Benzodiazepines in elderly

Benzodiazepines in Elderly

Dr Ravi SoniSenior Resident

Dept. of Geriatric Mental HealthKGMU, LKO

Objectives

• Prevalence of benzodiazepine use• Indications for taking benzodiazepines• Changes in pharmacokinetics and pharmacodynamics in

elderly• Types of utilizations• Adverse effects of BZDs in elderly• Abuse and dependence• Withdrawl and treatment

Introduction

• Benzodiazepines (BZDs) are most commonly prescribed medications for anxiety and insomnia in elderly

• Anxiety and insomnia are mostly chronic conditions in elderly with associated psychiatric comorbidity

• Many times the BZDs are misused

Prevalence of BZDs use

• Utilization of these medications in elderly accounts for 20 to 35% of the whole prescription treatment

• Whereas the elderly persons represent only 12 to 16% of total population

• Epidemiological studies show that about 25% of over 65 years old patients living in old age homes, are treated with BZDs.

• Studies in France with cohort of 2792 community dwelling subjects of 65 years and more, have shown that prevalence rate of BZDs use was 31.9% at baseline

Fourrier A, Letenneur L, Dartigues JF et al. (2001). Benzodiazepine use in an elderly community-dwelling population. Characteristics of users and factors associated with subsequent use. Eur. J. Clin. Pharmacol., 57: 419-425.

Continued…

• Use of hypnotics was more prevalent among women than men and increased significantly with age

• In general, the rate of use of BZDs is about 15 to 20% among persons aged 65 to 74 years and >25% in those aged ≥75 years

• Durations of use were from one to five years in 13 percent of the sample, from five to ten years in 19 percent, and for more than ten years in 25 percent

Morgan K, Dallosso H, Ebrahim S, et al: Prevalence, frequency, and duration of hypnotic drug use among the elderly living at home. British Medical Journal Clinical Research Ed 296:601–602, 1988

Continued…

• Benzodiazepines are even more frequently prescribed for elderly patients who are institutionalized

• Data from the united states indicated that all of the psychotropic drug prescriptions for patients of 65 years and older, 41% were antianxiety drugs, mainly BZDs

• Another study of psychotropic drug prescription in nursing homes showed that 32 percent of prescriptions were anxiolytics

Beardsley RS, Larson DB, Burns BJ, et al: Prescribing of psychotropics in elderly nursing home patients. Journal of the American Geriatrics Society 37:327–330, 1989

Holmquist IB, Svensson B, Hoglund P: Psychotropic drugs in nursing and old age homes: relationships between needs of care and mental health status. European Journal of Clinical Pharmacology 59:669–676, 2003

Indications for taking BZDs

Most common Indications:• Generalized anxiety disorder [any kind of Anxiety]• Chronic Insomnia• Adjustment problem

• Apart from this BZDs are also prescribed for multiple concomitant physical and psychological problems

Benzodiazepine pharmacology in the aged patients

• Elderly have weak therapeutic index for Bzds• Therapeutic index: interval of doses between sedative and

anxiolytic properties of Bzds• This interval is decreased in aged population

• SEDATION TRAP: over dosage that renders aged subjects more susceptible to tiredness, prevents them from being active and so decreases their socialization faculties

• Pharmacokinetics and pharmacodynamics both are changed due to aging

Greenblatt D, Harmatz J and Shader R (1991). Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part II). Clin. Pharmacokinet., 21: 262-273.

Absorption Age related changes affecting absorption:• Decreased gastric acid secretion• Decreased surface of intestinal epithelium

– Decreased absorptive surface area

• Decreased carrier-mediated transport mechanisms• Decreased intestinal motility

– Increased transit time

• Decreased mesenteric blood flow• Reduced tissue blood perfusion

– Dermal, subcutaneous, and muscular tissue

Slowing of the gastro-intestinal absorption of BZDs is only slightly modified in the aged and it is not troublesome in the utilization of Bzds

Distribution Age related changes affecting distribution: Decreased muscle mass Increased total body fat

– 18 to 36% in men– 33 to 45% in women

Decreased total body water– Falls by 10-15% until age 80

Blood-brain barrier (BBB)– Decreased integrity with age

Decreased albumin, increased α1acid glycoprotein

Increased volume of distribution of lipophilic drugsGreater half-lifeLonger interval to reach steady-state levelsLonger to evaluate drug effectE.g. diazepam

Metabolic Pathways for BZDsPathway Effect Examples

Phase I: oxidation, hydroxylation, dealkylation, reduction

Conversion to metabolites of lesser, equal, or greater activity

diazepam, chlordiazopexide, clobazam

Phase II: glucuronidation, conjugation, or acetylation

Conversion to inactive metabolites

lorazepam, oxazepam, temazepam

** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)

Concepts in Drug Elimination

• Half-life– time for serum concentration of drug to decline by

50% (expressed in hours)• Clearance– volume of serum from which the drug is removed

per unit of time (mL/min or L/hr)• Reduced elimination drug accumulation and

toxicity

Effects of Aging on the Kidney

• Decreased kidney size• Decreased renal blood flow• Decreased number of functional nephrons• Decreased tubular secretion• Result: glomerular filtration rate (GFR)

Volume of distribution increase and total clearance (Clt = Cl hepatic + Cl renal) decrease results in a half-life increase.Theoretically, half-life increase is corrected by:- decrease dosage- reduce frequency of dosing

Drug Interactions• Drug interactions are rare with BZDs with the exception of the association

of two BZDs which compete with each other to bind cerebral sites

• BZDs metabolized by oxidation are suggested to effect the drugs managed by cytochrome P 450, particularly the isoenzymes CYP 3A and CYP 2C19

• Drugs inhibiting actions of metabolites of these isoenzymes can decrease the rate of clearance of these BZDs and so increase their half-life and therefore their plasma concentration

• Cautious use of BZDs with fluoxetine, ketoconazole, itraconzole, azithromycin, erythromycin and clarithromycin

• The BZDs metabolized by conjugation are not affected by drug-drug interactions

Pharmacodynamics changes• The increased sensitivity of older people to benzodiazepines is due to age-

related alterations in the central nervous system receptors

• benzodiazepine receptors in the brain become more sensitive, causing increased – sedation– Unsteadiness– Memory loss– Disinhibition

• Psychomotor studies among elderly patients using benzodiazepines indicate that this patient group, especially those with dementia, hypoalbuminemia, or chronic renal failure, have a greater risk of sedation.

Utilization patterns of BZDs Categorization of the utilization BZDs has been proposed as

– Acute– Intermittent– Continuous

1. Acute Utilization: usually of about 7 days or less duration and consist generally of only one dose.

• Examples include – Acute treatments in emergency services for a psychotic agitation, – Pre-operative utilization or if amnesia is wished, – Treatment of the insomniac in the hospital and – Treatment of alcoholic withdrawal.

ERIC DAILLY AND MICHEL BOURIN, THE USE OF BENZODIAZEPINES IN THE AGED PATIENT: CLINICAL AND PHARMACOLOGICAL CONSIDERATIONS. Pak. J. Pharm. Sci., Vol.21, no.2, april 2008, pp.144-150

Continued….

2. Intermittent Utilization: When the BZDs is taken sporadically, generally two or three times per week and for periods not exceeding 60 to 90 days

• Long term with intermittent utilization in the measure where the treatment lasts 4 months and more

• The treatment of insomnia and anxiety disorders with BZDs is very frequent in the aged subject with an intermittent utilization of these products

• Aged subjects are using some relatively weak doses and discover a beneficial effect on morning activity


Continued….

3. Continuous utilization: defined by the fact that the subject is going to use the medicine every day

• going to take anxiolytics in a chronic manner

• For, anxiety disorder and insomnia

• The aged subjects and prescribers continue to take these products in a chronic manner in spite of recommendations of a short-term utilization

• Compared to subjects not using BZDs, continuous users are most often older and most often women, who often take this type of medicine after suffering a bereavement

• whatever the nature of chronic illnesses [cardiovascular or rheumatic diseases etc] their treatment is accompanied with a prescription of BZDs.


Continued….

• 85% of continuous users do not have any support or professional mental health help

• Tolerance to diazepam or other BZDs doesn't develop itself until after 22 weeks of treatment

• Only one efficiency survey was done to evaluate the continuous utilization of BZDs for chronic insomnia

• Survey compared behavior therapy vs BZDs vs placebo

• Behavior therapy was more useful, patients are more satisfied and effects are long lasting as compared Drugs


Adverse effects of BZDs in elderly

• Investigation of drug-associated hospital admissions among older patients has shown that up to 10 percent may be due to benzodiazepines (Grynpore et al,. 1988)

• Adverse drug reactions are more common in the old patients, who use BZDs for prolonged duration

• Impaired cognitive function appears to be major side effects of BZDs (Pomara et al., 1998)

• Cognitive impairment is characterized by – anterograde amnesia, – diminished short-term recall – increased forgetfulness (Gray et al.,1999)

• Cognitive impairment seems to develop insidiously as a late complication of benzodiazepine use.

• Long-acting benzodiazepines are most commonly associated with cognitive impairment.

Adverse effects of BZDs in elderly

• Benzodiazepines may contribute to psychomotor impairment and increase the risk of falls and automobile accidents (Cumming et al.,2003)

• Psychomotor impairment is characterized by – slowed reaction time and – diminished speed and accuracy of motor tasks

• Several studies showed evidence for increased risk of hip fracture [50% increase risk] and recurrent falls among elderly patients taking benzodiazepines

• The risk of falls has been associated with sudden increases in dosage and with continuous use of benzodiazepines (Cumming et al.,2003)

• BZDs with shorter half-lives appear to be no safer than longer half-life agents (Pierfitte et al.,2001)

BZDs and Suicide in the elderly

• BZDs, especially the hypnotics flunitrazepam and nitrazepam are common in drug poisoning suicides in the elderly in Sweden (Carlsten et al., 2003)

• Similarly, BZDs appear to be among the drugs most commonly used in overdose in England and Wales (Shah et al., 2002)

• BZDs should be prescribed with caution in elderly because higher chances for abuse and dependence

• Most of the old patients who live alone, having empty-nest syndrome, are more prone to take overdose of BZDs to deal with their anxiety and insomnia..they often feel that they should end their life and take 10 to 15 BZDs pills.

BZD Abuse and Dependence

• Elderly people frequently use BZDs for prolonged period of time

• Chronic pain, depression and isolation are common problems among elderly persons that can predispose them to BZDs use and dependence

• The risk of dependence among elderly persons increases with age

• Dependence is more common patients with medical conditions that require multiple medications and among patients who have depression and alcohol dependence (Fenandez et al.,2001)

• The prevalence of BZDs dependence in geriatric outpatient population was found to be 11.4% in one study (Holroyd et al.,1997)

Continued….

• In a retrospective study, 21 percent of patients aged 65 years or older who were admitted to a psychiatric unit had a diagnosis of substance dependence.

• A majority of substance-dependent patients had a diagnosis of benzodiazepine dependence

• The study also showed that women appear to be at greater risk of misdiagnosis and undertreatment: benzodiazepine dependence went unrecognized among 75 percent of the women

• It is very important to detect substance dependence in elderly because, unrecognized substance dependence may lead to inappropriate and inefficient treatment

Whitcup SM, Miller F: Unrecognized drug dependence in psychiatrically hospitalized elderly patients. Journal of the American Geriatrics Society 35:297–301, 1987

Who develops Dependence?

• Even with long term use mot everyone develops dependency

• More likely when (Kan et al.,2004)» Longer durations of treatment» Higher doses»More potent benzodiazepines» Shorter-acting drugs» A history of anxiety problems

Withdrawl from BZDs • Benzodiazepine dependence is characterized by a predictable discontinuation

syndrome

• Withdrawal is likely to occur after abrupt cessation of benzodiazepines or a significant sudden decrease in the absolute dosage among dependent patients

• Withdrawl symptoms: – agitation, anxiety, dysphoria, – Increased awareness of sensory stimuli, – Perceptual disturbances, depersonalization,– Confusion, delirium, and seizures

• appreciable increase of arterial pressure and a myocardial ischemia may occur as a result of abrupt cessation

• Symptoms of withdrawal among elderly patients may be different from those in younger patients

Continued…

• It was observed that post withdrawal psychotic reactions seem more notable in the aged than the young patient

• Prospective study was done for BZDs use and withdrawl in elderly medical inpatients

• Which has shown confusion and disorientation with or without hallucinations were predominant symptoms of withdrawal after benzodiazepines were stopped abruptly

• The elderly patients in that study did not develop other withdrawal symptoms, such as anxiety, insomnia, and perceptual changes (foy et al.2005)

Continued…

• Gradual tapering of the BZDs is effective in reducing the severity of the withdrawl symptoms similar to young patients

• Comparison was done between the severity of withdrawl symptoms and clinical outcomes in elderly and young patients

– Elderly patients showed significantly less severe withdrawl symptoms during a gradual taper and did as well in terms of outcomes as compared to their younger counterparts

• Reason given behind this: – slower clearance of the medication– Diminished neuronal capacity among elderly persons causes less

rebound over-activitySchweizer E, Case WG, Rickels K: Benzodiazepine dependence and withdrawal in elderly patients. American

Journal of Psychiatry. 146:1242–1243, 1989

Continued…

• Risks of withdrawal are increased particularly with – abrupt cessation of BZDs having a short half-life and presenting a rapid

reduction of plasma concentrations – elevated doses, elevated daily dosage and the long-term utilisation

• At the time of their cessation, BZDs having a – short or intermediate half-life, can generate symptoms of withdrawal which

appear between 24 and 36 hrs– long half-life can induce withdrawal symptoms after practically one week

• previous consumption of alcohol and a low level of education can facilitate a notable withdrawal syndrome

Treatment• No studies have been done regarding treatment of BZDs dependence in the

elderly

• Different studies tried to define designs to withdraw BZDs in elderly subjects

• Baillargeon et al presented a method based on a combination of cognitive-behavioral therapy and BZDs tapering (Baillargeon et al,. 2003)– Concluded that this combination was superior to gradual tapering alone in the

management of patients with insomnia and chronic BZDs use

• Petrovic et al proposed an initial replacement therapy with low-dose BZDs (lormetazepam 1 mg) (Petrovic et al,. 2002)

• Depending upon the above research the combination of cognitive behavior therapy, family therapy, involvement into support group with initial replacement with low dose BZDs [short acting], would be the best strategy

BZDs in Elderly: What should we do?

• Benzodiazepines should be prescribed with – caution– at low doses – for short periods

• Short half life BZDs like oxazepam, triazolam, alprazolam can be prescribed because– These agents do not accumulate in the blood, – Are rapidly cleared from circulation, and– Offer greater dosage flexibility

• But they are associated with risk of withdrawl symptoms and have higher abuse potential

Continued….

• Another strategy is to use BZD with a short half-life that are not oxidised, i.e. essentially BZD that are metabolized by conjugation, such as lorazepam or temazepam

DOs about BZDs in Elderly: – Daily dose should be limited– Duration of use should not exceed more than 2 months– Start with low dose– Titrate dosage gradually and individually– Monitor BZDs use in each follow up– Identify the possibility of Abuse and dependence– Gradually taper in dependent patient to avoid withdrawl symptoms– Consider patient’s comorbid medical conditions– Adjust dosage for renal and hepatic impairment

DONTs about BZDs in Elderly

• Avoid higher dosage from the beginning• Avoid BZDs for conditions not indicated• Avoid BZDs together with psychotropic drugs having sedative

properties• Avoid long acting BZDs• Avoid prescribing for longer duration without indication• Avoid drugs having interactions with BZDs [metabolism]• Avoid BZDs having high abuse potential• Avoid abrupt cessation of BZD continued for long duration

ANXYOLITICS

AlprazolamChlordiazepoxide

DiazepamLorazepamOxazepamTriazolam

HalazepamPrazepam

HYPNOTICS

Chloral hydrateEstazolam

FlurazepamLorazepamQuazepamTriazolam

TemazepamZolpidem

C.S.M. Medical University UP, Lucknow INDIA

Health & Medicine

Benzodiazepines in elderly