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Definitions of New
New drugs introduced in past 5 years
New causes of death or morbidity as reported in the TESS data
New abuses by the new generation of drug abusers
New considerations/knowledge into drug-drug interactions
Toxic Exposure Surveillance System (TESS from the AAPCC)
Annually published since 1984. 2000 data - Am J Emerg Med 2001
19:337-395. (2001 any day now)
Summarizes all poisonings reported to certified Poison Control Centers (currently 63 centers)
Last 5 years – averages 2 million exposures reported. Total data base is 29.2 million exposures
Toxic Exposure Surveillance System
Some text, 20-25 Tables, and a very interesting and must read appendix.
Tables include detailed analysis of all calls by many categories and several analyses of fatalities alone.
Data analysis can be requested for all or specific years on any of the required TESS form information items by AAPCC members.
Toxic Exposure Surveillance System
Selection bias - not mandatory to call a PCC, 60-70% toxic exposure ED visits and 60-70% coroner toxic death findings never reported.
Minimal requirements on confirmation, data represents information received over telephone, not direct observation and few exposures confirmed by toxin specific lab data
Abstract keywords do not include specific agents/classes - not Medline searchable.
Toxic Exposure Surveillance System
Meds typically account for 40% of exposures and 85% of fatalities.
Most cases inadvertent in kids, most RX deaths in geriatric patients. (Note nearly all adolescent abuse fatalities due to inhalations.)
10-12% of deaths due to therapeutic error, misuse or adverse reaction.
Classes analyzed include herbal/homeopathic, vitamins, ophthalmic, otic etc.
Changes in Deaths
Since 1983, analgesics and antidepressants have ranked 1st and 2nd in absolute number of deaths reported to Poison Control Centers.
In the first 16 available reports (through 1998); sedative/ hypnotics, cardiovasculars and asthma therapies were the next 3 most common drug causes although the first 2 did alternate rank several times.
In 1999, anticonvulsants (predominantly through valproic acid) entered the top five (in fact top 10 of drugs
Changes in Deaths
Prior to 1994, antidepressants barely ranked 1st , since 1997 analgesics have ranked 1st and have doubled the number of deaths. Drug interactions account for a significant # of antidepressants cases
Cardiovasculars have become predominantly SR calcium channel blockers and asthma therapies (Theophylline SR) dropped out of the top 10 in 1999. Dig #1 in therapeutic errors.
Starting with clozapine, new antipsychotics have supplemented old “sleepers” in helping to maintain the ranking of sedative hypnotics and represent 33% of deaths
Common factors?
Sustained-release formulations (can add long elimination half-life or active metabolites
Agents with cardiac and vasculature or CNS effects.
Oxidative metabolism, especially through CYP3A4
Large volume prescribing Elderly and or psychiatric patients QT prolongation Absent laboratory tests or antidotal therapy
Analgesics
New deaths – APAP deaths have essentially doubled over the last decade, both sole agent and combination products have increased
Aspirin remains constant Fentanyl patches and long-acting
oxycodone (Oxycontin) have increased significantly past three years – new abuse habits. Fentanyl either multiple patches or patch content sremoved and injected.
Oxycontin #1 prescribed drug in 2001
Antidepressants
Once responsible for >90% of deaths, TCA’s now represent ~60%, case volume is declining.
SSRI’s and SRI’s account for remainder nearly equally.
In contrast, European data suggests marked decreases in suicide deaths with SSRI’s (coroner identification) as compared to TCA’s
Antidepressants
TESS data includes adverse reactions (serotonin syndrome)
In recent years >80% of SSRI and SRI deaths were multidrug ingestions.
Scandinavian studies did not look at any SRI’s and compared solely to TCA’s
English studies didn’t distinguish between Ssri’s and SRI’s
Austrian study only found SSRI at autopsy in multidrug suicides
SSRI Antidepressants
Commonly present as sedation in a patient with “psych history”. Seizures may occur.
QRS widening is commonly suggested to separate TCA from pure SSRI ingestion. Not infallible – has been seen with citalopram
Differential includes too many agents to list NO common and readily available lab test No specific antidote (though for SSRI unlikely
one is needed
SRI Antidepressants
Also called SNRI Seizures clearly more likely,
especially with bupropion (most fatalities, especially with SR product)
QRS widening and dysrhythmias seem more common
SRI Antidepressants
SSRI’S
Paroxetine* Fluoxetine* Citalopram Fluvoxamine Sertraline
SRI’s
Bupropion Venlafaxine Nefazodone Mirtazapine
Red face type represents CYP 3A4 metabolsim effects. * indicates 2D6 effects. Both affect TCA’s
Atypical Antipsychotics
Prior to 1998 data atypicals not listed in TESS data separate from older phenothiazines. 1983-1997 data averaged < 10 deaths due to phenothiazines annually, most mixed ingestions.
Since then death to antipsycotics increased 100-150%, all due to atypical antipsychotics.
All have been multidrug ingestions and most have been suicides
Rare, agranulocytosis with clozapine (includes one “1 will kill kid”)
Atypical Antipsychotics
Clozapine, Risperidone, Olanzapine, Quetiapine
Also, potent 5HT2 antagonists Present with sedation in acute ingestion.
Chronic presentation is NMS vs Serotonin syndrome
Differential toxin diagnosis long. No specific lab test, usually rely on urine
drug screen (if available)
Atypical Antipsychotics
Ziprasoidone (Geodon) Approved 2001 Mechanism of action uncertain. Has
activity against dopamine, serotonin, norepinephrine, cholinergic and histamine receptors
Prolongs QT (>500 msec) in 0.06% of patients (worse than other atypicals but less than thioridazine)
Metabolized and affects CYP 3A4
Calcium Channel Blockers
Represent >60% cardiovascular deaths past five years. (several “1 will kill kids” cases)
5-10 NDA’s expected next 18 months. Common presentation: altered mental
status, hypotension, bradycardia. No common readily available lab test. Differential includes beta blockers, digoxin, clonidine, Type IA and IC antiarrhythmics.
Conventional, well published antidotal therapy absent. Recent promise with hyperinsulinemia
Calcium Channel Blockers
Specifically: amlodipine, diltiazem, nifedipine and verapamil.
The 10-100 times more active for peripheral vasculature agnets; Nicardipine, Isradipine, Felodipine, and Nisoldipine essentially nonexistent fatalities.
Beware SR, long acting, or cardiac and vasculature effects. Hope for “purely vascular” activity
Calcium Channel Blockers
Cardiovascular agents fatality rate rose 200% since 1983 - due predominantly to CCBs. In that same interval, no ACE inhibitor, ARB’s, diuretics, or peripheral alpha1 blockers deaths were reported.
Following a suicide attempt, serious consideration should be given to warning against continued access to CCBs, or is reasonable using the more peripheral vasculature selective agents, shorter acting agents and or immediate release dosage forms
Anticonvulsants
Several new agents on market Gabapentin (Neurontin) Topiramate (Topamax) Lamotrigine (Lamictal) Levetiracetam (Keppra)
All seem relatively benign from acute toxicity. Lamotrigine associated with Anticonvulsant
Hypersensitivity syndrome (especially with VPA)
VALPROIC ACID
Incidence of deaths annually prior to 1997 was < 5.
Currently averaging 10 per annum. Commonly presents with CNS depression
and GI symptoms. Marked inhibitor of CYP metabolism,
epoxide hydrolase and other hepatocellular free radical scavenging systems
Enjoying widespread use in multiple psychiatric diagnoses and now in SR form
VALPROIC ACID
Presents with sedation and GI symptoms. May have miosis
Diagnosis made with serum concentration. Caution in interpretation, as concentrations rise, protein binding saturates and toxicity at target organs increases disproportionately.
This does effective role for procedures like HD for removing drug in acute overdose
Rare and not dose-related pancreatitis and or hepatoxicity occurs
ODDS AND ENDS
Ultracet – Combination tramadol and acetaminophen – great
Aricept (rivastigmine) sells for $4 per tablet on street in East Coast metropolitan cities - ????
Metformin – not that new but still a problem
Conclusions Casual rules of thumb for a new
pharmaceutical agent Bad – SR, multiple types of and sites for
receptors affected Really need to learn CYP metabolism, all of
it. Especially since they are studying the enzymes for the resultant metabolites
Also need to learn p-Glycoprotein (and other drug carrier transport proteins) especially as relates to CYP 3A4 drug interactions
Conclusions Speaking of Bad and SR
New SR products approved this year: Ritalin LA Paxil CR Avinza (Morphine once daily capsule)
Approved 2001 Prozac weekly, Adderall XR, Metadate CD
2000 Depakote ER
