TOXICITY OF NEW GENERATION PHARMACEUTICAL AGENTS

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TOXICITY OF NEW GENERATION PHARMACEUTICAL AGENTS

• Frank Paloucek PharmD
• Paloucek_at_uic.edu

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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

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Toxic Exposure Surveillance System (TESS from the
AAPCC)

• Annually published since 1984.
• 2000 data - Am J Emerg Med 2001 19337-395. (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

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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.

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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.

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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.

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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

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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

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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

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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

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Antidepressants

• Once responsible for gt90 of deaths, TCAs now
  represent 60, case volume is declining.
• SSRIs and SRIs account for remainder nearly
  equally.
• In contrast, European data suggests marked
  decreases in suicide deaths with SSRIs (coroner
  identification) as compared to TCAs

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Antidepressants

• TESS data includes adverse reactions (serotonin
  syndrome)
• In recent years gt80 of SSRI and SRI deaths were
  multidrug ingestions.
• Scandinavian studies did not look at any SRIs
  and compared solely to TCAs
• English studies didnt distinguish between Ssris
  and SRIs
• Austrian study only found SSRI at autopsy in
  multidrug suicides

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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

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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

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SRI Antidepressants

• SSRIS
• Paroxetine
• Fluoxetine
• Citalopram
• Fluvoxamine
• Sertraline

• SRIs
• Bupropion
• Venlafaxine
• Nefazodone
• Mirtazapine

Red face type represents CYP 3A4 metabolsim
effects. indicates 2D6 effects. Both affect
TCAs
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Atypical Antipsychotics

• Prior to 1998 data atypicals not listed in TESS
  data separate from older phenothiazines.
  1983-1997 data averaged lt 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)

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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)

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Atypical Antipsychotics

• Ziprasoidone (Geodon)
• Approved 2001
• Mechanism of action uncertain. Has activity
  against dopamine, serotonin, norepinephrine,
  cholinergic and histamine receptors
• Prolongs QT (gt500 msec) in 0.06 of patients
  (worse than other atypicals but less than
  thioridazine)
• Metabolized and affects CYP 3A4

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Calcium Channel Blockers

• Represent gt60 cardiovascular deaths past five
  years. (several 1 will kill kids cases)
• 5-10 NDAs 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

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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

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Calcium Channel Blockers

• Cardiovascular agents fatality rate rose 200
  since 1983 - due predominantly to CCBs. In that
  same interval, no ACE inhibitor, ARBs,
  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

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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)

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VALPROIC ACID

• Incidence of deaths annually prior to 1997 was lt
  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

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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

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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

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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

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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

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• Paloucek_at_uic.edu