2. 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
3. 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
4. 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.
5. 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
6. 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
7. 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
8. 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.
9. 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
10. 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 drugs
Greater half-life
Longer interval to reach steady-state levels
Longer to evaluate drug effect
E.g. diazepam
11. Metabolic Pathways for BZDs
Pathway 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)
12. 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
13. 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
14.
15. 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
16. 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.
17. 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
18. 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
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
19. 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.
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
20. 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
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
21. 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.
22. 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)
23. 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.
24. 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)
25. 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
26. 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
27. 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
28. 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)
29. 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-activity
Schweizer E, Case WG, Rickels K: Benzodiazepine dependence and withdrawal in elderly patients. American
Journal of Psychiatry. 146:1242–1243, 1989
30. 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
31. 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
32. 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
33. 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
34. 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
