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Poisoning in the elderly
Pr Vincent Danel
Toxicologie clinique & Toxicovigilance
Grenoble, France
XXVI International Congress of the European Association
of Poisons Centres and Clinical Toxicologists
19-22 April 2006, Prague, Czech Republic
Why talk about elderly people?
People are aging in most countries
Over 70: 12% - 15%, and 20% very soon
Elderly people in emergency wards and ICU 
Poisoning is common in elderly people
 Adverse effects vs acute poisoning
 Intentional vs. unintentional
 Pharmaceuticals vs. non pharmaceuticals
Poisoning in elderly people is often severe
Who are they ? > 60? > 65? > 70?
Age-related changes in physiological
and pharmacological parameters
A high prevalence of chronic medical disorders
Frequent polypharmacy (a third of all prescriptions)
 Medication errors
 Adverse effects
 Drug interactions
• There is no clear definition of elderly people
• Differences between individuals are obvious
• Many confounding factors
TESS - Exposures and fatalities (age > 60)
%
18
16
14
12
10
8
6
4
2
0
Exposures
Fatalities
2002
2003
2004
TESS - Exposures and fatalities (age > 70)
%
10
8
6
Exposures
Fatalities
4
2
0
2002
2003
2004
Exposures and fatalities – TESS 2004 (60 - 99)
60-69
70-79
Exposures
Fatalities
80-89
90-99
0
1
2
3
4
5
6
%
Exposures and fatalities (French data – 8 years)
Paris and Nancy 1999-2004
over 60
Exposures
Fatalities
over 65
0
5
10
15
20
%
Strasbourg 1999-2004
Exposures
Fatalities
over 70
0
5
10
15
20
25
30
%
Death rates – TESS 2004
%
Death rates
0,15
0,1
0,05
0
Less
Over
70 years
n
60 years
Deaths (over 65)
60
40
20
0
Non Pharm.
Pharm.
Intentional
Unintentional
Poisoning in the elderly – is it more severe?
Lack of recognition of xenobiotic toxicity
Delayed and/or atypical presentation
Toxicologic aetiology overlooked
Pharmacokinetic and pharmacological changes
Polymedication and underlying diseases
Drugs most commonly responsible
Analgesics
 Paracetamol
 Opioids
 Salicylates and other NSAIDs
Cardiovascular medications
 Beta-adrenergic antagonists
 Calcium channel blockers
 Digoxin
Sedative- hypnotics
Antidepressants
Antipsychotics
Anticoagulants
Anticholinergic drugs
Theophylline
Commonly
prescribed
in elderly people
Clinical presentation
Poisoning often chronic or subacute, subtle, atypical
Neurobehavioural dysfunction is common – ‘delirium’
Commonly occuring, or life-threatening:
 Cardiac dysrhythmia and conduction disturbances
 Postural hypotension
 Respiratory failure
 Pulmonary oedema
 Gastrointestinal dysmotility
 Urinary retention
 Hypoglycaemia
 Bleeding diathesis
Neurobehavioural dysfunction
Antiarrhythmic drugs: digoxin, lidocaine, procainamide
Anticonvulsants: phenytoin, carbamazepine, valproic acid
Antidepressants: amitriptyline, fluoxetine
Antiemetics: promethazine, metoclopramide
Antihypertensives: clonidine, propranolol, verapamil
Antimicrobials: penicillin, ciprofloxacin, isoniazid
Antiparkinsonian: levodopa, amantadine
Antipsychotics: thioridazine
Bronchodilators: theophylline
Antineoplastics: methotrexate, vincristine, procarbazine, cytarabine
Histamine receptor antagonists: diphenhydramine, cimetidine
Immunosuppressants: corticosteroids, cyclosporin
Mood stabilizers: lithium
Muscle relaxants: carisoprodol, cyclobenzaprine, orphenadrin
Nonsteroidal anti-inflammatory drugs: salicylate, mefenamic acid
Opioid analgesics: meperidine, normeperidine
Sedative-hypnotics: diazepam, phenobarbital, meprobamate
Gastro-intestinal absorption
Gastric acid
secretion
Reduced
Gastric emptying
Delayed
Gastrointestinal
blood flow
Decreased
Mucosal absorption
surface area
Reduced
Reduced absorption
Reduced rate of
absorption
Contribution to xenobiotic toxicity mostly unknown …
Gastric mucosa changes  enzymatic changes? ADH?
Distribution (1)
Body fat (15  30%)
Increased
Increased Vd
(lipophilic agents)
Reduced
Reduced Vd
(hydrophilic agents)
Skeletal muscle mass (17  12%)
Body water (42  30%)
Higher initial
plasma level
more rapid
and
pronounced
peak effect
Hydrophilic
agents
Lipophylic
agents
digoxin
benzodiazepines
ethanol
amiodarone
lithium
calcium channel
theophylline
…..
 peak effect
and toxicity delay
 prolonged halflife
salicylates
Flunitrazepam 20-30 h  85 h
Chlorazepate 40 h  4–5 days
Distribution (2)
Reduced
Albumin
. Acute or chronic illness
. Protein intake
-acidglycoprotein
Increased (illness)
. diazepam
. digoxin
. phenytoin
. salicylates
. theophylline
Increased free
fraction
Larger Vd
Reduced free
fraction
Smaller Vd
. propranolol
. lidocaine
Metabolism
Hepatic mass
Blood flow
Phase I enzyme
activity (oxidations)
Phase II enzyme
activity (conjugation)
Reduced
Not clear …
No change in vitro
Conflicting data in vivo
 Hepatic extraction
Reduced clearance
Reduced clearance
Unchanged
Prediction is difficult:
• Age-independent genetic variability (cytochromes isoenzymes …)
• Enzymes induction or inhibition by xenobiotics, effect of age?
• Comorbidities, coadministered drugs ?
Hepatic function
High hepatic extraction
Oxidation
Imipramine
Chlordiazepoxide
Labetalol
Diazepam
Lidocaine
Meperidine
Metoprolol
Morphine
Reduced
hepatic
blood
flow
Quinidine
Theophylline
Thioridazine
Triazolam
Nifedipine
Nortriptyline
Propoxyphene
Propranolol
Verapamil
Bioaccumulation
Reduced
oxidative
processes
Renal elimination
Glomerular
filtration rate
(GFR)
Reduced
Not accurately
predicted by serum
creatinine level
Tubular secretion
rate
Reduced
Renal mass and
functioning
nephrons
Reduced
elimination rate
• Age-related decline in GFR is not universal
• GFR is not reduced in one-third of the elderly
• Overestimation of creatinine clearance (formulas)
Renal elimination of xenobiotics in the elderly ?
Better to assume that …
Diminished renal function
Antimicrobial agents
Benzodiazepines with active metabolites
Digoxin
Lithium
Meperidine
Metformin
Procainamide
Salicylates
Sulfonylureas and their active metabolites
Pharmacodynamic factors
Changes in receptor tissue density
Reduced capacity for compensatory response
Blunted homeostatic control mechanisms
Altered sensitivity to the effects of various agents
 Cognitive dysfunction (sedative agents)
 Respiratory depression (opioids analgesics, benzodiazepines, …)
 Dysrhythmia or conduction disturbance
(digoxin, calcium channel blockers)
 Hypoglycemia (ethanol)
Altered
 …
pharmacokinetics?
Preexisting or comorbid medical conditions
In summary, in the elderly
Altered drug/toxin distribution
(fat and water solubility, protein binding)
Reduced hepatic clearance of perfusion-dependent
and phase I enzyme metabolized substances
Reduced clearance of xenobiotics predominantly
cleared by the kidney
Increased sensitivity to target organ/tissue effects
Reduced ability to compensate for toxic effects
Do all these pharmacokinetic
and pharmacological changes
clearly modify the course of
poisoning in the elderly?
Benzodiazepine overdoses
Profound state of coma
Significant respiratory depression
Pronounced myorelaxant effect
Long delay before recovery
Flumazenil
 High doses needed
 for a longer period of time
Changes in body distribution
 Larger volume of distribution
 Delayed elimination
Decrease in oxidative metabolic processes
Increased neurological
and respiratory sensitivity
Management
Medication history
 Medication errors, adverse effects, drugs interactions
 Discontinuation of potentially dangerous medications
Toxicological analysis (drug level – toxicity correlation?)
Routine laboratory analysis
(sodium, potassium, renal function, …)
ECG, chest radiograph
No specific test!
Management : caution
Supportive therapy : more cautious
 Greater need for ventilatory support
 Caution in fluid volume resuscitation
 Nursing, body warming, phlebitis prevention, …
Gastrointestinal decontamination
 Multiple-dose activated charcoal  constipation
Antidotes
 Antidigoxin antibodies  cardiac failure, atrial fibrillation
 Flumazenil  withdrawal syndrome
Haemodialysis? earlier? lithium, salicylates
Drug withdrawal symptoms
 Chronic use of benzodiazepines or opioids