Historical note and nomenclature

The term "drug-induced neurologic disorders," a form of iatrogenic illness, specifically refers to unintended or undesirable effects on the nervous system that are either caused by drugs or associated with drug use. It includes neurologic disorders due to medications used for diagnostic procedures. The use of the word "induced" within the term "drug-induced neurologic disorders" does not necessarily imply a proven causal relationship of the drug to the disorder. The drug may affect the nervous system directly (primary neurotoxicity) or indirectly by other systemic disturbances caused by the drug (secondary neurotoxicity). Drug-induced neurologic disorders can include disorders caused by inappropriate use of a drug, overdose of a drug, or harmful drug interactions, but environmental and industrial toxins are excluded.

Terms that are commonly used to refer to adverse drug effects are defined by the World Health Organization as follows:

Adverse event or adverse experience. Any untoward medical occurrence that may present during treatment with a pharmaceutical product but does not necessarily have a causal relationship with this treatment.

Adverse drug reaction. An event that is related, or suspected to be related, to a medication. An adverse drug reaction is a response to a drug that is noxious, unintended, and occurs at doses normally used in man for prophylaxis, diagnosis, therapy of a disease, or modification of physiological function.

Side effect. Any unintended effect of a pharmaceutical related to the pharmacological properties of the drug and occurring at doses normally used in humans.

The American Society of Health-System Pharmacists has a somewhat different terminology (19):

Adverse drug event. Harm resulting from medical intervention involving a drug.

(a) Adverse drug reaction. A nonpreventable adverse drug event occurring with the usual use of a medication. This does not include adverse drug events due to medication errors that are considered preventable.

(b) Preventable harm due to medication errors. Drugs associated with a heightened risk of causing significant patient harm when used in error are referred to as "high-alert medications."

In the first half of the 20th century, increasing attention was given to adverse drug reactions, partly because of the increased rate of therapeutic development. For example, polyneuropathy as a complication of serum therapy was described in 1934 (02), and encephalopathy as a complication of pertussis vaccination was described in 1949 (12). In the late 20th century, there were attempts at conceptualizing, categorizing, and systematizing complications of treatment of neurologic disorders as well as neurologic complications resulting from treatment of diseases of other systems (30; 22; 08). Increasingly sophisticated surveillance systems have been developed for collection and analysis of adverse drug reactions.

Clinical significance

Drug-induced neurologic disorders can mimic neurologic disorders due to other causes; however, when a reasonable suspicion exists of association with a drug or a known or plausible pathogenetic mechanism for drug-induced neurologic disorders, the drug should be considered in the differential diagnosis. Questionnaires, algorithms, and computer-based approaches have been used to assess the causal relationship of the drugs to the adverse drug reactions. None of these methods have found universal application because they are tedious, time-consuming, and expensive. In clinical practice, causality is usually assessed by global judgment (ie, opinion of the causal relation of the drug to the event after taking into consideration the available relevant information, as shown in Table 1).

Table 1. Global Evaluation of Causal Relationship of a Drug to an Adverse Event

The answers are taken into consideration to allocate the adverse drug reactions to the following categories: (1) probable, (2) possible, and (3) unlikely. These are approximate terms, and the term "definite" is rarely used. "Possible" means that such a reaction can occur with the drug, and sometimes this term is used because the possibility cannot be excluded. Sufficient information for assessment may not be available in some cases.

Multiple approaches to grading the severity of adverse drug reactions have been proposed, as shown in Table 2.

Table 2. ADR Severity Scale

Anecdotal reports of suspected adverse drug reactions involving the nervous system are common in the medical literature but are generally of limited value because, by themselves, they cannot establish causality, nor can they provide an indication of the magnitude of the risk. This anecdotal information is not even systematically incorporated into commonly used drug information sources.

Epidemiology

Adverse effects of drugs involving the nervous system form only a small proportion of all neurologic disorders, but they are under-recognized and under-reported. Adverse drug reactions, both from clinical trials and post-marketing surveillance, are usually reported to the manufacturers of the product involved. Manufacturers make the initial assessment of these reports and file the adverse drug reactions with the health authorities of the countries involved according to regulatory requirements (Food and Drug Administration [FDA] in the United States). The World Health Organization also maintains a database for adverse drug reactions.

FDA-approved drug labeling is defined by the Code of Federal Regulations (1 CFR) of the United States and contains several distinct sections (03). Each section provides specific information such as drug safety, efficacy, patient information, target populations, and clinical as well as nonclinical data. To promote the safe use of drug products and protect public health, adverse drug reaction information is collected from clinical trials and post-marketing surveillance data and summarized in FDA-approved drug labeling as boxed warnings and precautions with different levels of severity and coverage. Serious warnings are about adverse drug reactions that lead to death or serious injury, whereas warnings describe clinically significant adverse drug reactions.

The Medical Dictionary for Regulatory Activities (MedDRA) is the standard medical terminology developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and is used worldwide to facilitate the sharing of regulatory information for medical products. MedDRA is used for coding adverse events in the FDA’s Adverse Event Reporting System. MedDRA is widely applied in analyzing adverse drug reaction report data and in mining public health data for potential safety concerns. MedDRA terminology has been successfully used to code and investigate adverse drug reactions. MedDRA has also been used to analyze adverse drug reactions in FDA drug labeling, but it may not provide an adequate assessment of drug toxicity and severity, potentially undermining the utility of drug labeling.

Combining MedDRA standard terminologies with data mining techniques facilitated computer-aided adverse drug reaction analysis of drug labeling and highlighted the importance of labeling sections that differ in seriousness and application in drug safety (29). Using adverse drug reactions primarily related to boxed warning sections, a prototype approach for computer-aided adverse drug reaction monitoring and studies can be applied to other public health documents.

The incidence of adverse drug reactions in hospitalized patients was determined by a meta-analysis of 39 prospective studies from American hospitals. The overall incidence of serious adverse drug reactions was 6.7%, and fatal adverse drug reactions was 0.3%, making these the fourth leading cause of death in the United States after heart disease, cancer, and stroke (18). The incidence is much higher than that assumed from the spontaneous reporting system, which identifies only about 1 in 20 adverse drug reactions. In a study of 18,820 hospital admissions in the United Kingdom, 1225 were related to an adverse drug reaction, giving a prevalence of 6.5%, with the adverse drug reaction directly leading to admission in 80% of cases (23). Assessment of 1263 consecutive admissions to the neurology unit of a Swiss university hospital over one year revealed drug-related problems in 29% of cases, and these were the cause of admission in 0.8% (27).

A systematic review of the incidence of adverse drug reactions in primary care reviewed studies published from 1990 to the end of 2018 and found that the CNS was the body system with the most adverse drug reactions reported (17). The most frequent adverse drug reactions were fatigue (55%), dizziness (18%), and tremor (16%).

Small numbers of adverse drug reactions are published in case reports, and many adverse drug reactions are not observed in clinical trials of new drugs. Most of the information received by pharmaceutical companies is inadequate for establishing the diagnosis of drug-induced neurologic disorders, but it is used for answering questions from physicians and for making decisions for inclusions of adverse drug reactions in basic drug information and package inserts.

Most of the products listed in the Physicians' Desk Reference mention at least one untoward effect that relates to the nervous system. Entries in the list of adverse drug reactions are not always based on medical judgment but may be a measure to protect the manufacturer against legal liability by having declared that such an adverse drug reaction has been reported. The adverse effects reported may not be causally related to the drug.

The frequency of adverse events in clinical trials can be calculated and compared with that in the placebo group. An adverse event is an adverse drug reaction only if the relation to the drug is proven or suspected. The size of clinical trials is limited and seldom involves more than 500 patients; therefore, rare adverse drug reactions cannot be expected to show up in these trials. Post-marketing surveillance continues for the lifetime of a drug to detect such adverse drug reactions. The frequency of occurrence of adverse drug reactions in this phase is difficult to determine because of generally poor, typically variable, and often biased reporting and lack of knowledge of the denominator. The number of patients exposed to the drug is sometimes estimated from the quantity of the drug sold and the standard dose for a patient. These figures are unreliable because the amount of drug used by individual patients varies greatly, and all the drugs sold are not administered to (or actually taken) by the patients.

A Swedish study showed that fatal adverse drug reactions accounted for approximately 3% of all deaths in the general population, and two thirds of these were due to hemorrhages, of which 29% involved the CNS (28). Antithrombotic agents were implicated in more than half of the fatal adverse drug reactions.

Pharmaceutical drug neurotoxicity ratings. Spencer and Schaumburg provided a simple but useful categorization of neurotoxicity ratings that they applied to both pharmaceutical drugs and to toxins of all kinds. The ratings will be applied here for some categories of pharmaceutical drugs: A, strong association between the drug and the adverse drug reaction; B, a suspected and plausible but still unproven association; C, the association is not likely to be causal (26). In the absence of specified ratings, the substance can be assumed to be "category A."

Table 3. Pharmaceutical Drug Neurotoxicity Ratings

Pathophysiology

Pathogenetic mechanisms of drug-induced neurologic disorders can be categorized by the primary organ or system affected:

(1) Direct neurotoxicity or primary neurotoxicity
(2) Indirect mechanisms or secondary neurotoxicity (ie, neurotoxicity due to drug-induced disturbances of other organs)
(3) Predisposing or risk factors for drug-induced neurologic disorders

A toxidrome or toxic syndrome can be defined as a constellation of findings that are evident either from the physical examination of the patient or from ancillary testing, which may result from drug overdose or withdrawal or exposure to a toxin.

Direct neurotoxicity. Drugs may produce direct neurotoxicity by multiple different mechanisms, including actions on neurotransmitters or their receptors, ion channels, neuronal metabolism, glial metabolism, or neuronal proteins. Examples include the following: (1) dystonic reactions and tardive dyskinesia with dopamine-receptor antagonists, most often antipsychotic drugs; (2) SILENT (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity) with lithium neurotoxicity (01); (3) levodopa-induced dyskinesias (32); (4) augmentation and impulse control disorders with dopaminergic medications (eg, in restless legs syndrome); (5) neuroleptic malignant syndrome; and (6) serotonin syndrome.

For direct neurotoxic effects, the drugs must either act on the peripheral nervous system or cross the blood-brain barrier. Despite this barrier, lipid-soluble molecules (eg, benzodiazepines) readily enter the brain. Damage to the blood-brain barrier facilitates the passage of drugs that normally do not cross the blood-brain barrier; in particular, diseases in which the blood-brain barrier is damaged (eg, multiple sclerosis, malignant brain tumors, and meningitis) may facilitate direct neurotoxic drug effects. Drugs may also cross the blood-brain barrier by being introduced into the ventricles or intrathecal space (eg, instillation of antibiotics via intraventricular catheter, myelography contrast dye).

Various direct mechanisms of neurotoxicity have been established for different drugs. These include (1) disturbances of brain energy metabolism (and sequelae); (2) uncoupling of oxidative phosphorylation (eg, aspirin, indomethacin); (3) disturbances of oxygen consumption; (4) enzymatic dysfunction; (5) ion channel disturbances; (6) mitochondrial dysfunction (eg, zidovudine-induced mitochondrial myopathy); (7) neurotransmitter disturbances (eg, atropine produces memory impairment by reducing CNS acetylcholine); (8) toxic metabolites, “Trojan horse” medication; (9) disturbance of the proteome; (10) drug-induced apoptosis; etc.

For example, direct neurotoxicity of levodopa in the development of levodopa-induced dyskinesia results from an interplay between the N-methyl-D-aspartic acid receptor (NMDAR) and neuroinflammation (32). Damage to dopaminergic neurons occurs through microglia- and astrocyte-mediated neuroinflammation and their interactions (32).

Activated microglia and astrocytes secrete pro-inflammatory factors, which further induce neuroinflammatory and neurotoxic mechanisms in the human brain through processes such as enhanced phagocytic activity and increased production of cytokines (eg, interleukin 1 beta and tumor necrosis factor-alpha) and reactive oxygen species (32). Glutamic acid-mediated changes in synaptic plasticity also play a major role in levodopa-induced dyskinesia through actions on the N-methyl-D-aspartic acid receptor, an ionotropic glutamate receptor closely associated with synaptic plasticity. Neuroinflammation can modulate NMDAR activation or expression because the release of inflammatory factors promotes the expression of the GluN1 and GluN2 subunits of the N-methyl-D-aspartic acid receptors in postsynaptic neurons. This allows the binding of excitatory neuronal glutamate and NMDAR released from presynaptic neurons and the inward flow of calcium ions to act on neuronal synaptic plasticity by regulating the long-term potentiation and MAPK/ERK phosphorylation pathways (also known as the Ras-Raf-MEK-ERK pathway, a chain of proteins in the cell that communicates a signal from a cell surface receptor to the DNA in the nucleus of the cell) through calmodulin-dependent kinase II.

Secondary drug-induced neurologic disorders. The nervous system may be secondarily affected by adverse drug reactions affecting other body systems. Examples of such secondary drug-induced neurologic disorders include (1) dizziness, syncope, and cerebral ischemia from drug-induced cardiac arrhythmias, hypotension, or orthostatic hypotension; (2) cerebral hemorrhage with anticoagulation, especially over-anticoagulation; (3) encephalopathy from drug-induced renal or hepatic failure; (4) convulsions from drug-induced hyponatremia, hypocalcemia, or hypoglycemia; and (5) tremor or myopathy from drug-induced hyperthyroidism (iatrogenic or surreptitious).

Predisposing conditions for drug-induced neurologic disorders. Risk factors that predispose a patient to the development of drug-induced neurologic disorders include (1) genetic predisposition (ie, pharmacogenetic factors); (2) old age; (3) compromised brain function (eg, degenerative, mass lesions, stroke, head injury); (4) systemic diseases (eg, organ failure, AIDS); (5) noncompliance; (6) pregnancy (teratogens); and (7) compromised metabolism or clearance of the drug or toxic metabolites (eg, hepatic or renal impairment).

Pharmacogenetics. Pharmacogenetics investigates the influence of genetic factors on the action of drugs. Existing drug development does not incorporate genetic variability in pharmacokinetics and pharmacodynamics of new drug candidates, with the potential for serious, but seemingly idiosyncratic, drug-gene interactions resulting in severe adverse drug reactions. Polymorphisms in the genes that code for drug-metabolizing enzymes, drug transporters, drug receptors, and ion channels can affect the efficacy of drug treatment and the likelihood of developing an adverse drug reaction. Examples of adverse drug reactions with a pharmacogenetic basis are malignant hyperthermia and extrapyramidal movement disorders in psychiatric patients on neuroleptic therapy.

P450 enzymes. Enzymes controlling drug metabolism are relevant to pharmacogenetics. The cytochrome P450 enzyme system consists of a large family of proteins involved in the synthesis or degradation of a vast number of endogenous compounds as well as the metabolism of exogenous toxins. P450 enzymes can alter, abolish, or enhance drug metabolism. Most clinically used drugs are cleared through the action of P450 enzymes: CYP2D6, CYP3A4, and CYP2C19. For example, drugs used in neurology and psychiatry practice, which are metabolized by the CYP2D6 enzyme, include tricyclic antidepressants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and opioid analgesics.

CYP2C19 is the gene encoding S-mephenytoin hydroxylase, and its mutations lead to poor metabolism of various drugs that include amitriptyline, citalopram, clomipramine, diazepam, imipramine, and mephenytoin.

Epigenetic factors. Gene regulation by genetics involves a change in the DNA sequence, whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region, representing a means of inheritance without associated DNA sequence alterations (05). Epigenetic factors may explain changes in gene expression that persist long after drug exposure has ceased. One hypothesis proposes that some iatrogenic diseases, such as tardive dyskinesia, are epigenetic in nature.

Drug-drug interactions. Drug-to-drug interactions contribute significantly to adverse drug reactions. There may be unpredictable potentiation of synergistic effects resulting in neurotoxicity if two drugs with similar mechanisms of action are used concomitantly. The interaction of a drug acting on the nervous system with a drug acting on another system that interferes with the metabolism of the CNS drug may lead to neurotoxicity. Anticonvulsants have clinically significant interactions with other drugs used in brain tumor patients. A drug interaction resulted in elevated phenytoin levels after initiation of erlotinib therapy in a patient who was receiving phenytoin (13).

In polypharmacy, there may be a combination of drug-drug and drug-disease interactions. An example is serotonin syndrome that developed after the use of tramadol and ziprasidone in a patient with an indwelling deep brain stimulator for Parkinson disease (07).

Systemic diseases. Patients suffering from systemic diseases are more prone to develop adverse drug reactions. In particular, drug-induced neurologic disorders are more likely to develop in patients with diseases of the kidneys and liver. For example, several cases of neurotoxicity resulting from treatment of herpes zoster with acyclovir or valacyclovir have been reported in patients with renal failure, whereas this is a rare side effect of these drugs in patients with normal renal function (24).

Risk factors related to drugs. Factors related to the drugs that influence neurotoxicity are:

Dose. Some of the neurotoxic effects are dose-related, and some occur only as an overdose effect. Management of non-neurotoxic side effects of drugs enables higher doses of these drugs to be given, leading to neurotoxicity. An example of this is high-dose chemotherapy enabled by the addition of granulocyte colony-stimulating factor (filgrastim), which counteracts neutropenia. Eventually, neurotoxicity becomes the limiting factor with this approach.

Rate of drug delivery. Faster rates of intravenous delivery of some drugs may produce transient neurologic disturbances.

Route of administration. Some drugs, which usually do not cross the blood-brain barrier, have neurotoxic effects only when applied directly to the CNS, such as by intrathecal or intraventricular routes.

Drug interactions. Interactions may occur with concomitant medications or substances in foods and beverages.

Potentially serious drug interactions include those that result in serotonin syndrome or drug interactions with monoamine oxidase inhibitors (06).

Serotonin syndrome is a potentially life-threatening syndrome caused by serotonergic drugs with overactivation of both the peripheral and central postsynaptic 5HT-1A and 5HT-2A receptors. Clinical findings include mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. Serotonin syndrome can occur via the therapeutic use of serotonergic drugs, intentional overdose of serotonergic drugs, or a complex drug interaction between two or more serotonergic drugs that work by different mechanisms.

Monoamine oxidase inhibitors combined with dietary tyramine (eg, aged cheeses and meats), sympathomimetic drugs (eg, amphetamines, ephedrine, or cocaine), or serotonergic drugs (eg, selective serotonin reuptake inhibitors or the illicit drug ecstasy [MDMA, 3,4-methylenedioxymethamphetamine]) may induce severe headache and accelerated hypertension. When MAO-A is inhibited, the body is vulnerable to overstimulation of postsynaptic adrenergic receptors with as little as 8 to 10 mg of ingested tyramine with life-threatening blood pressure elevations (06).

Drug-disease interaction. Drugs may unfavorably influence the course of the neurologic condition being treated (eg, exacerbation of Parkinson disease or parkinsonism with administration of antipsychotic drugs).

Drug withdrawal. Withdrawal of drugs after prolonged use may produce neurologic disorders (eg, tardive dyskinesia and other tardive syndromes after withdrawal of antipsychotic drugs).

Principles of management of drug-induced neurologic disorders

Clinical diagnosis. A careful history of drug use and a high index of suspicion are the most important factors in the diagnosis of drug-induced neurologic disorders. The physician should obtain a complete list of current medications and medications the patient has taken previously (from at least several months before the onset of the condition that is possibly drug-induced) and should consider other possible offending medications that might be available from family members and other sources. Drugs most likely to cause such disorders should be considered first.

Diagnostic procedures. Detection of biomarkers of neurotoxicity may be useful for detection of toxic effects of drugs in the absence of clinical features or any clues in routine laboratory studies and imaging procedures. Detection of genetic biomarkers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy can be useful in reducing the adverse effects of chemotherapy for cancer (20).

Prevention. This is the most important approach to reduce the incidence of adverse drug reactions. When several therapeutic alternatives are available, the one with the least neurotoxicity should be selected, particularly in susceptible patients with risk factors. Dose-related adverse effects may be reduced by slow, stepwise increases in dosage.

Epidemiological studies indicate that antithrombotic agent-associated cerebral hemorrhages constitute a significant proportion of adverse drug reactions. Preventive measures should be considered to reduce these fatalities.

Treatment. Usually, the first step is discontinuation of the responsible drug in case of severe adverse drug reactions. Symptomatic treatment may be given for persisting symptoms.

Special considerations

Patients with preexisting neurologic disorders, renal insufficiency, and advanced age may be particularly susceptible to the neurotoxicity of antibiotics, and this can be reduced by dosage adjustments in high-risk populations (14).

Developmental toxicity. Developmental toxicity refers to adverse effects on the developing organism that result from exposure before conception during the prenatal period or postnatally up to the time of sexual maturity. Adverse developmental outcomes include the following groups of developmental toxicities (11).

Mortality. Mortality resulting from developmental toxicity may occur at any time from early conception to post-weaning (eg, embryo-fetal death is a subset of mortality resulting from developmental toxicity). This incorporates pre- or peri-implantation loss, early or late resorption, abortion (including miscarriage), stillbirth, neonatal death, and peri-weaning loss.

Dysmorphogenesis (structural abnormalities). Dysmorphogenic effects are generally seen as malformations or variations of the skeleton or soft tissues of the offspring and are commonly referred to as structural abnormalities. Dysmorphology includes malformations, variations, deformations, and disruptions.

Alterations to growth. Alterations to growth are generally seen as growth retardation, although excessive growth or early maturation may also be considered alterations to growth. Body weight is the most common measurement for assessing growth rate, but crown-rump length and anogenital distance may also be measured. Sometimes it may not be clear if an effect is a direct structural alteration or an inhibition of growth (eg, reduced ossification could be either). A distinction must be made on review of all relevant data.

Functional impairment. Functional toxicities could include any persistent alteration of normal physiologic or biochemical function, but typically only developmental neurobehavioral effects and reproductive function are measured. Common assessments include locomotor activity, learning and memory, reflex development, time to sexual maturation, mating behavior, and fertility. Functional toxicity includes such outcomes as neurodevelopmental effects, deafness, endocrinopathy, and impairment of reproduction.

Teratogens. A teratogenic drug has the potential to cause developmental malformations or birth defects in a fetus when taken by a pregnant woman. Common central nervous system birth defect prevalence at birth in the United States (from selected states) is shown in the Table 3.

Table 4. Central Nervous System Birth Defect Surveillance Data from Selected States (1995–1999)*

The Swedish system for the classification of fetal risk of drugs was the first of its kind when it was implemented in 1978 (25). In Sweden, drugs for use in pregnant women are classified in four general categories (A to D). The U.S. Food and Drug Administration (FDA) introduced a classification system in 1979 (A to D, and X). However, the definitions differed considerably between the Swedish system and the FDA system, producing a different allocation of drugs to the various categories. Although the Swedish system was widely accepted, the FDA system proved more controversial, in part because of shortcomings in the category definitions. For example, the FDA system required an unrealistically high quality of data to be available, including the availability of controlled studies in pregnant women that fail to demonstrate a risk to the fetus, before a drug could be assigned to category A. Consequently, most drugs on the U.S. market were allocated to category C and interpreted as "risk cannot be ruled out."

Table 5. The Swedish System for Classification of Drugs Used During Pregnancy

Table 6. The FDA System for Classification of Drugs Used During Pregnancy (1979–2015)

Based on critiques of the prior FDA system since the early 1990s, the FDA instituted a new system in 2015. Clinicians and patients were often confused by the meaning of the pregnancy risk categories because the system was overly simplistic, led to misinformation, and did not adequately address the available information.

The FDA's A, B, C, D, and X risk categories, in use since 1979, have been replaced with narrative sections and subsections. The Pregnancy subsection provides information about dosing and potential risks to the developing fetus and registry information that collects and maintains data on how pregnant women are affected when they use the drug or biological product. The Lactation subsection includes drugs that should not be used during breastfeeding, known human or animal data regarding active metabolites in milk, as well as clinical effects on the infant. Other information may include pharmacokinetic data like metabolism or excretion, a risk and benefit section, as well as the timing of breastfeeding to minimize infant exposure. In the subsection entitled "Females and Males of Reproductive Potential," relevant information on pregnancy testing or birth control before, during, or after drug therapy and a medication’s effect on fertility or pregnancy loss are provided when available.

Neonatal abstinence syndrome. Maternal intake of opioids, antidepressants, antiepileptics, and antipsychotics may cause neonatal withdrawal syndromes ("neonatal abstinence syndrome"), which are caused by the birth-related discontinuation of fetal exposure to the responsible drug(s). Symptoms may occur within a few hours to 1 month after delivery and may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting, and persistent crying (04). Neonatal neurologic and behavioral effects can also be caused by residual pharmacological effects of drugs that have accumulated in neonatal tissues.

Geriatric age group. The elderly who are frequently on multidrug therapy and are two to three times more likely to experience adverse drug reactions than young people. Five to 20% of all hospital admissions are related to adverse drug reactions in older people, among which 40% to 70% could be prevented, but identifying these is challenging because they often present as common geriatric problems, such as falls or delirium, that are often attributed to the aging process or underlying diseases (31).

The brain is an especially sensitive drug target in old age. Elderly patients are particularly prone to adverse effects of psychotropic agents, including benzodiazepines, because of the altered pharmacokinetics. Memory and psychomotor impairment are more pronounced in the elderly on benzodiazepine treatment as compared with younger controls. The elderly are also more susceptible to antimuscarinic effects of some antidepressants and neuroleptic drugs and may manifest agitation, confusion, and delirium. These drugs should be used sparingly in elderly patients. If their use is essential, the dosage should be slowly titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose.