Anesthetics; Drugs of Abuse & Withdrawal

Anesthecs; Drugs of Abuse & Withdrawal

Kurt Kleinschmidt, MD, FACEP, FACMT Professor of Emergency Medicine Secon Chief and Program Director Medical Toxicology UT Southwestern Medical Center 1

Much Thanks To…

Sean M. Bryant, MD

Associate Professor Cook County Hospital (Stroger) Department of Emergency Medicine

Assistant Fellowship Director: Toxikon Consorum

Associate Medical Director Illinois Poison Center

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Overview

Anesthecs – Local – Inhalaonal – NM Blockers & Malignant Hyperthermia

Drugs of Abuse (Pearls)

Withdrawal

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1 Anesthetics; Drugs of Abuse & Withdrawal

History

1904-Procaine (short Duraon of Acon) 1925 (dibucaine) & 1928 (tetracaine) → potent, long acng 1943-lidocaine 1956-mepivacaine, 1959-prilocaine 1963-bupivacaine, 1971-edocaine, 1996-ropivacaine 4

Lipophilic Intermediate Amine Substituents Group Esters Structure

2 Disnct Groups 1) Amino Esters

Amides 2) Amino Amides

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Local Anesthecs Toxic Reacons • Few & iatrogenic • Blood vessel administraon or toxic dose

AMIDES have largely replaced ESTERS • Increased stability • Relave absence of hypersensivity reacons – ESTER hydrolysis = PABA (cross sensivity) – AMIDES = Muldose preps → methylparabens » Chemically related to PABA with rare allergic reacons

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Local Anesthecs Mode of Acon

• Reversible & Predictable Binding • Within membrane-bound sodium channels of conducng ssue (cytoplasmic side of membrane) → Failure to form/propagate acon potenals (Small-diam. fibers carrying pain/ temp sensaon)

• Sodium Channel (3 States) – Closed (resng or hyperpolarized) – Open – Inacvated BLOCKADE

Pain fibers - higher firing rate & longer AP → ↑ susceptible to local 7 anesthetics

ONSET OF ACTION HIGHER POTENCY ↓ pKa (uncharged) Higher lipophilicity Intermediate chain length

Higher protein binding 3-7 carbon equiv’s 8

Local Anesthecs Pharmacokinecs • Local vs. Systemic disposions • Lipophilic = crosses membranes! (BBB, placenta) • Distribuon depends on ssue perfusion • Lungs = uptake; buffers systemic toxicity? – Saturable kinecs (lung uptake is exceeded → Toxicity) • Peripheral vasodilaon (except cocaine)

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Local Anesthecs Pharmacokinecs Metabolism AMINO ESTERS PABA

Plasma Cholinesterase AMINO AMIDES Metabolites unrelated to PABA

Slower via Liver Factors that may ↑ Tox ↓ plasma cholinesterase ↓ Liver blood flow (CHF) 10

Local Anesthecs Clinical manifestaons

Direct cytotoxicity (nerve cells) • Excessive concentraons or Bad formulaons • Uncommon

Transient neurologic symptoms • Spinal anesthesia with lidocaine (intrathecal or infusion) • Mech = Unknown (NOT Na channel blockade)

Skeletal muscle changes • IM injecons (highly potent, longer acng agents) • Reversible (2 weeks)

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Local Anesthecs Systemic Toxicity

– Allergic reacons (Amino Esters -- PABA) - Rare – Methemoglobinemia • Reported with lidocaine, tetracaine, prilocaine • Topical/oropharyngeal benzocaine

OXIDIZING aniline

AGENTS phenylhydroxylamine & nitrobenzene

Vasovagal Reactions Reported 12

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Local Anesthecs Systemic Toxicity • Correlates with [plasma] – Dose, Rate, Site – Vasoconstrictor? – Potency – Metabolism (rate)

Brain & Heart - #1 Targets • Rich perfusion • Moderate ssue-blood paron coefficients • Lack of diffusion limitaons • Cells that rely on voltage-gated Na channels

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Local Anesthecs Systemic Toxicity CNS Excitation: Bupivacaine: block inhibitory Large IV bolus = pathways in May only see brady, amygdala → CNS depression ↑ excitatory & respiratory arrest! activity. Both Inhibitory & Excitatory neurons blocked as concentration ↑ → CNS ↓

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Local Anesthecs Systemic Toxicity CNS Effects Determinants – Potency & Dose – Rate of injecon – Drug interacons – Acid-base status • Acidemia → ↓ protein binding → ↑ free drug • Hypercarbia

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Local Anesthecs Systemic Toxicity Bupivacaine significantly more Cardiotoxic

CC/CNS ([Cardio collapse/CNS Tox]) – Lidocaine = 7 (CNS tox more evident) – Bupivacaine = 3.7

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Local Anesthecs Systemic Toxicity • Lidocaine – Na channel blockade greater if pt is tachycardic – Quickly dissociates at diastolic potenals • Rapid recovery Non Na+- • Bupivacaine channel Issues – Rapid binding & Slow dissociaon – S is less cardiotoxic vs. R – Uncouples & inhibits Complex I of respiratory chain – Inhibits carnine-acylcarnine translocase – Blocks GABAergic neurons – May ↓ Ca++ release from SR →↓ Contraclity

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Local Anesthecs Management CNS • DC administraon • Supporve care (CV monitoring) • Benzos, Barbs (Thiopental, Propofol) • NM blocking agents (EEG monitoring) • HD not effecve (HP for lidocaine?)

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Local Anesthecs Management

CV • Recognize! (CNS effects may preoccupy) • Correct physiologic derangements – Hypoxemia, acidemia, hyperkalemia • Maximize Oxygenaon • Support Venlaon/Circulaon • Hypotension (adrenergic agonists) • Bradycardia (atropine)

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Local Anesthecs Management

CV • Dysrhythmias – Oen refractory to standard care • Pacing, Bypass • Lidocaine for bupivacaine? (relavely less toxic) • Prolonged CPR/Resuscitaon efforts • Na Bicarbonate? (To prevent acidosis) • Insulin? (same magical reasons as elsewhere) LIPIDS 20

http://lipidrescue.squarespace.com/welcome/

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Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose-Response to Bupivacaine-induced Asystole in Rats Weinberg, Guy L. MD; VadeBoncouer, Timothy MD; Ramaraju, Gopal A. MD; Garcia-Amaro, Marcelo F. MD; Cwik, Michael J. PhD Issue:Volume 88(4), April 1998, pp 1071-1075 Began as a chance observation in the lab. This was a “confirmation” study

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Inhalaonal Anesthecs

• Ether – Paracelsus – put hens “to sleep” – The 1st descripon – 1735 used for “headaches & fits” – 1864 Mass Gen. Hospital dental procedure - Public Demo – Oliver Wendell Holmes (anesthesia = without feeling) • Nitrous Oxide • Chloroform – Replaced ether as choice for OB (1840s) • Volale Anesthecs (Fluroxene, Halothane, Methoxyflurane) – 1840’s – 1940’s = combusbility and direct organ toxicity

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Inhalaonal Anesthecs

Improved Clinical Properes

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Inhalaonal Anesthecs Pathophysiology

Unique Receptor = Improbable (Because there are so many agents → anesthesia)

• Funcon modulated from within cells • Interact with many ion channels (target?) • Side effects = effects in nonneural ssue (cardiac)

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Inhalaonal Anesthecs Pathophysiology

Goal = Reversible changes in neuro funcon • Loss of percepon and reacon to pain • Unawareness of immediate events • Loss of memory of events

Mechanism = Uncertain • Physical-chemical behavior within hydrophobic regions of biological membrane lipids & proteins

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Inhalaonal Anesthecs Pharmacokinecs Potency – Physiochemical Properes • Meyer-Overton lipid solubility theory – Potency correlates directly with relave lipid solubility

• Volume expansion theory – High pressures (100-200 atm) reverse anesth. effects – Suggests that drugs cause anesthesia by ↑ membrane volume at normal atm pressure

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Inhalaonal Anesthecs Pharmacokinecs Factors that influence absorpon & distribuon • Solubility in blood • Solubility in ssue • Blood flow through lungs • Blood flow distribuon to various organs • Mass of the ssue

GOAL: Develop & Maintain satisfactory partial pressure

in the Brain!

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Inhalaonal Anesthecs Pharmacokinecs

• Linked to pharmacodynamics • Strive to achieve & maintain desired [alveolar]

Minimum alveolar concentraon (MAC) • Potency • The [alveolar] at 1 atm that prevents movement in 50% of subjects in response to a painful smulus

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Inhalaonal Anesthecs

NITROUS OXIDE Advantages • Mild odor • Absence of airway irritaon • Rapid inducon & emergence • Potent • Minimal respiratory & circulatory effects • Safe 32

Inhalaonal Anesthecs

NITROUS OXIDE • Abuse Potenal • Asphyxia - Death/Brain damage from asphyxia (2°) • Impuries – Nitric oxide, nitrogen dioxide • Barotrauma – 35x more soluble in blood than Nitrogen – Pressure in air-containing spaces (bowel, ears, chest)

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Inhalaonal Anesthecs

NO → oxidizes cobalt in B12 → Inactive form

Methionine & THF both required for DNA & myelin36 synthesis!!!

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Inhalaonal Anesthecs NITROUS OXIDE Hematologic Effects • BONE MARROW SUPPRESSION • Occurs in all paents • Recovery generally occurs (4 days) • PERNICIOUS ANEMIA-Like – This has ↓ B12 Absorpon due to absence of Intrinsic Factor (vs NO – acve B12 can’t be made by the body)

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Inhalaonal Anesthecs

NITROUS OXIDE Neurologic Effects • Only aer chronic exposure • Is a disabling polyneuropathy • Subacute Combined Degeneraon of Spinal Cord • Sensorimotor polyneuropathy • Posterior & Lateral cord involvement • Numbness & paresthesias in extremees • Weakness & truncal ataxia 38

Inhalaonal Anesthecs NITROUS OXIDE Management • Removal of source • B12 – Helps best if brief exposure – Won’t help chronically exposed paents? • Folinic acid 30 mg IV – May reverse BM abnormalies • Methionine Supplementaon – Experimentally (Primates) reduced

demyelinaon 39

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Inhalaonal Anesthecs HALOTHANE HALOTHANE HEPATITIS

(1) Mild Dysfuncon – 20% of exposed paents – Asymptomac – Modestly ↑ transaminases within days – Complete recovery

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Inhalaonal Anesthecs HALOTHANE (2) Life-Threatening Hepas – 1 in 10,000 paents – Fatal hepac necrosis in 1 of 35,000 paents – A diagnosis of exclusion – Increased risk » Mulple exposures » Obesity (fat reservoir, prolonged release) » Female » Age (middle age) » Ethnicity (Mexican) 41

Inhalaonal Anesthecs HALOTHANE HALOTHANE HEPATITIS 20% oxidative metabolism via CYP – trifluoroacetic acid

Volatile Metabolites: Free Radicals or Haptens

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Inhalaonal Anesthecs

• Enflurane – weakly associated • Immune form of hepas (all but sevoflurane)

Isoflurane, Desflurane Low Hepatotoxic Potenal

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Inhalaonal Anesthecs HALOTHANE ABUSE Ingeson • AGE, depressed CNS, low BP, shallow breathing, bradycardia & extrasystoles, & Acute Lung Injury • Coma resolves in 72 hours • Sweet fruity odor of breath

Intravenous • Coma, hypotension, Acute Lung Injury

Inhalaon • Most reported cases = hospital personnel 44

Inhalaonal Anesthecs

NEPHROTOXICITY Methoxyflurane (intro 1962) • Vasopressin-resistant polyuric renal insufficiency • Nephrogenic DI • Polyuria = negave fluid balance • High Na, Osmolality, BUN • Lasted 10-20 days (up to > 1year) • Tox = Inorganic Fluoride (F) released during biotransformaon of methoxyflurane – F inhibits adenylate cyclase (ADH interference)?

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Inhalaonal Anesthecs

Currently Used Anesthecs • Halothane, Isoflurane, Enflurane, Desflurane, Sevo. • Enflurane & Sevoflurane biotransform by deF – 5% of sevoflurane is metabolized – Transient decrease in urine-concentrang ability – Rarely clinically relevant • Pre-exisng RI = risk of renal dysfuncon?

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Inhalaonal Anesthecs Anesthec-Related CO Poisoning Desflurane, Enflurane, Isoflurane • Contain a difluoromethoxy moiety – Can be degraded to Carbon Monoxide

• CO producon

– Inversely propor. to H2O content of CO2 absorbents – Soda lime and Baralyme = CO2 absorbents – May dry with high gas-inflow rates – Worst = first case Mon. aer weekend of drying

• COHb up to 36% (no M&M reported)

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Anesthesia Is GOOD!!!

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Neuromuscular Blockers History Curare: Sir Walter Raleigh (Guyana 1595) – 1898: King’s American Dispensatory • “Curare is a frighully poisonous extract, prepared by the savages of South America” – Curare pivotal in mech. of NM transmission • Claude Bernard frog studies – “curare must act on the terminal plates of motor nerves” – 1878: Curare 1st clinical use (tetanus & Sz) – Malicious use of NM Blockers! (Swango...)

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Neuromuscular Blockers Purpose Reversibly inhibits transmission at the skeletal NMJ – All = 1 +charged quaternary ammonium moiety → binds to the postsynapc niconic (nAch) receptor at the NMJ → ↓ acvaon by Ach

nAch receptor Ligand-gated ion channel 4 different protein subunits Pentameric structure with central channel

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Goldfrank’s 8th ed, page 1026

Excitation-Contraction coupling in skeletal muscle

Calcium Release Unit the intimate association of DHPR, RYR-1, & SR

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Neuromuscular Blockers Modulaon of postsynapc Ach receptor Depolarizing (phase I block) • Succinylcholine (the only one clinically) • 2 molecules bind to each α site of nAch receptor • Prolonged open state of ion channel! • Fasciculaons!!

• Succ not hydrolyzed efficiently by true AchE • Voltage-gated Na channel in peri-junconal region – Prolonged inacve state → desensizaon block → Muscle= temporarily refractory to presyn Ach release (phase I block)

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Neuromuscular Blockers Modulaon of postsynapc Ach receptor Nondepolarizing (phase II block) • Compevely inhibit effects of Ach • Prevent muscle depolarizaon! • One molecule of NDNMB binds to α site – Compevely inhibits normal channel acvaon

• DO NOT block voltage-gated Na channels on mus mem – So…Direct electrical smulaon of muscle contracon = possible • Also block nAch receptors on prejunconal nerves – Inhibits Ach-smulated Ach producon & release

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Neuromuscular Blockers Pharmacokinecs

Highly water soluble (won’t cross BBB) Speed of onset - 1/ molar potency (The > affinity for receptor, the fewer molecules/Kg ssue required)

In general: small, fast contracng muscles • Most suscepble (e.g. extraocular vs. large slow) • Respiratory Sparing Effect Recovery fastest for diaphragm and IC muscles

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Neuromuscular Blockers Complicaons

Paent Awareness • NMBs do not affect consciousness • Pupillary light reflex preserved in healthy paents Histamine Release • Nonimmunologic dose- and rate-related release • Tubocuarine>atracurium & mivacurium>Succ • NO release w/ pan, roc, vec Anaphylaxis • 60% anaphylactoid rxns during anestheisa – NMBs • Of the NMBs, Rocuronium 43%, Succ 23% (Pancuronium=least) 56

Neuromuscular Blockers Complicaons

Control of Respiraon Subparalyzing doses – Blunt hypoxic venlatory response (HVR) – But not the venlatory response to hypercapnia Autonomic Side Effects Tubocurarine – Blocks nAch rec at PNS ganglia → Tachycardia

– At SNS ganglia → ↓ sympathec response – Histamine release HYPOTENSION! 57

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Neuromuscular Blockers Complicaons

Autonomic Side Effects • Muscarinic receptors mostly unaffected • Pancuronium – Blocks PNS transmission at Cardiac M Recs (Atropine-like effect) – Block of presynapc M receptors at SNS terminals – ? Indirect NE-releasing effect at postgang fibers

→ Dose- and injecon rate-related increase in Heart Rate, BP, CO, and Sympathec Tone 58

Neuromuscular Blockers Complicaons

Autonomic Side Effects Succinylcholine – Rarely: Dysrhythmias -bradycardia, junct & vent rhythms – Due to Smulaon of Cardiac M Receptors – May be prevented with atropine (15-20 mcg/kg IV)

Bradycardia » May be severe in children with large/repeated doses

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Neuromuscular Blockers Interacons

Potenate duraon or effect of NDNMB • Respiratory acidosis, hypoK, hypoCa, hyperMg, hypoP, hypothermia, shock, liver or kidney failure

Resistance (mild) to effect of NDNMB • Acute sepsis & inflammatory states

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Neuromuscular Blockers Succinylcholine TOX 1) Prolonged Effect – Decreased plasma cholinesterase (or abnormal acvity) – OP or Carbamate Poisoning – Hepac Dz, Malnutrion, Pregnancy – Phase II block (large doses over short period – 8mg/kg)

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Neuromuscular Blockers “Normal or RI Patients” 1 mg/kg raises [K] approximately 0.5 mEq/ L Succinylcholine TOX 2) Hyperkalemia Exaggerated with myopathy or proliferaon of extrajunconal Ach rec Suscepbility aer neuro injury begins in 4-7 days! Denervaon Assume Head or SC injury, CVA, neuropathy cardiac arrest Muscle pathology after Sucks is Trauma, compartment syndrome, musc dystrophy due to Crical illness hyperkalemia Hem shock, neuropathy, myopathy, ICU > 1 wk Thermal burn or cold injury Sepsis (x several days)

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Neuromuscular Blockers

Succinylcholine TOX 3) Rhabdomyolysis – Especially at risk = underlying myopathy – Ex; Kids with Duchenne musculary dystrophy

– Life-threatening hyper K? » Mortality is highest with rhabdomyolysis (30%)

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Neuromuscular Blockers

Succinylcholine TOX 4) Muscle Spasms – Masseter Muscle Rigidity (MMR) » Pediatric Paents: 0.3-1% (Succ + Halothane)

– Trismus, myoclonus, chest wall rigidity » Can’t be aborted by NDNMB (indep of neural acvity)

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Neuromuscular Blockers

Succinylcholine TOX Also Volatile Anesthetics! 5) Malignant Hyperthermia » Inherited hypermetabolic condion » 1:20,000 children, 1:50,000 adults » Duchenne MD, central core Dz, King-Denborough syndrome, osteogenesis imperfecta, myotonia

MH-triggering agents (within 12 hours) » Interact with an abnormal RYR-1 channel (mostly) » Prolonged open state » Rapid efflux of calcium from SR (accelerated) » Hypermetabolic – pCO2, temp, tone, lactate (all ↑)

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Malignant Hyperthermia

Signs and Symptoms of MH (First 30 Min)

Tachycardia 90% Hypercarbia 80% Rigidity 80% Hypertension 75% Hyperthermia 70%

May be a late sign

Earliest signs = EARLY & RAPID INCREASED CO2 production and artrerial,venous end tidal CO2 66

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Malignant Hyperthermia Management • Aggressive Supporve Care volume, cooling, hyper K…

DANTROLENE » Prior Mortality Rate = 70% (now < 5%!!!) » Parally blocks Calcium release from SR » Dose = 2-3 mg/Kg » Maintence dosing for any reoccurance (25%) IV q 4-6 hrs for 24-48 hours

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Neuromuscular Blockers

NDNMBs TOX • Persistent Weakness – Administraon longer than 48 hours – Crical illness associated (mulfactorial) • 2.5-3.5 – fold increase in ICU mortality & ICU stay

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Neuromuscular Blockers

Unique Toxicity • Metocurine – connes iodine, hypersensivity and shellfish allergy • Rapacuronium – fatal bronchospasm, withdrawn.

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Drugs of Abuse/Withdrawal

Tolerance • Physiologic process: increasing drug concentraons required • Shi in dose-response curve to the right • Receptor modulaon (opioids), metab (barbs), or both (EtOH) • “Cross Tolerance” Key to treang W/D

Dependence • Implies that cessaon leads to withdrawal

Withdrawal • Physiologic (autonomic instability, N/V/D, hyperacvity, AMS) • Psychological (emoonal symptoms & craving)

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Hallucinogens • Lysergamides • Tetrahydrocannabinoids – LSD – Marijuana – Ergine – Hashish • Indolalkylamines / Typtamine • Belladonna Alkaloids – Psilocin & Psilocybin – Jimsonweed – Dimethyltryptamine (DMT) – Deadly nightshade – 5-Methoxy-DMT • Miscellaneous – Bufotenine – Salvia divinorum • Phenylethylamines – Ketamine – Mescaline – Phencyclidine (PCP) – MDMA (Ecstasy) – Methcathinone (Khat, Jeff) – Methamphetamine 72

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Hallucinogens • Many flavors • Common acon - CNS serotonin receptors (5-HT) • Affects many psychological & physiologic processes (Mood, personality, affect, appete, motor funcon, sexual acvity, temperature regulaon, pain percepon) • > 14 known 5-HT receptor subtypes; Each with different effects & degrees of effect by different structures • Other neurotransmiers also contribute to effects

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Drugs of Abuse/Withdrawal Amphetamines

Now = Serotonergic Methyl additions = ↑ CNS & duration

Primary mechanism of Tox  release of catecholamines (DA, NE) from presynaptic terminals & block reuptake by competitive inhibition 74

Dopamine Release due to Amphetamines

• Low Dose – Released from cyto by exchange diffusion at dopa uptake transporter site in membrane • Moderate Dose – Amphetamines diffuse into presyn terminal → affect NT transporter on vesicular membrane → releasing dopa into cyto → Dopa undergoes reverse transport at Dopa Uptake Receptor → Dopa in synapse • High Dose – amphetamines diffuse into the vesicle → alkalinizes vesicles → Dopa release from vesicles → Membrane Reverse Transport → Dopa in Synapse

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Drugs of Abuse/Withdrawal

Amphetamines Methamphetamine • CNS effect more substanal (chemistry!) • Prolonged half-life (19-34 hours)

• Primary ingredient = ephedrine – Hydrogenated to Methamphetamine • Meth Lab Tox Lead, HCl acid, HCl gas, anhydrous ammonia, red phosphorus, iodine

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Drugs of Abuse/Withdrawal

Amphetamines 3,4-Methylenedioxymethamphetamine (MDMA) • Entactogen (means touching within) – Euphoria, expands consciousness, Inner peace – Desire to socialize, heightened sexuality • One-tenth the CNS smulant effect

• Serotonergic (5-HT chemistry!) • Hyponatremia – Hypovolemic (dancing/sweang), Euvolemic (SIADH), Hypervolemic (water drinking)

• Long-term neuropsychiatric effects 77

Other Phenylethylamines Mescaline

Goldfranks Substuon at the para Toxicology posion of the phenyl ring → ↑ hallucinogenic or 2006 2CB, Nexus, 5HT effects. Bromo

Myristicin is also phenylethylamine based

2CT-7, Blue Mystic 78

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Peyote & Mescaline • A spineless cactus • Lophophora williamsii • Disk-shaped buons are cut from the roots, on the top of the cactus and dried • Peyote buons - round, fleshy tops of the cactus that have been sliced off and dried.

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Peyote & Mescaline • Bier-tasng buons – Eaten whole – Dried → crushed into a powder → Τea • 6-12 buons (270-540 mg of mescaline) typical • Equivalent to roughly 5 grams of dried peyote • Legal use in the US - Nave American Church → religious ceremonies & treatment of physical and psychological ailments. • Used for centuries for the psychedelic effects experienced when it is ingested

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Peyote Mescaline

• Contains a large spectrum of phenethylamines …the principal of which is mescaline • Clinical – Visual hallucinaons and radically altered states of consciousness – Usually pleasurable and illuminang – Occasional - Anxiety or revulsion – Not physically addicve – N/V & Diaphoresis oen precede hallucinaons – Effects lasng for up to 12 hours 81

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Indolalkylamines (Tryptamines)

Bufotenine

www.nida.nih.gov 82

Lysergamides

• LSD is the synthec one • Natural lysergamides – Morning glory (Rivea corymbosa, Ipomoea violacea) • These seeds have many alkaloids • 200-300 seeds - hallucinogenic – Hawaiian baby wood rose (Argyreia nervosa)

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• A dried grain spike of rye grass infected with ergot (Claviceps purpurea). Some of the grains have been replaced by a dark, compact, fungal mass called a sclerotium (superficially resemble rat droppings). • The sclerotia contain • vasoconstricting ergotamine alkaloids • lysergic acid alkaloids which are the precursor for LSD 25.

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Is an Lysergic acid Indole diethylamide

LSD Lysergic Acid The morning glory seeds contain a lysergic acid alkaloid called ergine (d-lysergic acid amide, the "natural" LSD). The more potent synthetic LSD is d-lysergic acid diethylamide 85

Psilocybin • Found in Psilocybe, Panaelous, and Concocybe genera • Grow in Pacific Northwest and southern US; oen in pastures • In the GI tract, is metabolized to Psilocin (acve hallucinogen) • Effects same as LSD but duraon is shorter; ~ 4 hours

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Toads and Hallucinaons

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The Bufo genus

• All species have parod glands on their backs that → various xenobiocs (dopamine, epinephrine, serotonin) • Many species → bufotenine • Only B. alvarius → 5-MeO-DMT

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N Other Hallucinogen Flavors • PCP • Ketamine

Piperidine 89

PCP • Developed in 1950s • Dissociave anesthec • Never approved for human use (Delirium & Bad agitaon as awoke from anesthesia) • Brain Effects – Disrupts NMDA receptor for glutamate – Glutamate receptors… • Percepon of pain • Cognion - including learning and memory • Emoon – Dopamine acon altered • Neurotransmier • Euphoria and "rush" due to many abused drugs. 90

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Ketamine • Dissociave anesthec • Made in 1963 to replace PCP • Current Use - Anesthesia and veterinary medicine. • “Street” K mostly diverted from veterinarians' offices. • Manufactured → Liquid. • Illicit ketamine – Evaporizaon → powder → Snorted or compressed into pills. • Versus PCP - Much ↓ potency & ↓ Duraon.

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Cocaine Derivaon and Types Mechanical Hydrocarbon Cocaine Alkaloid Leaf (benzoylmethylecgonine)

Dissolve in HCl Extracted into Aqueous Phase white powder Cocaine HCl Evaporated Salt in Solution (cocaine hydrochloride)

Dissolve in water • Decomposes if heated Hydrocarbon Solvent Add a strong base • Insufflated (Ether) extracts cocaine base • Applied to other Free-Base Evaporated w/ Heating Crack mucous membrane Liquid • Dissolved in water tobacco or marijuana cigarette is dipped… dried… Smoked Injected or Ingested93

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Cocaine Metabolism

N-Demethylation Non-Enzymatic Hydrolysis

Cholinesterase

Norcocaine Benzoylecgonine

Goldfranks Toxicology 2006 Robert Hoffman Cocaine Chapter Ecgonine Methyl Ester 94

Mechanism Cocaine blocks the Pre-Synaptic reuptake of biogenic amines

Serotonin Dopamine Neuronal Adrenal Norepinephrine epinephrine

Addiction Locomotor Hypertension Tachycardia Reward Effects Seizures Cocaine → ↑ Cerebral Excitatory amino acids Psychomotor agitation Hyperthermia Sedation → ↓ CNS & peripheral Seizures effects of biogenic amines95

An important consideraon for Treatment

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Drugs of Abuse/Withdrawal

Cocaine Withdrawal – Emoonal component = YES • Intense craving

– Physical component = DEBATABLE • Washed-Out Syndrome – Catecholamine Depleon – Lethargy & Adynamic

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U.S. : 100 Proof = 50% EtOH by volume

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No specific Receptor

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é NADH/NAD!!

Gluconeogenesis is Inhibited Pyruvate is reduced to lactate Oxaloacetate is reduced to malate

PREVENTS… flow of metabolites in the direction of gluconeogenesis

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Ethanol EtOH induced hypoglycemia due to high redox ratio!

Malnourished & Children Highest Risk!

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Ethanol

Also cofactor for α-KGD (Krebs) & transketolase (PPP) & important for neuronal conduction

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Ethanol

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Disulfiram Reacons

Cyto ALDH 1 & (Mito ALDH 2 = KEY)

Accumulation of Acetaldehyde = histamine release?.... symptomatology Also inhibits DA beta-hydroxylase (NE synthesis), via chelation of Cu 50% inhib of CYP 2E1, induces 2B1 & 2A1

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- GABA Withdrawal - Cl GABA Cl Pathophysiology Barb Benzo Ethanol

Cl- GABA Receptor Cl- Chloride Channel

Inside Cell → ↑ Negative (Hyperpolarized) Cell Firing ↓

Action Potential Acute 0 EtOH Effects

-30 Threshold Potential mV Resting -70 Potential

Membrane Potential Potential Membrane -90 New Resting 1 2 3 4 Potential Time (ms)

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Chronic Suddenly Disinhibited Action Remove Potential EtOH EtOH → New ↓ In-Cell0 Cl- Effects Resting Potential

-30 Threshold Potential mV Original -70 Resting Tolerance!

Potential (Cell Δ) Membrane Potential Potential Membrane -90 Resting Potential 1 2 3 4

Time (ms) 108

36 Anesthetics; Drugs of Abuse & Withdrawal

Ethanol/Sedave Hypnoc Withdrawal MILD Alcoholic Hallucinos. Tremor Visual or auditory Tachycardia Persecutory HTN Within a few hours Diaphoresis Independently? Anxiety Clear Mentation Disturbing Delirium Tremens 24 hrs after Lasts 3-5 days Altered sensorium May=hallucinate (visual or tactile), Seizures “rum fits” Sz’s, psycomotor 6-48 hours after agitation. Single, Generalized, Brief, short postictal Autonom Instable 109

Drugs of Abuse/Withdrawal

Gamma-Hydroxybutyric Acid

110

111

37 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

GHB Withdrawal – Potenally severe & life-threatening – Rapid development (within hours of use) – Agitaon, disorientaon, hallucinaons, HTN, tachycardia, hyperthermia, tremor, Sz – Consistent with sedave-hypnoc W/D • Treatment the same

112

Drugs of Abuse/Withdrawal Inhalants

113

Drugs of Abuse/Withdrawal

Inhalants

114

38 Anesthetics; Drugs of Abuse & Withdrawal

Slip em a Mickey!

115

Drugs of Abuse/Withdrawal

Metabolites may be Cannabinoids detected in the urine of chronic W/D? users Tremor for several weeks Sweaty Fever Nausea Irritable Restless Sleepless Nervous

116

Drugs of Abuse/Withdrawal Nicone – Terary amine, colorless, bier, H2O soluble – Weakly alkaline (pKa=8.0-8.5) – Solanaceae family of plants • Nicoana tabacum • N. rusca (higher concentraon, Turkish tobacco) – Lobeline • Lobelia inflata (Indian tobacco) – Cyssine (mescal beans) – Coniine • Lethal alkaloid in poison hemlock

117

39 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

• Oen biphasic; with niconic smulaon early ; followed by “loss of smulaon” due to receptor fague • Note can have both sympathec and parasympathec signs and symptoms • Voming is #1 most common; occurs early. • Death due to CV collapse and respiratory depression 118

Drugs of Abuse/Withdrawal Nicone Withdrawal

119

Opioids

120

40 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal Opioids • 2D6 polymorphisms affect clinical effects • Heroin – beer BBB penetraon bc of more hydrocarbon groups →the “Rush” • 6-MAM – Not natural; confirms heroin presence – More potent than morphine

121

Drugs of Abuse/Withdrawal

Opioids Heroin (3,6-diacetylmorphine) Hydrochloride salt – White or beige powder (insufflaon) – H2O soluble = IV administraon Heroin base – More prevalent form – Brown or black – Relavely insoluble in H2O – Insufflaon – Chasing the dragon

» Spongiform leukoencephalopathy 122

Dextromethorphan • D-isomer of codeine analog levorphanol • No analgesic, respiratory, or CNS effects at therapeuc doses • Dextrophan is acve metabolite → ↑ serotonin release → Affects NMDA receptor at PCP site (→ Hallucinaons) → Sigma receptor effects • Toxicity: Hyperexcitable, lethargy, ataxia, diaphoresis, HTN, nystagmus, dystonia, seizures; occasionally opioid-like

Does Narcan work? Variable 123

41 Anesthetics; Drugs of Abuse & Withdrawal

Meperidine • Meperidine → Nor-meperidine T½ 3-4 hrs 15-30 hrs • Serotonin ↑ due to ↓ reuptake of the NT & ↑ release • Toxicity: twitches, tremors, myoclonus; seizures

MAOIs potentiated: The unique drug reaction Agitation Irritability compared to other opioids? Hyperpyrexia Tachycardia

Hypertension 124

Tramadol • Analog of codeine • Analgesia: – Mu-agonism is 10% of codeine – NE and serotonin reuptake ↓ → pain modulaon

Toxicity - lethargy, tachycardia, agitation, seizures, hypertension. • Narcan reverses sedaon and some ot the analgesia; but…its use has → seizures • Physical dependence has occurred

125

Drugs of Abuse/Withdrawal

Opioids Averse Effects • Acute lung injury • Seizures (tramadol, propoxyphene, meperidine) • Na channel blockade (propoxyphene) • Decreased BP (histamine release) • Rigid Chest (fentanyl) • Myoclonus (fentanyl, meperidine)

126

42 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

Opioid Withdrawal – Uncomfortable – Generally not life-threatening Physiologic – Heroin W/D = 4 – 8 hours Tachycardia – Methadone W/D = 36 – 72 hours Tachypnea – Psychological Diaphoresis • Craving Tearing Not • Dysphoria Yawning Delirium • Anxiety Rhinorrhea Seizures Myalgias • Insomnia CV collapse Piloerection Hyperpyrexia Abdominal pain

N/V/D 127

Drugs of Abuse/Withdrawal

Critical Care Toxicology 128

You are geng

sleepy… 129

43