Drug-induced neurological disorders (DINDs), also known as drug-induced neurological adverse reactions, are defined as drug-induced dysfunction or structural damage to the nervous system [1]. The damage to the nervous system is multifaceted and can be caused by the direct toxic effects of drugs on the nerves or secondary to non-neurological adverse reactions; symptoms can occur at the beginning of treatment or when the drug is suddenly stopped, or months or even years later; lesions can damage both the central nervous system (CNS) and the peripheral nervous system (PNS); they can manifest as neurological symptoms or present with psychiatric The damage can be transient and reversible, or persistent and irreversible. If the signs and symptoms of pharmacogenic neuropathy are recognized early and appropriate measures are taken in time, the condition can be effectively improved; if the clinical features are not well understood, the diagnosis and treatment can be delayed, leading to irreversible damage and serious consequences. Therefore, it is of great clinical significance to improve the understanding of pharmacogenic neuropathy.
1. Factors affecting pharmacogenic neuropathy
The reason why pharmacogenic neuropathy is common is related to the sensitivity of the nervous system to toxic chemicals.
1.1, organismal factors
1.1.1, neural development and aging The structure of the nervous system is exceptionally complex, with a lengthy developmental period characterized by cell migration, differentiation and synaptic pruning. The process of formation of basic brain structures is stage-specific, and each process depends on the successful completion of all its predecessors; therefore, toxic damage to any process in neural development can lead to structural damage and dysfunction [2]. Neonates and infants are susceptible to the toxic effects of drugs due to the immature development of the brain and blood-brain barrier (BBB), which can produce neurotoxic effects even at very low concentrations. The elderly are also prone to neurological adverse reactions due to decreased liver and kidney function, reduced activity of drug metabolizing enzymes, and inadequate excretion, metabolism, or detoxification of drugs; coupled with the loss of neurons and reduced number of receptors during the aging process, the storage and release of neurotransmitters are reduced and inactivation is slowed down [3-5].
1.1.2, Structural characteristics of the nervous system Mature nerve cells and their interconnected circuits are essential for the maintenance of body function. Neurons are post mitotic cells and cannot regenerate, therefore the consequences due to cell death cannot be compensated by the proliferative repair of surviving cells. Neurons are also very active cells, with often large dendrites (e.g., Purkinje cells in the cerebellum) and long axons (e.g., motor neurons), which maintain their function by moving metabolites between the cell body and its dendrites and axons (by retro- and cis-axonal plasma transport) through an efficient system with high metabolic demands, making them highly sensitive to hypoxia and hypoglycemia [2]. Neurons with long protrusions are more vulnerable to attack at multiple sites, including the cytosol, dendrites, myelin sheaths, ganglia, and terminal synaptic expansions.
1.1.3, blood-brain barrier and blood-nerve barrier The adult BBB is effective in preventing the entry of circulating charged molecules or macromolecular compounds into neural tissue, but it does not prevent the entry of lipid-soluble substances or prevent the adverse effects of toxins that can destroy the BBB. areas of relative weakness of the BBB or blood-nerve barrier include areas associated with neuroendocrine activity (e.g., the last region, hypothalamus, pineal gland), areas with barrier porous sites (e.g., autonomic ganglia), and motor and sensory nerve endings, are potential sites of toxin attack. In addition, drugs that act on the CNS usually pass through the BBB, and they may damage the nervous system while exerting therapeutic effects.
1.1.4, Individual differences Genetic factors are the main determinants of individual differences in drug action. Genetic factors related to drug metabolizing enzymes determine the structure and function of drug metabolizing enzymes, thus affecting drug metabolism. The permeability of the BBB is increased in the presence of CNS lesions or damage such as infection, ischemic or hemorrhagic lesions, and trauma, making the body susceptible to adverse reactions during drug therapy. Sometimes the disease itself does not affect the BBB, but the patient’s sensitivity to certain drugs is increased, even if the dose of drugs used is not large, there can be neurological adverse reactions, such as Alzheimer’s disease patients are very sensitive to sedatives. Non-neurological diseases, such as liver and kidney disease, hypoproteinemia, cardiac dysfunction, water-electrolyte disorders and endocrine disorders, etc., are also factors that can easily cause neuropsychiatric adverse drug reactions.
1.2, drug factors
1.2.1, drug metabolism and seizure Many drugs are metabolized by the liver, and their metabolic end products are often non-toxic; however, the toxicity of drugs is enhanced after certain metabolic steps. For example, 2,5-hexanedione (hexanedione), which is derived from n-hexane (n-hexane), and some organophosphates metabolized to form active ozone are neurotoxic. Sequestration allows the drug and its metabolites to enter the plasma lipids, proteins or body lipids and form a “sump”, which is then slowly released and detoxified and excreted, thus not showing neurotoxic effects. Then, toxic effects may occur when the rate of drug accumulation exceeds the rate of sequestration, metabolism and excretion [2]. People with hepatic or renal impairment are at high risk of drug toxicity, which can occur even at very small doses.
1.2.2 Drug interactions Drugs used in combination can cause changes in pharmacological or physicochemical properties due to interactions, or adverse reactions due to inhibition or enhancement of the metabolic enzyme activity of one drug (or several) by another drug. The more types of drugs used in combination, the higher the chance of adverse reactions. Some drugs affect the absorption of other drugs taken together in the gastrointestinal tract by altering gastrointestinal dynamics, pH or flora, aggravating adverse reactions. Different drugs have different binding rates with plasma proteins, and when multiple drugs enter the body at the same time, they will compete for plasma protein binding sites, so that the protein binding rate of drugs with weak affinity decreases, resulting in an increase in the concentration of free drugs in the plasma, which can easily lead to toxic side effects.
1.2.3, the method of drug use too large doses or too long a course of treatment, too fast administration, improper route of entry, too long or too short intervals between doses, and improper discontinuation of drugs can cause adverse neurological reactions.
2 Mechanism of pharmacogenic neuropathy
ATP is a key component of energy transfer and utilization in the body, and under normal oxygenation, ATP is mainly synthesized in the mitochondria through oxidative phosphorylation, with only a small fraction derived from glycogenolysis. Glycogen reserves in the brain are extremely low, and even at rest, the energy produced by glycogenolysis can only last for 5 minutes at most, so when ATP synthase is inhibited, it causes a lack of brain energy supply. The neurotoxic effect of oligomycin is mainly produced by the inhibition of ATP synthase. In biological oxidation, oxidation is the energy-producing reaction, phosphorylation is the energy-absorbing reaction, and oxidation and phosphorylation usually proceed in pairs (coupling). If phosphorylation does not proceed properly or oxidative phosphorylation uncoupling occurs under the action of drugs, energy is mainly dissipated in the form of heat and ATP cannot be formed, resulting in insufficient energy supply, which can interfere with brain energy metabolism to a certain extent. The neurological symptoms caused by barbiturate poisoning are related to uncoupling. H+ in the body comes from the process of deH+ (oxidation) of sugars, fats and proteins, while H+ in the brain mainly comes from sugars. Some drugs affect the metabolism of sugar and reduce the source of H+ in the brain. For example, during treatment with drugs such as insulin, there is a risk that the source of H+ in the brain may be affected by inducing hypoglycemia and causing impaired energy metabolism in the brain and adverse neurological effects. Mitochondria are susceptible to damage by endogenous and exogenous factors (e.g. cyanide, CO). Zidovudine can induce mitochondrial myopathy during the treatment of AIDS, which is related to its impairment of mitochondrial function [6].
2.2. Causes disorders of neurotransmitter metabolism and altered receptor sensitivity Many drugs acting on the nervous system affect the synthesis, storage, release and inactivation of neurotransmitters, which can cause disorders of neurotransmitter metabolism and lead to adverse neurological reactions. For example, 5-hydroxytryptamine (5-HT) reuptake inhibitors and tricyclic antidepressants exert their pharmacological effects on depressive symptoms by inhibiting 5-HT reuptake and increasing the concentration of 5-HT in the synaptic gap, and 5-HT syndrome can occur with inappropriate use. Dopamine (DA) receptor agonists and blockers are commonly used in clinical practice, the former including dehydromorphine and levodopa, and the latter such as phenothiazines, butylphenols and thiazides, which exert therapeutic effects mainly by acting on DA receptors. After long-term use of these drugs, the sensitivity of the receptors may change, resulting in adverse effects. The dyskinesia seen with levodopa and phenothiazines may be related. Adverse reactions due to anticholinergic drugs such as atropine are related to the effects on acetylcholine and its receptors.
2.3, drug-induced secondary neurological adverse reactions Drug-induced non-neurological adverse reactions can sometimes cause neuropsychiatric disorders, called drug-induced secondary neurological adverse reactions, which are not rare in clinical practice. The mechanism is related to drug-induced water-electrolyte disorders, vitamin deficiency, liver and kidney damage, and respiratory, circulatory or endocrine dysfunction.
3, the main manifestations of pharmacogenic neuropathy
Neurological adverse drug reactions are widespread, including CNS, PNS and muscular system, and their symptoms involve motor, sensory, autonomic function and mental behavior [7]. The onset can be acute, subacute or chronic.
3.1. Central nervous system lesions
3.1.1, Encephalopathy Drugs cause encephalopathy through direct toxic effects on the CNS (e.g., antiepileptics, cephalosporins, penicillin, and immunoglobulins) or by interfering with metabolic processes in brain cells (e.g., hypoglycemia and hyponatremia). Its onset is of three types: acute, subacute and chronic. Most symptoms are mild and subside within a few days. Typical symptoms are headache, dizziness, nausea, fatigue, confusion, impaired attention and short-term memory, impaired motor coordination, and abnormal gait. In severe cases, coma may occur, commonly with overdose, when drug blood levels reach toxic levels; tricyclic antidepressants, opioids, benzodiazepines, and antiepileptics are more likely to cause it. Reversible posterior leukoencephalopathy syndrome (RPLS) presents with symptoms such as headache, seizures and vision loss, and is most often seen in patients with severe hypertension, pre-eclampsia, and the application of immune agents such as cyclophilin or tacrolimus after organ transplantation; it can also be caused by drugs such as acyclovir, amphotericin B, cisplatin, cytarabine, isophosphamide and methotrexate [1,2].
3.1.2 Cognitive impairment Cognitive function is closely related to the function of cholinergic neurons, and hallucinations, delirium, and cognitive impairment can occur when cholinergic activity is reduced. There are many drugs that can cause delirium states, including amphetamines, anticonvulsants, antidepressants, antituberculosis drugs, antimalarials, anti-inflammatory drugs, cardiac glycosides, diuretics, antihypertensives, H2 antagonists, antipsychotics, opioids, sympathomimetics, and sedatives [9]. Anticholinergics, antihypertensive agents (e.g., calcium antagonists, adrenergic agents), antiepileptics (sodium valproate, phenytoin, lamotrigine), antipsychotics, benzodiazepines, glucocorticoids, cytokines (interleukins, interferon IFN-α), and desipramine all cause reversible dementia-like manifestations [1].
3.1.3, Cerebrovascular disease With the exception of contraceptives, drugs that can cause cerebrovascular disease are relatively rare [1,2,9]. The mechanisms of drug-induced cerebrovascular disease may be: ① Drug-induced hemodynamic changes. Drugs can induce or exacerbate acute cerebrovascular disease by altering cerebral blood flow supply through constricting and elevating blood pressure, dilating and lowering blood pressure, and affecting cardiac conduction and myocardial contractility. Drugs that increase blood pressure, such as sympathomimetic drugs, glucocorticoids, erythropoietin and cyclosporine, can induce hemorrhagic cerebrovascular disease. Antihypertensive drugs and nitrate coronary expansion drugs may induce or aggravate ischemic cerebrovascular disease, mainly due to rapid hypotension resulting in insufficient blood supply to the junctional area of cerebral artery supply, which can lead to watershed infarction. Some psychotropic drugs and antiepileptic drugs can cause heart rate slowdown, conduction block, arrhythmia and decrease in myocardial contractility, resulting in a significant decrease in cardiac blood output, causing cerebral perfusion deficiency and cerebral infarction; ② Drugs cause blood rheological changes. Procoagulants and antifibrinolytics cause thrombosis and cerebral infarction by enhancing coagulation and reducing the function of the fibrinolytic system, respectively. Platelet function inhibitors, anticoagulants, and thrombolytic agents increase the risk of cerebral hemorrhage or hemorrhagic cerebral infarction; ③ Drug-induced vascular lesions. Contrast agents, vasoconstrictors such as ergot preparations and hypoglycemia caused by hypoglycemic drugs all induce persistent vasospasm and damage the intima. Alcohol, ephedrine, amphetamines and other psychoactive substances, certain antibiotics, chemotherapy drugs and contraceptives cause autoimmune endovasculitis or directly damage the endovascular lining, causing platelet aggregation leading to thrombosis, or increasing the fragility of the wall inducing intracranial hemorrhage. Pharmacogenic cerebral vasculitis mainly involves small arteries and is pathologically characterized by polymorphonuclear cells only without giant cell infiltration [10].
3.1.4, Headache Epidemiological studies have shown that more than 8% of headache cases are drug-induced [11]. The International Headache Society states that medication overuse headache (MOH) is an important component of chronic daily headache (CDH). There is no absolute criterion for drug overuse, but it is usually considered as drug overuse when the use of drugs such as tretinoin, ergotamine, opioids or compounded analgesics is more than 10 days per month, or when the use of common analgesics is more than 15 days per month. There are many other drugs that can cause headache, including vasodilators (nitrates, calcium antagonists, dipyridamole), sympathomimetics, hypoglycemic agents, antibiotics, anti-inflammatory drugs, antidepressants, H2 antagonists, hormones, proton pump inhibitors, and antiepileptics. In general, the diagnosis of MOH can be made based on the temporal relationship between drug intake and the onset of headache symptoms, but because headache is a common clinical symptom, it is sometimes difficult to confirm whether the headache is drug-induced [9].
Idiopathic intracranial hypertension (IIH) is a specific cause of headache, with a population annual incidence of 1 per 100,000, but a 19-fold higher incidence in obese women aged 24-44 years; 10% of these cases are at risk of blindness due to the severity of the symptoms.IIH typically presents with persistent headache, transient visual blurring, and intracranial noise (beeping in the ear or heartbeat, etc.) [1]. Physical examination reveals optic papillary edema, sometimes with abducens nerve palsy and diplopia. Lumbar puncture shows increased cerebrospinal fluid pressure with normal composition. Tetracycline, retinoids, glucocorticoids, estradiol receptor agonists and antagonists, nonsteroidal anti-inflammatory drugs, growth hormone, cimetidine, nalidixic acid, methomyl-sulfamethoxazole, amiodarone, and lithium salts have been associated with the development of IIH [9]. Other causes of increased intracranial pressure, such as venous sinus thrombosis, should be excluded.
3.1.5 , Seizures Drug-induced epileptic seizures can be seen in patients with epilepsy or non-epilepsy and appear during or after withdrawal of medication. Antipsychotics, antidepressants, antineoplastic agents (antimetabolites, vincristine, isocyclophosphamide, and cisplatin), antibiotics (penicillin, cephalosporins, and quinolones), aminophylline, and allopurinol are epileptogenic [12] and are often associated with pharmacogenic encephalopathy. Less common epileptogenic drugs include opioids, baclofen, digoxin, dopamine preparations, methylphenidate, and otancilon [1]. Withdrawal seizures are most often seen within a few days after abrupt discontinuation of medications taken for a longer period of time, such as barbiturates, benzodiazepines, and baclofen [2].
3.1.6 , cerebellar syndrome The clinical features of impaired cerebellar function are ataxia, dysarthria and intention tremor, which are the most common features of chronic mercury poisoning [9]. Several other drugs such as 5-fluorouracil, phenytoin, lithium salts and acrylamide overdose can also cause cerebellar dysfunction [1]. The cerebellar syndrome due to phenytoin toxicity is dose-dependent and reversible in the early stages; however, if long-term drug use leads to cerebellar atrophy, the lesions are irreversible. Aminoglycosides, amiodarone, barbiturates, carbamazepine, and piperazines can also lead to cerebellar syndrome.
3.1.7, extrapyramidal syndromes Drug-induced extrapyramidal adverse reactions are more common, and the mechanism involves complex interactions between DA, 5-HT and NE between the cortex and basal ganglia. The main manifestations are Parkinson’s syndrome, dystonia, dyskinesia and tremor [1,2,6,13]. It can be acute, chronic or delayed and is usually reversible, but can recur.
Acute dystonic reactions can be caused by DA-depleting drugs such as antihistamines, antipsychotics, antiemetics (domperidone, metoclopramide), buprenorphine, and antimalarials, and usually occur on day 1 of drug administration, affecting head, neck, and trunk muscles with neck retraction, tongue protrusion, dental closure, and motility crises [9]. Neuroleptic malignant syndrome (NMS) is caused by acute blockade of DA D2 receptors in the striatum, hypothalamus and spinal cord and is an acute and serious complication of antipsychotics. It is characterized by high fever, fluctuating levels of consciousness, muscle rigidity (often axial), dystonia, autonomic dysfunction, and increased creatine kinase and myoglobin concentrations in the blood. Death is often due to rhabdomyolysis, diffuse intravascular coagulation and acute renal failure, with a mortality rate of about 10% [9,14].
Chronic dystonia can be caused by antiparkinsonian drugs (levodopa preparations and DA agonists), phenytoin, phenobarbital and butorphanolazine. Gastrocnemius or foot muscle spasms (morning stiffness phenomenon), which often appear in the early morning in Parkinson’s disease, are due to a progressive weakening of the response to levodopa or DA agonists (wearing-off) [9].
Delayed-onset syndrome is a group of abnormal involuntary movement symptoms with delayed onset caused by DA receptor blocking agents. Delayed dyskinesias (rhythmic involuntary movements of the tongue, face and jaw) are the most common and can appear several years after discontinuation of the drug. Delayed dystonia (usually facial and cervical), inability to sit still (appearing during neuroleptic treatment or within 3 months after discontinuation), twitching (delayed Tourettism), myoclonus (predominantly in the cervical or upper arm muscles, associated with high drug doses) and tremor can all be caused by long-term antipsychotic application, with partial but rarely complete recovery of symptoms after discontinuation in 1/3 of cases [9]. The above syndromes occur mostly after the application of typical antipsychotics, while atypical antipsychotics are rare [14].
3.2, Peripheral neuropathy
Peripheral neuropathy can originate in neurons, axons, or myelin sheaths, causing loss of neuronal or axonal function; or affect ion channels, causing ion channel disease and affecting peripheral nerves; or damage nerve endings, resulting in neuromuscular lesions [2]. Neuronal lesions are more likely to involve sensory nerves, and proprioceptive deficits appear earlier or are more severe than pain, but nerve conduction velocities can be normal. Desmoplastic peripheral neuropathy is due to destruction of the myelin sheath of the Schwann cells or internodes, and the degree of recovery depends on the proliferation and activation of surviving Schwann cells. Axonal disease is due to axonal destruction and occurs gradually, affecting first the long axons and distal ends, with sensory signs often preceding motor signs [8], followed by weakening of ankle reflexes and propagation of signs to the proximal end. The nerve damage sometimes progresses further even after drug withdrawal, then peaks and gradually regains function due to regeneration of damaged axons [9], which is very slow and often irreversible because the axon growth rate is only 1.5-3 mm per day. Axonal ion channel disease is associated with abnormal axonal conduction due to altered ion channel function and is often caused by natural toxins.
3.3, Muscle disease
Drug-induced skeletal muscle damage is relatively rare and most may be caused by actual denervation [2], which usually manifests clinically as limb weakness, myalgia, myalgias, myoclonus, swelling and muscle atrophy [15]. Myalgia or weakness occurs in 1-5% of statin users, and rhabdomyolysis may develop in severe cases. The skeletal muscle cytotoxicity of statins is in the following order: cerivastatin > fluvastatin > simvastatin/atorvastatin/provastatin. Betelgebiet increases plasma statin concentrations and increases the risk of myopathy, so it should not be combined with statins [1]. Tetracyclines, polymyxins, clindamycin, aminoglycosides, phenytoin, lithium, and chlorpromazine can cause neuromuscular blockade and should be avoided in patients with myasthenia gravis. Penicillin and beta blockers can occasionally cause myasthenia gravis syndrome. Herbicides containing diazacholesterols or chlorophenoxyisobutyric acid can cause myasthenia; licorice, diuretics, and alcohol abuse can cause hypokalemic paralysis. Skeletal muscle can regenerate rapidly after removal of the appropriate agent, but in severe cases can be fatal due to rhabdomyolysis leading to acute renal failure [2].
4, Principles of management of pharmacogenic neuropathy
Clinically, in cases of suspected pharmacogenic neuropathy, a detailed history should be taken immediately, especially to understand the drug use, and neurological examination and necessary ancillary tests, including hematology, neuroelectrophysiology, neuroimaging and neuropsychological determination, should be performed [16]. If neurological signs and symptoms are found, they should be determined to be due to primary disease, general adverse drug reactions, or pharmacogenic neurological damage [17]. If the latter is the case, the drug should be discontinued immediately, the dose should be reduced, or the dose should be maintained under close observation, as appropriate, and symptomatic treatment should be administered [2]. The administration of vitamins and essential trace elements may help in the recovery of neurological symptoms.