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Drugs of Abuse and Withdrawal

Dan  Rusyniak  drusynia@iupui.edu  

Medical Toxicology Board Review

Addiction

•  All  addic:ve  drugs  increase  [dopamine]  •  Compulsive  use  despite  nega:ve  consequences  

•  Stress-­‐  and  cue-­‐evoked  craving  •  Persistence  with  high  relapse  rates  

Tolerance

•  Increasing  doses  to  elicit  the  same  effect  – Metabolic  (increased  metabolism)  – Cellular  Adapta:on  

•  Receptor  down/up  regula:on  •  Receptor  desensi:za:on  •  Changes  in  gene/protein  expression  

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Cross-Tolerance

•  Tolerance  the  effects  of  a  substance  as  a  result  of  con:nued  exposure  to  a  different  substance  with  similar  pharmacologic  ac:on  – Can  subs:tute  drugs  with  similar  ac:on  

Dependence

•  Physical  –  withdrawal        •  Psychological  –compulsive  need  for  drug  despite  absence  of  physical  withdrawal  

Classes of Drugs of Abuse

• Depressants  •  S+mulants  • Hallucinogens  

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CNS Depressants

•  Opiates/Opioids  •  GABA  agonists  •  Ethanol  

 

Opioid/Opiates

•  Opiates  – Morphine,  Codeine,  Thebaine  

•  Semisynthe:c  – Morphine  deriva:ves  (heroin,  hydromorphone)  –  Codeine  deriva:ves  (hydrocodone,  oxycodone)  –  Thebaine  (buprenorphine)  

•  Synthe:c  –  Diphenylpropylamine  deriva:ves  (methadone)  –  Phenylpiperidine  deriva:ves  (fentanyl)  

Opioid Receptors

•  μ1:  supraspinal  &  peripheral  analgesia,  euphoria  •  μ2:  spinal  analgesia,  respiratory  depression,  dependence,  miosis*,  GI  dysmo:lity*,  CV  effects  

•  δ:  spinal  analgesia,  GI  dysmo:lity,  mood  •  κ1:  spinal  analgesia,  miosis  •  κ2:  dysphoria,  psychotomime:c  •  κ3:  supraspinal  analgesia  

•  *Liale  tolerance  develops  

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Potency

Opioid   Route   Equal  analgesic     Dura+on  (hr)  

Morphine   IV  PO  

10  mg  30  mg  

3-­‐5  4  

Codeine    

IM  PO  

120  mg  200  mg  

4-­‐6  3-­‐4  

Hydromorphone   IV  PO  

1.5  -­‐  2  mg  7.5  mg  

3-­‐4  4-­‐6  

Oxycodone   PO   20  mg   4-­‐6  

Methadone   PO   20  mg   4-­‐12  

Fentanyl   IV   0.1  mg   1-­‐2  

Star:ng  dose  of  Morphine  ~0.1  mg/kg  3mg  of  Dilaudid  =  20  mg  morphine  100  ug    of  fentanyl  =  10  mg  morphine    

Opioid Analgesia: Two edge Sword

•  Hyperalgesia  =  exacerbated  painful  response  to  noxious  s:mula:on  

•  Allodynia  =  normal  non  noxious  s:mula:on,  is  perceived  as  painful.  

•  Both  hyperalgesia  and  allodynia  occur  in  animals/humans  taking  chronic  opioids  

Unique Toxicities

•  Morphine,  hydromorphone  –  Histamine  Release  •  Tramadol,  Meperidine,  Propoxyphene  –  Seizures  •  Propoxyphene  –  Cardiac  Na  channel  blocker  •  Methadone  –  Long  T  ½,  QTc  prolonga:on  •  Tramadol,  Meperidine  –  Serotonin  Syndrome  •  Codeine  –  Ultrarapid  and  Slow  metabolizers  •  Hydrocodone  –  Hearing  Loss  •  Fentanyl  –  Rigid  chest    

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Heroin

•  3,6-­‐diacetyl  morphine  •  Natural  –  Tetanus  and  Botulism  •  Chasing  the  dragon  associated  with  leukoencephalopathy  

•  Non-­‐cardiogenic  pulmonary  edema  

Desomorphine

•  Krokodil •  8-10 X the strength of morphine •  Easily made from codeine (OTC)

–  (alkali, gasoline, lighter fluid, red phosphorus, iodine, HCl 30%)

•  ~ 30 minutes to make •  Cost  is  $4-­‐6  ($50-­‐150  heroin)  

крокодил

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Antidotes

•  Naloxone    – T1/2=  60-­‐90min  – All  routes  but  oral  

•  Nalmefene  – T1/2  =  11  hours  – parenteral  

•  Naltrexone  – T1/2  =  4  hours  – Oral  only  

GABA agonists

•  Benzos/Barbs  –  GABAA  – Chloride  ionosphere  – Amnes:c  – Roofies  (flunitrazepam)  

•  GHB  –  GABAB  – G-­‐Protein  – Rapid  awaking  – Body  building,  Gay  community,  date  rape  

Alcohol dehydrogenaseAldehyde dehydrogenase

GHB Metabolism

O

OHNH2

HO

O

O

OHH2N

O

OHO

Glutamate

GABA

Succinate semialdehyde

Glutamic acid decarboxylase

GABA Transaminase

OH

OHO

GHB

HOOH

1,4 butanediol

GBL

O

O

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Ethanol

•  GABAA  agonist,  NMDA  antagonist,  nonspecific  •  AKA  =  starva:on,  dehydra:on,  ethanol  •  Metabolism    

– 15  mg/dl/hr  in  males  – 18  mg/dl/hr  in  females  (less  ADH  in  stomach)  

•  Disulfiram  inhibits  aldehyde  dehydrogenase  – Also  inhibits  Dopamine-­‐β-­‐OH  (refractory  hypotension)  

Wrenn,  K.D.,    et  al.  1991,  Am  J  of  Med;91(2):119-­‐28  

Stimulants

•  Amphetamines  – Methamphetamines  – Hallucinogenic  Amphetamines  – Ephedra  – Cathinones  “Bath  Salts”  

•  Cocaine  

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α1   D1/2  

Reverse transport Amphetamines

NE Increase Release Amphetamines

Dop

Increase Monoamines

Inhibit Metabolism Amphetamines

5HT

5HT2a  

Blocks reuptake Cocaine Amphetamines

Misc

•  Cocaine  -­‐  Na  Channel  blocker  •  Harrison’s  Narco:c  Act  of  1914  

–   banned  importa:on  (except  for  medical  purposes)  

•  Controlled  Substance  Act  of  1970  –   prohibited  the  manufacture,  distribu:on,  and  possession  of  cocaine  (except  for  medical  purposes)  

•  Cocaine  &  Meth  are  Schedule  II  •  Amps  >  T1/2  

Beta Blockers

•  Un-­‐apposed  alpha  •  Coronary  artery  vasoconstric:on  

Lange  et  al.  1990;  Ann  Int  Med;  112  (12),  897-­‐903  

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Cocaine - Levamisole

•  70%  of  cocaine  shipments  

•  Agranulocytosis  •  Necro:zing  derma::s  

Buchanan  et  al.  J  Med  Tox.  June  2010  

MDMA

•  3,4-­‐methylenedioxymethamphetamine  •  Decreases  serotonin  terminals  •  Hyperthermia  in  associa:on  with  dancing  •  Hyponatremia  and  cerebral  edema  •  Hepa:c  failure  (e:ology  unknown)  

Stimulant Lab Effects

•  Hypokalemia  – Na/K  ATPase  

•  Hyperglycemia  –  Increase  glucose  release  – Decrease  insulin  release  

•  Hyponatremia  – Vasopressin  release  

•  Rhabdo  

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Stimulant Hyperthermia

•  Increased  heat  genera:on  – Skeletal  muscle  (ac:vity)  – Non-­‐shivering  thermogenesis  (iBAT  and  Skeletal)  –  Increased  metabolic  rate  

•  Decreased  heat  dissipa:on  – Cutaneous  vasoconstric:on  (alpha-­‐1,  5-­‐HT2A)  

•  Highest  risk  is  in  a  warm  environment  

Death in Custody

•  Agitated  delirium  •  S:mulant  drugs  •  Warm  environment  •  Struggling  •  Hobble/prone  posi:on  

hap://www.salem-­‐news.com/gphotos/1346644336.JPG  

Chronic Complications

•  Psychosis  – Schizoaffec:ve  symptoms  – Punding  (repeta:ve  non-­‐useful  tasks)  – Delusions  parasitosis  

•  Seizures  •  Choreathetoid  (Crack  dancing)  •  Dental  Decay  

– Decreases  saliva:on    

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Bath Salts

Federal Analog Act

•  Includes:  The  chemical  structure  of  which  is  substan:ally  similar  to  the  chemical  structure  of  a  controlled  chemical  in  Schedule  I  or  II  

•  Does  not  Include:  Any  substance  to  the  extent  not  intended  for  human  consump:on  before  such  an  exemp:on  takes  effect  with  respect  to  that  substance  

Why were they Legal?

MDPV  

MDMA  

Mephedrone  

Methamphetamine  

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Inhalants

•  Vola:le  Hydrocarbons  •  Paint  thinners,  gasoline,  solvents,  Gasoline    •  Toluene  •  Halogenated  Hydrocarbons  •  Nitrates    •  Gold  and  Silver  paints  

Specific Effects

•  Toluene  –  RTA,  CNS  white  maaer  changes  –  Increased  urine  hippuric  acid  

•  Halogenated  hydrocarbons  –  Sudden  sniffing  deaths  –  Also  butane  and  propane  

•  Nitrites  (amyl,  butyl,  cyclohexyl)  –   Methemoglobinemia,  Hypotension  –  React  with  c-­‐GMP  PD  inhibitors  (e.g.,  sildenafil)  

•  N-­‐hexane  -­‐  neuropathy  

Hallucinogens

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Tryptamines  

Ergoline   Phenethylamine  

Classes

5HT2a/c  

Hallucinogens

5HT

5HT1a  

Release Serotonin Phenethylamine

5-HT agonists Tryptamines

Colorado River Toads

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Peyote

Hawaiian Baby Woodrose & Ergots

Ketamine

Dextromethorphan

PCP

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Ketamine

Methoxetamine

PCP

Ca++ Na+

glycine glutamate

Ethanol

NMDA Receptor

PCP  Ketamine  Methoxetamine  

PCP & Ketamine Analogues

•  NMDA antagonists – Antagonize glutamate – Dissociates somatosensory cortex from higher

centers •  Weak biogenic amine reuptake inhibitors

– DA > 5HT, NE •  S:mulates  σ-­‐receptors  •  High  concentra:ons    

– Nico:nc  agonist  – Muscarinic  agonist

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BZP/Phenyl Piperazines

PMA

DMT 2-DPMP

Piperazines

•  benzyl  piperazines  (e.g.,  BZP)  –  Inhibit  DA  uptake  no  effect  on  5HT  – QTc  prolonga:on  

•  phenyl  piperazines  (e.g.,  TFMPP  or  Molly)  –  Inhibit  5HT  reuptake  &  5HT  receptor  agonists  – No  effects  on  dopamine  

Paramethoxyamphetamine • PMA, “Death,” “Dr. Death,” “Chicken Yellow” • Sometimes confused with MDMA

• PMMA, 4-MTA similar

• Severe hyperthermia

• Many deaths NH2

CH3 O

H3C

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2CI-NBOMe • Smiles, 25i • Renal failure • Repetative Seizures • Deaths

Benzodifurans

•  Fly,  Dragonfly  •  Potent  5HT2  agonists  •  Onset  of  ac:on  6  hours  •  Dura:on  2-­‐3days  •  Prolonged  vascular  spasm  •  Liver  &  renal  failure  

Salvia Divinorum

•  Herb  in  the  mint  family  •  Oaxaca,  Mexico  •  Potent  Kappa  Opioid  receptor  antagonist  

•  Hallucina:ons  

Salvinorin-­‐A  

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Kratom

•  South  East  Asia  •  Low  dose  s:mulant  •  High  dose  (opioid  like)  •  Few  (if  any  cases)  •  Not  Krypton  

•  Central  CB1  •  Tachycardia  •  Hypotension  •  Sensory  •  Percep+on  •  Mild  hallucina+ons  •  Hyperemesis  

K2/Spice •  Legal  (currently)  synthe:c  cannabinoids  –  JWH-­‐018;  CP  47,497;  and  HU-­‐210  

•  Limited  clinical  data    •  Higher  toxicity  then  THC  

– Seizures  – Adrenergic  symptoms  – Syncope  

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Blueberry Spice

•  Toxin  induced  inters::al  nephri:s    

Δ9-THC

JWH-018

Why it is currently Legal

Withdrawal

Intoxica+on  •  Seda:ves  

–  CNS  depression  –  CV  depression  –  Decreased  GI  

•  S:mulants  –  CNS  excita:on  –  CV  ac:va:on  

Withdrawal  •  Seda:ves  

–  CNS  excita:on  (sz,  DTs)  –  CV  ac:va:on  (arrhythmias)  –  Increased  GI  

•  S:mulants  –  CNS  depression  (fa:gue,  apathy)  

 

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CNS Depressants Cause Life Threatening Withdrawal

•  Ethanol  •  Benzodiazepines  •  Barbiturates  •  GHB  •  Baclofen  •  Opioids  (rare)