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8/20/14
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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)
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