Drugs of Abuse

1
Drugs of Abuse

• Imran Shariff
• And
• Dr. Rachel Haroz
• Assistant Professor of Emergency Medicine
• 2/8/10

2
Drug Dependence 3 or more in a 12 mo period

• Tolerance
• either need for markedly increased amounts of the
  opioid used to achieve intoxication, or
• markedly diminished effect with continued use of
  the same amount of the substance
• Opioid withdrawal
• (a) three (or more) of the following, developing
  within minutes to several days after cessation or
  reduction of opioid use, or administration of an
  opioid antagonist
• dysphoric mood, nausea or vomiting, muscle aches,
  lacrimation or rhinorrhea, pupillary dilation,
  piloerection, or sweating, diarrhea, yawning,
  fever, insomnia
• (b) the symptoms above cause clinically
  significant distress or impairment

3
Drug Dependence 3 or more in a 12 mo period

• Need larger amounts or over a longer period than
  was intended
• Persistent desire or unsuccessful efforts to cut
  down or control opioid use
• Great deal of time spent in obtaining opioids,
  using opioids, or recovering from their effects
• Important social, occupational, or recreational
  activities given up or reduced because of opioid
  use
• Continued use despite knowledge of having a
  persistent or recurrent physical or psychological
  problem that is likely to have been worsened by
  opioids

4
Opioid Abuse

• Clinically significant impairment or distress,
  characterized by one (or more) of the following,
  occuring within a 12-month period
• Failure to meet major vocational, academic or
  parental obligations
• Recurrent consumption use in hazardous situations
  
• Recurrent opioid-related legal problems
• Continued opioid use despite social or
  interpersonal problems

5
Case 1
6

• CC unresponsiveness
• HPI 20 y/o F with history of heroin dependence
  s/p recent rehab, chronic pain, suicidal
  attempts, found unresponsive at home. She had
  gone to a party the night before and had a
  drink given to her by a friend. The next
  morning her family finds her lying in bed, frothy
  at the mouth, unresponsive, and short of breath.
  

7

• HPI
• The family provides more background
  informationthe patient had become dependent on
  heroin 1 month prior due to not being able to pay
  for Percocet off the street. She was using
  Percocet for chronic pain from a MVA 2 years
  prior. She was then convinced by her family to
  attend drug rehab.
• After rehab she fell into pressure from friends
  and resumed etoh abuse. Patient was also using
  Methadone given to her by one of her friends.

8
Past Medical History

• Depression
• Suicidal attempt
• Polysubstance abuse
• Asthma
• PTSD
• Borderline personality disorder

• Abortion 1 yr prior
• 2007 MVA driver sustained multiple fracture

9
Medications
Allergies Penicillin-Rash

• Klonopin 1mg three times a day
• Escitalopram 20mg once daily
• Gabapentin 300mg once daily
• Montelukast 10mg once daily
• Albuterol prn
• Fexofenadine daily
• Advair inhaler bid

10

• Social History
• Tobacco
• Etoh use since 15 y/o, DUI x2
• THC, Heroin after MVA
• Family Hx (-)
• ROS
• -anxiety, alcohol intoxication, diffuse pain.

11
Physical ExamParamedics Bp 141/79 P135 R16
SO2 BVM 100ER BP 85/59 P 112 R 14 SO2 100

• General somnolent with agonal breathing
• Eyes pupils constricted b/l, no conjunctival
  erythema
• ENT tongue/septum intact, no ulcers/bleeding, no
  etoh odor
• Neck neck veins distended
• Cardiac s1, s2, s3 Tachycardiac
• Chest b/l nipple piercing, b/l crackles,
  abdominal breathing
• Abdomen no scars, nondistended, decreased bowel
  sounds, soft, nontender, no rebound/guarding
• Ext faint dp/radial pulse b/l, (doppler)
• Skin cool, no rashes, no track marks

12
Besides Opioids what are other drugs that cause
miosis?
13
CAUSES OF PUPILARY CONSTRICTION
Opioids Heroin Morphine Hydromorphone Oxycodone Hy
drocodone Codeine Propoxyphene
Cholinergics Nerve agents Organophosphate
insecticides Carbamate insecticides Pilocarpine
Edrophonium Physostigmine
Sympatholytics Clonidine Oxymetazoline Tetrahydraz
oline Antipsychotics Misc Phencyclidine
Sedative-hypnotics Barbiturates Benzodiazepines Al
cohols (deep coma)  Zolpidem
14
Labs

• WBC 13.3
• Hb14.2
• Hct43.2
• Plt253
• 7.22/51.5/ Pa0239/ 02sat 67.2
• Coags
• INR 1.2
• PT 14
• PTT 35
• Lactate 2.3

• Na 135
• K 6.6-gt3.3
• Cl 100
• Bicarb 23
• BUN 15
• Cr 1.7
• Glu 147
• Ca 8.5
• tbili 0.6
• tp 7.3
• alb 4.2
• alk ph 48/alt 18/ast 38

15
Labs

• Drug screen methadone/THC
• Ethanol level normal
• Acetaminophen/Salicylate level normal
• EKG sinus tachy with right axis deviation QTC
  452 ms
• XrayLeft upper lobe infiltrate, infection vs
  pulmonary edema

16
Patient Course

• 2mg Naloxone with no response and then an
  additional 2mg Naloxone.
• Patient becomes more hypoxic and hypotensive-gtIVF
  and Intubated.
• PEA arrest.
• ACLS protocol and the patient is started on
  Dopamine.
• Also requires neosynephrine and vasopressin

17
Patient Course

• Trop 0.06-gt0.13
• MB 10.7-gt20.5
• CK 391-gt1689
• PROBNP 9503
• Bedside echo
• Severe LV dysfunctin with diastolic
  dysfunction/mild mitral and tricuspid regurg
• Right vent hypokinesis
• Estimated 10 EF

• Cath Lab results
• R dominant, LAD muscle bridge, otherwise nl
  coronaries. LV mid/apical akinesis
• EF 10 no MR or AI
• PCWP 25 PA 31/23 (23) RV 33/16 (21)
• RA 60 LV (83/22) Ao 86/51 (61)
• CO 3.78 l/min
• SVR in1418 ds/cm5
• Intra-Aortic Balloon Pump placed

18
CXR
19
Hospital Course

• Continued on Norepinephrine and Dobutamine
• Vancomycin and Ceftriaxone for pneumonia
• IABP removed and Extubated on Day 4, Blood
  cultures negative
• Repeat Echo on Day 5
• mild to moderate ant/anterolateral HK, EF 45-50
• Narcotic Dependence, Pain Management

20
Discharge

• Klonopin 1mg tid
• Escitalopram 40mg daily
• Gabapentin 300mg bid
• Levofloxacin 250 mg for five days for CAP
  pneumonia
• Follow up with Psych, Cardiology, Drug Rehab,
  Psych therapy

21
Methadone Toxicity
22
Methadone opioid effects

• CNS and PNS
• Mu, kappa, delta receptors
• Mu opioid agonist
• respiratory depression
• analgesia
• euphoria
• miosis
• Stimulation of peripheral mu opioid receptors,
• smooth muscle of the bronchi and intestines
• cough suppression and constipation
• Also binds to NMDA as antagonist against
  glutamate.

Opioid Craving/Tolerance
Corkery et al 2004
23
Methadone Pharmacokinetics

• peak plasma level within 2 to 4 hours,
• half-life of 25-52 hours during long-term
  maintenance therapy
• Methadone and its inactive metabolite, an
  N-demethylated pyrolidine, may be detected in
  either urine or plasma.
• Nontolerant person, a 40- to 50-mg dose -gt coma
  and respiratory depression.
• Rapid escalation of methadone doses have been
  associated with choreoathetoid movements due to
  enhanced striatal dopamine release

Corkery et al 2004
24
Methadone Cardiac affects

• Blocks nerve conduction
• Prolonged QT
• Bradarrythmias/tachyarrythmias
• Heart Failure

Image Courtesy of Mississippi College
25
Biventricular Failure Case Report

• 37 y/o M on 60mg of Methadone daily for 3 years
• Methadone treatment stopped due to relapse
• Incarcerated for 12 weeks
• Restarted on 60 mg Methadone
• Within 3 hours
• Hyporeflexic coma with miosis-gthypoventilation-gtb/
  l pulm edema -gt acute circ failure
• Dobutamine and Norepinephrine started

26
Bi-ventricular Failure following Methadone
overdoseHeggs et all, 2008
27
Bi-ventricular Failure following Methadone
overdoseHeggs et all, 2008

• Improved after 24 hrs
• Started 40mg Methadone at time of transfer out
  of ICU
• 3 hours later new onset coma, sinus pauses
• Echo at 3 and 9 days showed progressive
  improvement

28
Bi-ventricular Failure following Methadone
overdoseHeggs et all, 2008

• Low tolerance after interruption of opioid
  maintenance therapy
• Methadone and Cardiac Toxicity
• Conductive disorders
• Possibility of Toxicity and Cardiac failure with
  low doses
• Absence of correlation between blood levels and
  tolerance

29
Stunned Myocardium?

• Short-term
• Complete or near complete reduction of coronary
  blood flow
• Reestablishment of coronary blood flow
• Results in LV dysfunction of limited duration

30
The role of Naloxone in drug induced acute lung
injury
Nucleus Medical Art, Inc.
31
Common xenobiotic causes of acute lung injury

• Amiodarone
• Amphetamines
• Amphotericin
• Bleomycin
• Calcum channel blockers
• Carbon monoxide
• Cocaine
• Colchicine
• Cyclic antidepressants
• Cytosine arabinoside

• Ethchlorvynol
• Irritant gases
• Lidocaine
• Opioids
• Protamine
• Salicylates
• Sedative-hypnotics
• Smoke inhalation
• Streptokinase
• Vinca alkaloids
• Goldfranks 8th ed

32
OPIATE RELATED ACUTE LUNG INJURY

• First described by William Osler in 1880
• essentially all opioids implicated
• setting reversal of respiratory depression with
  subsequent development of hypoxemia and pulmonary
  rales

33
RADIOLOGICAL FINDINGS

• BILATERAL COALESCENT INFILTRATES
• PREDOMINANTLY ALVEOLAR
• FLUFFY BUTTERFLY DISTRIBUTION WITH A HAZINESS OF
  THE VESSELS
• OCCASIONALLY INTERSTITIAL PATTERN
• TRANSIENT CARDIOMEGALY

34
MICROSCOPIC/ HISTOLOGIC FINDINGS

• EXUDATIVE PNEUMONITIS (HEMORRHAGIC)
• RAPIDLY PROGRESSING ACUTE EXUDATION OF
  NEUTROPHILIC PMNS IN CLEAR FLUID

35
PROPOSED MECHANISMS

• HYPERSENSITIVY TO THE OPIOID (OR ADULTERANT)
• UNDERLYING CARDIOGENIC ABNORMALITY
• NEUROGENIC CAUSES
• LOCALIZED HISTAMINE RELEASE
• PHYSIOLOGIC RESPONSE TO HYPOXIA
• INCREASED OSMOTIC PRESSURE GRADIENT

36
CAPILLARY PERMEABILITY

• HYPOXIA INDUCED INCREASE IN PULMONARY CAPILLARY
  PERMEABILITY
• 1972 - KATZ ET AL. AM REV OF RESP DIS
• 5 PTS WITH HPE VS 5 PTS WITH LVF
• SEVERE HYPOXIA
• MEASURED SERUM AND PULMONARY EDEMA PROTEIN LEVELS
  AT INTUBATION
• LVF - 40 of serum protein level
• Hpe - 98 of serum protein level

37
Jornal Brasileiro de Pneumologia
38
MUELLER MANEUVER

• VENTILATOR ASSOCIATED ALI
• LARGE PRESSURE GRADIENT CREATED ACROSS ALVEOLAR
  MEMBRANE - FLUID DRAWN INTO ALVEOLAR SPACE
• RESULT OF ATTEMPTED INSPIRATION AGAINST CLOSED
  GLOTTIS - NEGATIVE INTRATHORACIC PRESSURE

39

• GLOTTIC LAXITY MAY PREVENT ADEQUATE AIR ENTRY
  DURING INSPIRATION
• SPONTANEOUS BREATHING MAY RETURN PRIOR TO
  ADEQUATE UPPER AIRWAY FUNCTION

40
NALOXONE

• PURE COMPETITIVE OPIOID ANTAGONIST AT THE MU,
  KAPPA AND DELTA RECEPTORS
• USED TO REVERSE RESPIRATORY DEPRESSION IN PTS
  WITH OPIOID TOXICITY
• IV, IM, SQ, IN, IL, NEB, ET (NOT PO)
• ONSET OF ACTION 1-2 MIN
• DURATION OF ACTION 20-90
• DOSE - 0.05MG UP TO 10MG

41

• OTHER USES
• ETOH, CLONIDINE, CAPTOPRIL, VALPROATE OVERDOSES
• REVERSAL OF HYPOTENSION IN SEPSIS
• MORPHINE INDUCED PRURITIS
• SAFE ADVERSE EFFECT PROFILE
• ASSOC WITH RESEDATION, OPIOID WITHDRAWAL,
  DYSRHYTHMIAS, HYPERTENSION

42
NALOXONE AND ALI

• MULTIPLE CASE REPORTS ASCRIBE ALI TO
  ADMINISTRATION OF NALOXONE
• HINE CH. ET AL ANALYSIS OF FATALITIES FROM ACUTE
  NARCOTISM IN A MAJOR URBAN AREA. J FORENSIC SCI
  198227372-74
• 5 YEAR PERIOD 255 DEATHS ATTRIBUTED TO NARCOTICS,
  (IN ANOTHER 172 - CONTRIBUTING)
• 90.4 HAD EVIDENCE OF PULMONARY EDEMA
• VERY FEW RECEIVED NALOXONE

43
NALOXONE INDUCED OPIOID WITHDRAWAL

• RAPID MASSIVE SYMPATHETIC DISCHARGE OF
  CATECHOLAMINES
• IN DOGS - MUCH MORE DRAMATIC IF PCO2 IS ELEVATED

44
CURRENT HYPOTHESIS

• COMBINATION OF FACTORS
• UNDERLYING RESPIRATORY DEPRESSION AND HYPOXIA
• INCREASED CAPILLARY PERMEABILITY
• POTENTIATED BY ADMINISTRATION OF NALOXONE WITH
  RAPID SYMPATHETIC SURGE
• INCREASED INTRATHORACIC PRESSURE - PULMONARY
  EDEMA

45
Heroin-related noncardiogenic pulmonary edema a
case series.Sporer KA, Dorn EChest. 2001
Nov120(5)1628-32.

• DESIGN Retrospective chart review 1994 1998 at
  an urban academic hospital.
• Heroin-related NCPE was defined as
• A patient develops significant hypoxia (room air
  saturation lt 90 with a respiratory rate gt
  12/min) within 24 h of a clinically apparent
  heroin overdose.
• Accompanied by radiographic evidence of diffuse
  pulmonary infiltrates not attributable to other
  causes

46
Heroin-related noncardiogenic pulmonary edema a
case series.Sporer KA, Dorn EChest. 2001
Nov120(5)1628-32.

• MEASUREMENTS AND RESULTS
• 27 patients identified in a 53-month period,
• Male 85 average age, 34 years
• 20 pts (74) hypoxic on ED arrival
• 6 pts (22) had symptoms develop within the first
  hour
• 9 pts (33) required mechanical ventilation,
• All but one were extubated within 24 h.
• 18 pts (66) were treated with only 02
• Unilateral pulmonary edema occurred in four pts
  (15) and more localized disease occurred in two
  pts (7)

47
Heroin-related noncardiogenic pulmonary edema a
case series.Sporer KA, Dorn EChest. 2001
Nov120(5)1628-32.

• CONCLUSION NCPE is an infrequent complication of
  a heroin overdose. The clinical symptoms of NCPE
  are clinically apparent either immediately or
  within 4 h of the overdose. Mechanical
  ventilation is necessary in only 39 of patients.
  The incidence of NCPE related to heroin overdose
  has decreased substantially in the last few
  decades.

48
Case 2
49

• 22 year old male presents to Aria Health ER
  with complaints of anxiety and palpitations
• Admits to injecting heroin several hours prior -
  states did not get usual high
• No chest pain but discomfort

50

• T 99.8 R 16 P156 BP130/80 99 RA
• Appears anxious, slightly diaphoretic
• Pupils 6mm but reactive
• Tachycardic, no murmur
• Clear lungs
• Neuro exam nonfocal

51

• EKG sinus tachycardia at 145

52
Labs

• Wbc - 7.8
• Hg - 14.1
• Plts - 153
• CK - 60
• Trop - 0.04
• AST - 131
• ALT - 180
• Lactate - 10.5

• Glu - 186
• BUN - 11
• Cr - 1.2
• Na - 137
• K - 2.9
• Cl - 96
• CO2 - 24

53
Thoughts?
54

• UDS - positive only for opiates
• Acetaminophen/ASA negative
• INR 1.1
• UA negative

55
Adulterants
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57
J Forensic Sci. 2008 Mar53(2)452-4. An epidemic
of illicit fentanyl deaths in Cook County,
Illinois September 2005 through April
2007. Denton JS, Donoghue ER, McReynolds J,
Kalelkar MB. McLean and Peoria County Coroners
Offices, Bloomington, IL 61702, USA.
sdenton_at_gmail.com Between September 2005 and
April 2007, 350 fentanyl intoxication deaths were
investigated and certified by the Cook County
Medical Examiners Office. Investigations revealed
that the majority of these fatalities were by
intravenous injection of a white powder followed
by a rapid collapse. The fentanyl was
clandestinely produced in a lab in Toluca, Mexico
and sold by the Mickey Cobra street gang. The
term "Drop Dead" was coined for this "tainted
heroin." Postmortem samples were screened by
ELISA and confirmed by standard GC-MS methods.
Fentanyl fatalities peaked at 47 per month in May
and June 2006. Fifty-two percent were single
fentanyl intoxications, with the remainder
accompanied by either cocaine, morphine from
heroin, or alcohol. This epidemic stressed the
limited resources of the toxicology laboratory
and autopsy service of the Medical Examiners
Office. The clandestine lab was terminated,
distributing gang members and leaders arrested,
and the epidemic ceased in April 2007.
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11 of drug related deaths Were positive for
clenbuterol
61
Clenbuterol
62

• ?2 adrenergic agonist
• Used outside the US for asthma and COPD
• Used as an alternate for anabolic steroids -
  increases muscle mass
• Illegally used to promote growth in animals
• Used by bodybuilders for same benefit

63

• Human intoxication in past largely related to
  consumption of contaminated livestock
• Concentrates in lung, liver and kidney
• Heat stable
• January 2005 - heroin contaminated with
  clenbuterol
• Affected 26 patients in 5 states
• Insufflated, injected

64
Pharmacokinetics

• 70-80 orally bioavailable
• T 1/2 - 3.5-6 hours
• Te- 25-39 hours
• Peak serum levels 2-3 hours after oral dosing

65
Physiologic effects

• ?2 adrenergic agonist
• Metabolic effects- leading to muscle hypertrophy
• Lipolytic
• Anabolic

66
Clinical Effects

• Sympathomimetic toxidrome
• Tachycardia, palpitations, tremor, anxiety,
  agitation, vomiting, vertigo
• (Hypotension)
• Myalgia-arthralgias, headache
• Tachypnea/dyspnea

67

• Electrolyte abnormalities
• Hypokalemia
• Hypophosphatemia/hypomagnesemia
• Hyperglycemia
• Hyperlactemia
• Increased venous pO2

68
Cardiovascular Effects in Chronic Users

• Dose used by bodybuilders 20-200mcg 1-3 times a
  day
• Often used in combination with anabolic steroids

69

• Left ventricular hypertrophy
• Arrhythmias
• Acute myocardial infarction

70
Mechanisms

• Compensatory hypertrophy secondary to increased
  hemodynamic demand from an increased muscle mass
• Mediated by cyclo-oxygenase mediator (blocked by
  fenbufen)
• Association with polyamines (blocked by
  propranolol)

71

• Increased rate of arrhythmias likely due to a
  combination of LVH and electrolyte abnormalities
• Hyperthermia, low cardiac output and tachycardia

72
Treatment

• Supportive Care
• Electrolyte Repletion
• Benzodiazepenes
• Beta-blocker
• Esmolol
• Propranolol

73
Caveats

• Testing is difficult and may take days
• Sympathomimetic toxidrome may be secondary to
  cocaine, amphetamines
• AVOID BETA-BLOCKERS
• Electrolyte abnormalities represent shifts not
  total body depletion so avoid over repletion

74
Back to our case

• Recommended Labetolol/Esmolol and BZ
• Given BZ
• Blood Pressure 86/60 HR 120
• Given IVF
• Trop peaked 2.4