Peer Review Testing for Benzodiazepines ____ Relationship Between Benzodiazepine Concentration

• Journal List
• Ochsner J
• five.xiii(2); Summer 2013
• PMC3684331

Ochsner J. 2013 Summer; 13(ii): 214–223.

Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects

Charles E. Griffin, 3

^*Department of Anesthesiology, University of Southern California, Los Angeles, CA

Adam 1000. Kaye

^†Thomas J. Long School of Chemist's and Health Sciences, University of the Pacific, Stockton, CA

Franklin Rivera Bueno

^‡Section of Anesthesiology, Louisiana State University Wellness Sciences Eye, New Orleans, LA

Alan D. Kaye

^‡Section of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, LA

Abstract

Groundwork

Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this land and worldwide many decades ago for a wide range of weather. Because of an increased agreement of pharmacology and physiology, the mechanisms of activity of many BZDs are at present largely understood, and BZDs of varying potency and duration of activity take been developed and marketed. Although BZDs accept many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity tin can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are particularly prone to toxicity.

Methods

This review details the present cognition nearly BZD mechanisms of activity, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous organisation effects.

Conclusion

For any patient taking a BZD, the prescribing physician must advisedly evaluate the risks and benefits, and college-risk patients require conscientious considerations. Clinically appropriate utilise of BZDs requires prudence and the agreement of pharmacology.

Keywords: Adverse effects, benzodiazepines, key nervous system

INTRODUCTION

Benzodiazepines (BZDs) are one of the most widely prescribed pharmacologic agents in the United States (more than 112 one thousand thousand prescriptions in 2007).^one BZDs are used for numerous indications, including anxiety, insomnia, muscle relaxation, relief from spasticity acquired by cardinal nervous system pathology, and epilepsy. BZDs are too used intraoperatively because of their amnesic and anxiolytic properties. However, these properties become undesired side effects in nearly all other clinical instances.

The severity of BZD-induced adverse effects forces physicians to exercise caution and pay attention to side furnishings when prescribing this grade of agents. Tolerance, dependence, age-related physiological changes, and drug-drug interactions are all important considerations. This review explains the mechanisms of action of BZDs, compares and contrasts popular BZDs on the market today, and describes specific BZD-mediated furnishings and side effects.²

BENZODIAZEPINE PHARMACOLOGY

General/Pharmacodynamics

BZDs deed every bit positive allosteric modulators on the gamma amino butyric acid (GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective ion aqueduct.

GABA is the nearly common neurotransmitter in the primal nervous arrangement, plant in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces the excitability of neurons. GABA produces a calming outcome on the brain.² The 3 GABA receptors are designated A, B, and C. This article focuses primarily on the GABA-A receptor, with which BZDs interact.

The GABA-A receptor complex is composed of 5 glycoprotein subunits, each with multiple isoforms (Figure ane). GABA-A receptors incorporate 2 α subunits, ii β subunits, and 1 γ subunit. Each receptor complex has ii GABA-binding sites but only 1 BZD-bounden site. The benzodiazepine binding site is in a specific pocket at the pairing (intersection) of the α and γ subunits. Within the α subunit of isoforms one, two, three, and v resides a histidine residuum (H101, H101, H126, and H105, respectively) that possesses a high analogousness for BZDs.ⁱⁱⁱ Isoforms four and 6 of the α subunit contain an arginine residue and practice not have an affinity for BZDs.³ BZDs bind to the pocket created by the α and γ subunits and induce a conformational change in the GABA-A receptor, allowing GABA to bind. BZDs demark to the pocket created by α and γ subunits and induce a conformational alter in the GABA-A receptor. This alteration, in plow, induces a conformational change in the GABA-A receptor's chloride aqueduct that hyperpolarizes the jail cell and accounts for GABA'south inhibitory consequence throughout the central nervous organisation.³

Specific Benzodiazepine Receptors

The BZD receptor has been classified into several types, based on α subunit isoforms and clinical effects related to each blazon. The BZ1 receptor contains the α1 isoform. The BZ1 receptor is highly concentrated in the cortex, thalamus, and cerebellum;^4,v it is responsible for the BZDs' sedative effects^half-dozen and anterograde amnesia and for some of the anticonvulsive effects of diazepam.⁷ Lx percent of GABA-A receptors contain the α1 subunit. Therefore, amnesia is a common side effect of BZD apply because the majority of GABA-A receptors contain the BZ1 receptor responsible for amnesia.⁸ A major factor in predicting amnesia run a risk is lipid solubility; the greater the lipid solubility, the greater the gamble of amnesia. BZDs with high lipid solubility take higher assimilation rates and faster onset of clinical effects than BZDs with low lipid solubility.²

BZ2 receptors comprise the α2 isoform^four and mediate the anxiolytic and, to a large extent, the myorelaxant effects of BZDs.⁶ BZ2 receptors are highly concentrated in areas such as the limbic system, motor neurons, and the dorsal horn of the spinal cord.^vii The anxiolytic effects of BZDs are believed to be mediated through BZ2 receptors located in the limbic system, and myorelaxant properties are mediated via α2-containing receptors in the spinal string and motor neurons.⁷ Not all BZDs interact with the aforementioned type of BZ receptor or with equal affinity to a specific receptor. These differences in α subunit isoforms, BZ receptor type affinity, and location within the primal nervous organization account for the different effects of the various BZDs.^seven

Benzodiazepine Pharmacokinetics

The pharmacokinetic backdrop of a drug make up one's mind its onset of action and the elapsing of its effect. Specifically, pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug (ie, what the body does to the drug). Pharmacodynamics describes the responsiveness of receptors to a drug and the mechanism by which these effects occur (ie, what the drug does to the body). Individuals respond differently to the same drug, and often these unlike responses reflect the pharmacokinetics and/or pharmacodynamics amid different patients.

Pharmacokinetics (determination of the onset of activeness and the duration of drug effect) is afflicted by route of assistants, absorption, and volume of distribution. BZDs can exist administered via intramuscular, intravenous, oral, sublingual, intranasal, or rectal gel forms. Characteristics of the drug—including lipid solubility, bounden to plasma proteins, and molecular size—influence the book of distribution. Pharmacodynamics and pharmacologic drug effects are described in terms of dose-response curves that describe the relationship between the dose and the resulting pharmacologic outcome. Dose-response curves predict the outcome of the drug on the patient as doses increment. Titration of a drug should go along based on the expected pharmacodynamics. Key considerations during titration of medications include making the advisable choice for the patient's condition (eg, renal failure, liver failure, previous drug exposure), appropriate choice of incremental dosing (ie, time and quantity), and periodic monitoring.⁹

Preexisting disease processes and age-related changes affect elimination half-life, an specially important consideration when administering BZDs. Elimination half-life is the time necessary for plasma concentration of a drug to decrease to 50% during the elimination phase. Because emptying half-life is direct proportional to the volume of distribution and inversely proportional to its clearance, renal and hepatic illness (contradistinct volume of distribution and/or clearance) affect elimination half-life.

Emptying one-half-life does non reflect time to recovery from drug effects. Emptying half-life is an estimate of the time needed to reduce the drug concentration in the plasma by half. Subsequently almost v elimination one-half-lives, a drug is nearly totally eliminated from the torso. Therefore, drug accumulation is likely if dosing intervals are less than this flow of time.

From a pharmacological perspective, BZDs are usually well absorbed by the gastrointestinal tract after oral assistants. After intravenous administration, BZDs quickly distribute to the brain and central nervous system. BZD activity is terminated past redistribution similar to that of the lipid-soluble barbiturates. Post-obit intramuscular injection, absorption of diazepam or chlordiazepoxide is boring and erratic, whereas assimilation of intramuscular administration of lorazepam or midazolam appears to be rapid and complete. Lorazepam is well captivated after sublingual administration, reaching acme levels in 60 minutes.ⁱⁱ

BZDs and their metabolites are highly protein bound. They are widely distributed in the torso and preferentially accumulate in lipid-rich areas such every bit the central nervous system and adipose tissue. Equally previously mentioned, the more lipophilic agents generally take the highest rates of assimilation and fastest onset of clinical furnishings. Most BZDs are oxidatively metabolized by the cytochrome P450 enzymes (phase I), conjugated with glucuronide (stage II), and excreted almost entirely in the urine.

Some BZDs exert additional action via product of agile metabolites, an of import consideration when prescribing these agents. Midazolam, one of the brusk-acting BZDs, produces no active metabolites. Nonetheless, diazepam, a long-interim BZD, produces the active metabolites oxazepam, desmethyldiazepam, and temazepam; these metabolites further increase the elapsing of drug activity and should be a serious consideration in some patient groups, especially the elderly and those with extensive hepatic disease.²

BENZODIAZEPINES IN CLINICAL Practice

Full general

BZDs are classified in terms of their elimination one-half-life. Short-acting BZDs have a median emptying half-life of 1-12 hours, intermediate-interim BZDs have an boilerplate elimination one-half-life of 12-40 hours, and long-acting BZDs have an average elimination one-half-life of 40-250 hours.ⁱⁱ As noted before, v one-half-lives are generally necessary for an agent to be eliminated from the body, making the number of hours that a drug is in the body considerably longer. The table lists various BZDs and their characteristics.²

Table.

Benzodiazepines Commonly Prescribed in Clinical Practice

Another way to characterize BZDs is by relative authorization. The first BZDs were depression to medium potency. These include long-interim chlordiazepoxide, the start BZD discovered, too equally oxazepam and temazepam. Because of their effectiveness and relatively low toxicity, they became first-line agents for conditions such every bit insomnia and anxiety. Afterwards, high-potency BZDs (alprazolam, lorazepam, and clonazepam) were discovered. These new drugs led to new indications for usage: as a handling for panic disorders,¹⁰ as adjuncts to selective serotonin reuptake inhibitors for treatment of obsessive-compulsive disorder, and as adjuncts to antipsychotics for treatment of acute mania or agitation.¹¹ The newer high-authority BZDs showed improved therapeutic effects besides as faster onset of action, making them the preferred BZDs for virtually applications. Yet, with increased say-so comes an increase in the risk of undesired effects. Therefore, when prescribing drugs in this BZD group, clinicians must consider private properties such equally absorption, distribution, elimination one-half-life, and lipid solubility.

Alprazolam

Alprazolam (Figure 2) is a brusque-acting loftier-potency BZD with an elimination half-life of 6-27 hours (Table). Alprazolam was first studied for employ in panic disorders and was proven to exist well tolerated and effective.¹² Alprazolam is unremarkably prescribed for panic disorders and anxiety. The recommended dose for anxiety starts with 0.25-0.v mg tablets, administered by rima oris 3 times per day. The maximum recommended daily dose of alprazolam for anxiolysis should not exceed 4 mg. For panic disorders, the same tablet form and route of administration are recommended at a maximum recommended dose of 6-10 mg/d. A common issue with alprazolam is rebound anxiety that occurs with sharp discontinuation because of the drug's short elimination half-life.

Chemical structure of alprazolam.

Clonazepam

Clonazepam (Effigy 3) was the second high-potency BZD discovered. Clonazepam behaves both as a GABA-A receptor agonist in a highly-potent, long-acting manner and also as a serotonin agonist.^eleven Clonazepam has anticonvulsant and anxiolytic effects. One report proved clonazepam to be at least equally effective every bit lithium for treating acute mania.¹¹ In association with serotonin reuptake blockers, clonazepam appears to accelerate treatment response to panic disorder.¹² In another study, clonazepam proved as effective for treating panic disorders as alprazolam, and termination did not cause rebound feet symptoms¹³ considering of clonazepam'due south long emptying half-life. Because clonazepam displays low lipid solubility, it is less probable to cause anterograde amnesia compared to the other high-potency BZDs. For example, clonazepam is half as lipid soluble equally alprazolam, and then patients' amnesic side effects are reduced. Clonazepam as well has a relatively weaker binding affinity for GABA-A receptors than the other high-authorization BZDs.^eleven Clonazepam, when used to treat panic disorders, should be initiated at a dose of 0.25 mg tablets, taken orally twice a twenty-four hour period for iii days, after which the dose should be increased to 0.five mg tablets twice daily. The maximum daily dose should non exceed ane-4 mg. For treating seizure disorders, adults should kickoff with 0.v mg tablets taken orally iii times per day. For this indication, the maximum daily dose should not exceed twenty mg. In the pediatric population, first with a dose of 0.01-0.03 mg/kg orally divided into 2 or iii doses is recommended. The maximum dose in this population should non exceed 0.1-0.2 mg/kg in 3 doses.

Chemical structure of clonazepam.

Lorazepam

Lorazepam (Effigy 4) is some other loftier-potency BZD that displays short-acting characteristics. Information technology is slightly less lipid soluble compared with alprazolam, suggesting a lower risk of amnesic side effects compared to alprazolam. Lorazepam binds GABA-A with less affinity than alprazolam but with greater affinity than clonazepam. Lorazepam has proven constructive equally an anticonvulsant and also works well every bit an adjunct to antipsychotics in the treatment of acute agitation and mania.^14,15 Post-obit intramuscular injection, lorazepam is absorbed rapidly and completely. Afterward sublingual administration, lorazepam reaches peak plasma levels in roughly sixty minutes.² Lorazepam is unique in that it undergoes direct glucuronidation without prior cytochrome p450 metabolism. Because of this characteristic, lorazepam tin exist used in patients with hepatic or renal dysfunction with only minor effects on the drug's pharmacokinetics.^xvi

Chemical structure of lorazepam.

Lorazepam dosing largely depends on the indication. For alcohol withdrawal, clinicians prescribe ii mg tablets orally every 6 hours for a total of 4 doses, followed by 1 mg every 6 hours for a total of 8 doses. For anxiolysis, dosing begins with 2-3 mg/d orally, divided into 3 doses per day. Maximum daily doses should non exceed 10 mg. The safety and effectiveness of oral forms take not been established in children nether the age of 12. However, the same dosing recommendations for adults utilize to children over the age of 12. For sedation, such equally in the intensive care unit (ICU), 0.01-0.ane mg/kg/h intravenously is recommended.

Midazolam

Midazolam (Figure five), a short-acting BZD, is roughly 1.5-2 times as potent as diazepam¹⁷ and has a greater hypnotic consequence than diazepam because it interferes with GABA reuptake. Midazolam is primarily used preoperatively as an anxiolytic and sedative hypnotic agent (not as a long-term drug in a clinic setting mainly because of its short duration of activity). It is available in intravenous, intramuscular, oral, sublingual, rectal, and intranasal preparations. The parenteral preparation used in clinical practice has an acidic pH of 3.5, making it h2o soluble.^18,xix The h2o solubility of the drug makes the improver of propylene glycol unnecessary, decreasing the pain of injections compared with diazepam. This characteristic explains why midazolam causes less venous irritation and less thrombophlebitis than diazepam.²⁰ At physiologic pH, still, midazolam is 1 of the near lipophilic BZDs. This lipophilia accounts for midazolam's rapid assimilation and crossing of the claret-brain barrier and, hence, the rapid onset of clinical effects. Midazolam is rapidly redistributed, leading to a short duration of action and a brusque emptying one-half-life. This short half-life makes midazolam suitable for continuous infusion. Midazolam, like other BZDs, causes peripheral vasodilation and a subsequent decrease in arterial blood pressure. This issue is more than pronounced than that seen with diazepam. Midazolam is primarily metabolized by cytochrome p450 into the inactive metabolite i-hydroxymidazolam. For this drug, anterograde amnesia is unremarkably a desired result, particularly in an operative setting. The amnesic furnishings of midazolam are more intense than diazepam'due south simply shorter than lorazepam's.²¹

Chemical structure of midazolam.

Recommended dosing of midazolam in the preoperative setting for sedation/anxiolysis is usually 1-v mg intravenously upwards to 1 hour before surgery in otherwise healthy patients. In higher-risk patients, such as those older than 60 years or those with chronic obstructive pulmonary affliction, no more than than 3 mg intravenously upward to one hour before surgery is recommended. In pediatric patients, the rubber and efficacy of oral midazolam syrup has not been established for those nether vi months. Therefore, the oral syrup form should only be given to children older than 6 months, and upward to 1 mg/kg (maximum dose 20 mg) administered orally is recommended for patients between 6 months and 6 years. Another option for pediatric preoperative sedation is intramuscular or intranasal commitment in a dose of 0.1-0.five mg/kg (maximum dose 10 mg). Midazolam tin also be given intravenously to pediatric patients at a maximum recommended total dose of 10 mg. Most children crave substantially lower dosages to attain desired furnishings.

Diazepam

Diazepam (Figure half-dozen) is a long-acting, medium-dominance BZD that is used equally an anticonvulsant and for anxiolysis, sedation, and myorelaxation. Diazepam, one of the most mutual BZDs used for anxiety,² is available in intramuscular, intravenous, oral, and rectal gel forms. Diazepam interacts with equal analogousness on all BZD-sensitive receptors in the central nervous arrangement.⁷ Anxiolytic furnishings are seen at low doses considering of diazepam's interaction with α2-containing receptors in the limbic system. At higher doses, diazepam may provide myorelaxation in addition to anxiolysis; the myorelaxant event is primarily mediated through α2-containing receptors in the spinal string and motor neurons and to a lesser extent through interaction with α3-containing receptors.⁷ Of course, at college doses, sedation and anterograde amnesia are also noted, but these effects are α1-mediated.²² Diazepam is unique in that its metabolism in the liver produces the active metabolites oxazepam, temazepam, and desmethyldiazepam, each of which exerts its own activeness. These metabolites and their actions business relationship for diazepam's long elimination half-life, which increases approximately one hour for each year of age over 40 (eg, the diazepam elimination one-half-life in a 75-yr-old would exist approximately 75 hours). Thus, when prescribing this drug, clinicians must consider potential side effects related to active metabolite buildup, such as oversedation and anterograde amnesia. These side effects tin can be serious and long-lasting, peculiarly in the elderly and in those with hepatic or renal dysfunction. For intravenous administration, diazepam must be prepared in solution with propylene glycol to be water soluble; this solution can cause pain on injection and, in some cases, thrombophlebitis.

Chemic structure of diazepam.

Diazepam, when used for anxiety, can exist given as ii-10 mg orally, 2-4 times per twenty-four hour period depending on symptom severity and the patient's age. Both intramuscular and intravenous forms are too available for anxiolysis and should be given in doses of 2-10 mg every 3-iv hours, depending on symptom severity and age considerations. Equally an offshoot to antiseizure therapy or for muscle relaxation, 2-x mg orally upward to iv times per twenty-four hour period is recommended. For status epilepticus, physicians initially administer 5-x mg intravenously every 15 minutes up to a maximum dose of 30 mg. If needed, this dose may be repeated in ii-4 hours.

Side Effects

Common side furnishings among all BZDs include drowsiness, sluggishness, and fatigue. At higher dosages, dumb motor coordination, dizziness, vertigo, slurred speech, blurry vision, mood swings, and euphoria tin can occur, every bit well as hostile or erratic beliefs in some instances. BZDs are eliminated slowly from the trunk, so repeated doses over a prolonged period can result in significant aggregating in fat tissues. Thus, some symptoms of overmedication (dumb thinking, disorientation, confusion, slurred speech) can appear over time. Tolerance, dependence, and withdrawal are adverse effects associated with long-term use.²

Drug interaction is some other effect with BZDs. They are metabolized in the liver via the cytochrome p450 system and subsequently glucuronidated and renally excreted. Drugs that either attenuate (oral contraceptive pills, antifungals, and some antibiotics) or potentiate (carbamazepine, phenytoin, rifampin, St. John's wort) cytochrome p450 enzymes will either increase or decrease the elimination half-life of BZDs, respectively.²

Severe adverse effects may occur when BZDs are administered with other drugs such as opioids. In combination with opioids, cardiovascular and hemodynamic perturbations become more significant. Respiratory depressant effects on spontaneous ventilation are enhanced dramatically when opioids are used in combination with BZDs, and these effects are dose dependent. Respiratory depressant effects are also exaggerated in patients with chronic obstructive pulmonary disease.

Venoirritation may occur with diazepam and lorazepam; both agents are commonly administered in a hospital or palliative intendance setting in intravenous formulations.ⁱⁱ

Age-RELATED PATHOPHYSIOLOGIC CHANGES

Every bit people age, they feel a steady decline in the function of homeostatic mechanisms in the body, notably the central nervous system, liver, and kidneys. Research has demonstrated that as a role of aging, numerous key nervous organization changes occur, including the death of neurons and their replacement with proliferating glial cells, decreases in intracellular enzymes, and reductions in dendritic synapses.^23,24 The physiological changes of crumbling in the liver result in prolonged clearance of drugs. Reject in renal part begins after the age of 40 at a rate of approximately 1% per twelvemonth, or a i mL/min/y reject in creatinine clearance.²⁵ In the aggregate, these crumbling-related physiological changes are particularly important in terms of BZD accumulation. In general, there is increased sensitivity—including greater confusion and disorientation—to the furnishings of BZDs in the elderly compared with the immature. This increased sensitivity is directly related to the accumulation of BZDs and related active metabolites. The elderly take subsequent increased intensity of BZD-mediated responses and the duration of BZD-mediated effects.

BENZODIAZEPINE-INDUCED Key NERVOUS SYSTEM TOXICITY AND ALTERED STATES

Full general

Cerebral impairment is a broad term that encompasses several symptoms of BZD-induced central nervous system toxicity, such as anterograde amnesia, sedation, drowsiness, motor impairment, inattentiveness, and ataxia. These symptoms are usually more prominent in elderly populations because of the metabolic changes associated with normal crumbling. In 1991, Beers compiled the famous "Beers List" of pharmacological agents that can be hazardous to the elderly. Numerous BZDs were placed on this listing because of their cognition-impairing qualities observed when drug levels accumulate.²⁶ The effects of cognitive impairment can event in serious consequences, including an increased hazard of falls and college rates of fractures, also every bit a higher incidence of motor vehicle accidents. Injury is i of the leading causes of death in the elderly, and most fatal injuries are a result of falls.²⁷

In addition to cognitive impairment, BZDs have the run a risk of dependence. Withdrawal symptoms are commonly observed following abrupt abeyance, peculiarly at higher doses. The following sections further expand on the numerous furnishings and the consequences of high doses of BZDs or poorly tolerated BZDs.²⁵

Anterograde Amnesia

The 3 wide memory classes are sensory, short term, and long term. Sensory and short-term memory seem to exist unaffected by BZD usage.²⁷ Long-term memory, on the other manus, is affected by BZDs. The subcategories of long-term memory are explicit (intentional, conscious memories) and implicit (unconscious, unintentional memories).²⁷

Within explicit retentivity is a subcategory called episodic retentiveness; it is the retention of personally experienced events, involving the recall and recognition of data such as words, stories, pictures, etc. BZDs impair episodic memory.²⁷ The other type of explicit retentiveness is semantic memory; information technology involves the stored knowledge of information such as language and rules that does non need to be remembered in any specific context. Semantic memory is not impaired by BZDs.²⁷

Implicit memory is as well dumb by BZDs, merely not in the same manner as explicit retentiveness. Numerous studies to assess BZD-induced memory harm have all demonstrated a "differential time course" of BZD-induced impairments in implicit and explicit memory,²⁷ meaning that impairments in implicit retentiveness tend to coincide with meridian plasma levels of BZDs and practice not terminal as long every bit the impairments in explicit memory. Impairments in explicit memory occur earlier (in reference to drug administration) and terminal longer than implicit memory impairments. Two hypotheses have aimed to explain this observation: (1) impairments in implicit retentiveness crave relatively higher drug levels in serum than explicit memory impairments, and (2) a specific type of BZD receptor is activated simply at college drug levels, making this receptor at to the lowest degree partly responsible for implicit retentiveness impairments.²⁷ Thus, BZDs impair long-term retentivity, more than specifically, anterograde memory (amnesia for events occurring later the inciting event [drug assimilation]). Currently no literature supports whatever significant evidence of BZDs causing retrograde amnesia (amnesia for events occurring earlier the inciting event).

In the perioperative setting, BZDs are used specifically for their amnesic properties, but in nearly all other instances, amnesia is an undesired side result. Although amnesia tin can occur in whatsoever patient, it is especially worrisome among the crumbling population, because age-related organ decline reduces the ability to metabolize and eliminate drugs, including BZDs. This trouble can atomic number 82 to toxic accumulation of BZDs and their breakdown products, the result of which may manifest in morbidity and fifty-fifty mortality. In many instances, a patient prescribed a BZD for an approved indication (such equally anxiety, muscle spasms, or sleep disorders) in a dose that appears to be safe experiences severe memory loss or confusion after several doses. This result occurs because many BZDs are relatively slowly eliminated from the body considering of their lipophilic properties, and they accumulate in fatty tissues. Equally a upshot, a patient taking a typical standard dose may suffer meaning retentiveness loss. The patient may be unable to recognize loved ones and/or friends and may have difficulty remembering meaning portions of his or her life, sometimes equally much as several years. Cognitive impairment may as well limit the patient's ability to work finer as well.

Another unfortunate potential consequence that tin can occur as a result of the amnesic furnishings of BZD is sexual abuse. Sexual abuse, in full general, occurs at an estimated charge per unit of 64/100,000 women each year.²⁸ Many of these cases occur via the administration of a pharmacological amanuensis (eg, a date rape drug), some of which are BZDs.²⁸ This scenario most commonly occurs in conjunction with booze consumption either when the victim knowingly ingested a BZD or when an assaulter surreptitiously placed the drug into the victim'south beverage. The latter is commonly referred to as drug-facilitated sexual set on (DFSA). In 1 case, a woman ingested an alcoholic beverage that, unknown to her, independent 1 mg of flunitrazepam. She was subsequently sexually assaulted and, considering of flunitrazepam's anterograde amnesic effects, had no recollection of the outcome. Police later plant the major metabolite of flunitrazepam, 7-amino flunitrazepam, in a urine sample collected from the patient for toxicological examination.²⁹ An important clinical observation is that BZDs are a grade of drugs used in DFSAs and their amnesic effects are potentially strong enough to facilitate such crimes.²⁹

Disinhibition

Another apropos event of toxic aggregating of BZDs and their metabolic byproducts is loss of inhibition that can atomic number 82 one to conduct out of graphic symbol, placing the patient in dangerous situations because of an dumb perception of inherent risk. Mutual scenarios involve high-risk sexual behavior and reckless driving. Ane study suggested that BZD usage approximately doubles the risk of motor vehicle accidents.^xxx

A PubMed literature search using the keywords driving and anxiety and the results' cross-references identified 14 placebo-controlled, double-blind studies that examined the furnishings of anxiolytic drugs on driving ability by conducting on-the-road driving tests during normal traffic. One review concluded that subsequently unmarried-dose administration of BZDs and related compounds, driving performance was significantly impaired.³¹ Furthermore, driving studies showed that the impairing effects of BZDs and related compounds may even so exist nowadays afterwards one week of daily handling (demonstrated for diazepam, lorazepam, alpidem, and suriclone), although tolerance may develop. Not surprisingly, the review recommended that patients using BZDs practice caution when operating a motor vehicle.³¹

Delirium

Another agin effect of BZDs, ordinarily seen in the intensive care setting, is delirium, an acute status characterized by dumb attention and noesis. BZDs increase the risk of delirium, especially in elderly patients in the intensive intendance unit.³² Studies have demonstrated an astonishing 78%-87% incidence rate of delirium in elderly patients in the ICU.^33-37 Delirium is a serious problem and tin can lead to increased morbidity, increased mortality, and longer infirmary stays.³³ Morbidity and mortality increment because the risk of nosocomial infections increases the longer the patient stays in the hospital. Another study has demonstrated that BZDs given prior to intensive intendance admission were associated with delirium within the get-go 48 hours of access.³⁸ Clinicians must be mindful of the risks of delirium when administering BZDs to hospitalized patients.³²

CONCLUSION

BZDs are commonly prescribed for a wide range of weather condition, including use as sleep aides, muscle relaxants, and anxiolytics. However, dose-related side effects tin be seen, including amnesia and central respiratory low. Other drugs—including opioids, alcohol, and over-the-counter sleep aids—can accept additive or synergistic effects on the central nervous arrangement and respiratory function. Sure subpopulations of patients tin can take pregnant and severe BZD-mediated furnishings. The prudent clinician should weigh the risks and benefits of these agents earlier prescribing.

Footnotes

The authors take no fiscal or proprietary interest in the subject matter of this article.

This commodity meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/

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