symptomatic treatment. After the plasma salicylate concentration is reduced, the patient’s mental status is improved. Delirium caused by celecoxib and ibuprofen has also been reported.
Eight, anti-microbial drugs
1. Antibiotics
Antibiotics that have been reported to cause delirium include cefuroxime, cefepime, ertapenem, meropenem, azithromycin, gentamicin, chloramphenicol, levofloxacin, moxifloxacin, ciprofloxacin, and compound sulfamethoxazole. Patients with renal disease are prone to neurological reactions with antibiotics, of which delirium is more common and mostly dose-related.
2, antiviral drugs
The U.S. Food and Drug Administration issued drug instructions point out that acyclovir, valacyclovir and famciclovir can cause delirium, seizures and other central nervous system adverse reactions, elderly patients or patients with kidney injury are at higher risk, while taking nephrotoxic drugs can increase the risk of reversible central nervous system symptoms. Oseltamivir can induce abnormal behavior and delirium and lead to injury, and neurological symptoms in pediatric patients tend to be sudden and abrupt. Serious adverse effects of zanamivir also include delirium.
3, antifungal drugs
Winn et al. reported a case of meningitis in which intrathecal amphotericin B caused severe toxic delirium and brain wave abnormalities, which recovered after discontinuation of the drug. The authors concluded that the adverse effect was dose-related. Adverse events of delirium associated with fluconazole and itraconazole have also been reported.
IX. Cardiovascular system drugs
The drugs involved in delirium adverse events include antiarrhythmic drugs quinidine; anti-anginal drugs nitroglycerin, isosorbide nitrate, tocainide; cardiac drugs digoxin; antihypertensive drugs sodium nitroprusside, colistin, methyldopa, etc.
Ten, adrenocorticotropic hormone
Delirium mostly occurs in the first 2 weeks of treatment. About half of the patients can recover completely within 2 weeks after dose reduction or discontinuation, and more than 90% of the patients can recover within 6 weeks. For severe symptoms, phenothiazine antipsychotics may be given. Tricyclic antidepressants can aggravate symptoms and are not recommended.
XI. Other
Chronic ingestion of alkaline calcium salts can cause lactobase syndrome, including hypercalcemia and metabolic alkalosis, and hypercalcemia crisis can cause delirium, abdominal pain, and renal stones. Other drugs that have been reported to cause delirium include the immunosuppressant cyclosporine, the anesthetics ketamine, bupivacaine, propanacol, and desflurane, the central respiratory stimulants methylphenidate and niclosamide, the wheezing drug terbutaline, the cough suppressant dextromethorphan, the skin disinfectant hexachlorophen, the procoagulant aminocaproic acid, and the antimalarial drug hydroxychloroquine.