3.1 kleinschmidt anesthetics, doa wd kck edit of 2010 ... · anesthetics; drugs of abuse &...

Anesthetics; Drugs of Abuse & Withdrawal

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Anesthe'cs; Drugs of Abuse & Withdrawal

Kurt Kleinschmidt, MD, FACEP, FACMT Professor of Emergency Medicine Sec=on Chief and Program Director

Medical Toxicology UT Southwestern Medical Center

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Much Thanks To… Sean M. Bryant, MD Associate Professor Cook County Hospital (Stroger) Department of Emergency Medicine Assistant Fellowship Director: Toxikon Consor7um Associate Medical Director Illinois Poison Center

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Overview

Anesthe'cs – Local –  Inhala=onal – NM Blockers & Malignant Hyperthermia

Drugs of Abuse (Pearls) Withdrawal

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History

1904-‐Procaine (short Dura=on of Ac=on) 1925 (dibucaine) & 1928 (tetracaine)

→ potent, long ac=ng 1943-‐lidocaine 1956-‐mepivacaine, 1959-‐prilocaine 1963-‐bupivacaine, 1971-‐e=docaine, 1996-‐ropivacaine 4

Structure

2 Dis'nct Groups 1) Amino Esters

2) Amino Amides

Esters

Amides

Lipophilic Group

Intermediate Amine Substituents

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Local Anesthe=cs Toxic Reac=ons

•  Few & iatrogenic • Blood vessel administra=on or toxic dose

AMIDES have largely replaced ESTERS •  Increased stability • Rela=ve absence of hypersensi=vity reac=ons

– ESTER hydrolysis = PABA (cross sensi=vity) – AMIDES = Mul=dose preps → methylparabens

» Chemically related to PABA with rare allergic reac'ons

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Local Anesthe=cs Mode of Ac=on

•  Reversible & Predictable Binding •  Within membrane-‐bound sodium channels of conduc=ng =ssue (cytoplasmic side of membrane) → Failure to form/propagate ac=on poten=als

(Small-‐diam. fibers carrying pain/temp sensa=on)

•  Sodium Channel (3 States) –  Closed (res=ng or hyperpolarized) –  Open –  Inac=vated BLOCKADE

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

anesthetics 7

ONSET OF ACTION ↓ pKa (uncharged)

HIGHER POTENCY Higher lipophilicity Intermediate chain length Higher protein binding 3-7 carbon equiv’s 8

Local Anesthe=cs Pharmacokine=cs

•  Local vs. Systemic disposi=ons •  Lipophilic = crosses membranes! (BBB, placenta) •  Distribu=on depends on =ssue perfusion •  Lungs = uptake; buffers systemic toxicity?

– Saturable kine=cs (lung uptake is exceeded → Toxicity)

•  Peripheral vasodila=on (except cocaine)

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Local Anesthe=cs Pharmacokine'cs

Metabolism AMINO ESTERS PABA

AMINO AMIDES Metabolites unrelated to PABA

Plasma Cholinesterase

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

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Local Anesthe=cs Clinical manifesta=ons

Direct cytotoxicity (nerve cells)

•  Excessive concentra=ons or Bad formula=ons •  Uncommon

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

Skeletal muscle changes •  IM injec=ons (highly potent, longer ac=ng agents) •  Reversible (2 weeks)

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Local Anesthe=cs Systemic Toxicity

– Allergic reac=ons (Amino Esters -‐-‐ PABA) -‐ Rare – Methemoglobinemia

• Reported with lidocaine, tetracaine, prilocaine •  Topical/oropharyngeal benzocaine

OXIDIZING AGENTS

aniline

phenylhydroxylamine & nitrobenzene

Vasovagal Reactions Reported 12


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

Brain & Heart -‐ #1 Targets

•  Rich perfusion •  Moderate =ssue-‐blood par==on coefficients •  Lack of diffusion limita=ons •  Cells that rely on voltage-‐gated Na channels

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Local Anesthe=cs Systemic Toxicity CNS Excitation: block inhibitory pathways in amygdala → ↑ excitatory activity. Both Inhibitory & Excitatory neurons blocked as concentration ↑ → CNS ↓

Bupivacaine: Large IV bolus = May only see brady, CNS depression & respiratory arrest!

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CNS Effects Determinants – Potency & Dose – Rate of injec=on – Drug interac=ons – Acid-‐base status

• Acidemia → ↓ protein binding → ↑ free drug • Hypercarbia

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Bupivacaine significantly more Cardiotoxic

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

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Local Anesthe=cs Systemic Toxicity •  Lidocaine

– Na channel blockade greater if pt is tachycardic – Quickly dissociates at diastolic poten=als

• Rapid recovery

•  Bupivacaine – Rapid binding & Slow dissocia=on – S is less cardiotoxic vs. R – Uncouples & inhibits Complex I of respiratory chain –  Inhibits carni=ne-‐acylcarni=ne translocase – Blocks GABAergic neurons – May ↓ Ca++ release from SR →↓ Contrac=lity

Non Na+-channel Issues

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Local Anesthe=cs Management

CNS • DC administra=on •  Suppor=ve care (CV monitoring) • Benzos, Barbs (Thiopental, Propofol) • NM blocking agents (EEG monitoring) • HD not effec=ve (HP for lidocaine?)

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CV

•  Recognize! (CNS effects may preoccupy) •  Correct physiologic derangements

– Hypoxemia, acidemia, hyperkalemia • Maximize Oxygena=on •  Support Ven=la=on/Circula=on •  Hypotension (adrenergic agonists) •  Bradycardia (atropine)

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CV • Dysrhythmias

– Open refractory to standard care • Pacing, Bypass •  Lidocaine for bupivacaine? (rela=vely less toxic) • Prolonged CPR/Resuscita=on efforts • Na Bicarbonate? (To prevent acidosis) •  Insulin? (same magical reasons as elsewhere)

LIPIDS 20

http://lipidrescue.squarespace.com/welcome/ 21


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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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Inhala=onal Anesthe=cs •  Ether

–  Paracelsus – put hens “to sleep” – The 1st descrip=on –  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) •  Vola%le Anesthe%cs (Fluroxene, Halothane,

Methoxyflurane) –  1840’s – 1940’s = combus=bility and direct organ toxicity

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Inhala=onal Anesthe=cs

Improved Clinical Proper%es

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Inhala=onal Anesthe=cs Pathophysiology

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

•  Func=on modulated from within cells •  Interact with many ion channels (target?) •  Side effects = effects in nonneural 7ssue (cardiac)

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Inhala=onal Anesthe=cs Pathophysiology

Goal = Reversible changes in neuro func=on •  Loss of percep=on and reac=on 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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Inhala=onal Anesthe=cs Pharmacokine=cs

Potency – Physiochemical Proper=es • Meyer-‐Overton lipid solubility theory

– Potency correlates directly with rela=ve 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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Factors that influence absorp=on & distribu=on •  Solubility in blood •  Solubility in =ssue • Blood flow through lungs • Blood flow distribu=on to various organs • Mass of the =ssue

GOAL:

Develop & Maintain satisfactory partial pressure

in the Brain! 30


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

Minimum alveolar concentra%on (MAC) • Potency •  The [alveolar] at 1 atm that prevents movement in 50% of subjects in response to a painful s=mulus

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NITROUS OXIDE Advantages

• Mild odor • Absence of airway irrita=on • Rapid induc=on & emergence • Potent • Minimal respiratory & circulatory effects •  Safe

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NITROUS OXIDE • Abuse Poten=al • Asphyxia -‐ Death/Brain damage from asphyxia (2°) •  Impuri=es – Nitric oxide, nitrogen dioxide • Barotrauma

– 35x more soluble in blood than Nitrogen – Pressure in air-‐containing spaces

(bowel, ears, chest) 33


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Methionine & THF both required for DNA & myelin

synthesis!!!

NO → oxidizes cobalt in B12 → Inactive form

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NITROUS OXIDE Hematologic Effects

•  BONE MARROW SUPPRESSION •  Occurs in all pa=ents •  Recovery generally occurs (4 days) •  PERNICIOUS ANEMIA-‐Like

– This has ↓ B12 Absorp=on due to absence of Intrinsic Factor (vs NO – ac=ve B12 can’t be made by the body)

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NITROUS OXIDE Neurologic Effects

• Only aper chronic exposure •  Is a disabling polyneuropathy •  Subacute Combined Degenera=on of Spinal Cord •  Sensorimotor polyneuropathy • Posterior & Lateral cord involvement • Numbness & paresthesias in extreme=es • Weakness & truncal ataxia

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Inhala=onal Anesthe=cs NITROUS OXIDE

Management • Removal of source • B12

– Helps best if brief exposure – Won’t help chronically exposed pa=ents?

•  Folinic acid 30 mg IV – May reverse BM abnormali=es

• Methionine Supplementa'on – Experimentally (Primates) reduced demyelina=on 39


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Inhala=onal Anesthe=cs HALOTHANE

HALOTHANE HEPATITIS (1) Mild Dysfunc%on

– 20% of exposed pa=ents – Asymptoma=c – Modestly ↑ transaminases within days – Complete recovery

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(2) Life-‐Threatening Hepa%%s – 1 in 10,000 pa=ents – Fatal hepa=c necrosis in 1 of 35,000 pa=ents – A diagnosis of exclusion – Increased risk

» Mul=ple exposures » Obesity (fat reservoir, prolonged release) » Female » Age (middle age) » Ethnicity (Mexican)

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HALOTHANE HEPATITIS

Volatile Metabolites: Free Radicals

or Haptens

20% oxidative metabolism via CYP – trifluoroacetic acid

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Inhala=onal Anesthe=cs •  Enflurane – weakly associated •  Immune form of hepa''s (all but sevoflurane)

Isoflurane, Desflurane Low Hepatotoxic Poten'al

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Inhala=onal Anesthe=cs HALOTHANE ABUSE

Inges'on •  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

Inhala'on •  Most reported cases = hospital personnel

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NEPHROTOXICITY Methoxyflurane (intro 1962)

•  Vasopressin-‐resistant polyuric renal insufficiency •  Nephrogenic DI •  Polyuria = nega=ve fluid balance •  High Na, Osmolality, BUN •  Lasted 10-‐20 days (up to > 1year) •  Tox = Inorganic Fluoride (F) released during biotransforma=on of methoxyflurane

– F inhibits adenylate cyclase (ADH interference)?

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Currently Used Anesthe'cs • Halothane, Isoflurane, Enflurane, Desflurane, Sevo. •  Enflurane & Sevoflurane biotransform by deF

– 5% of sevoflurane is metabolized – Transient decrease in urine-‐concentra=ng ability – Rarely clinically relevant

• Pre-‐exis=ng RI = risk of renal dysfunc=on?

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Inhala=onal Anesthe=cs Anesthe'c-‐Related CO Poisoning

Desflurane, Enflurane, Isoflurane •  Contain a difluoromethoxy moiety

– Can be degraded to Carbon Monoxide

•  CO produc'on – 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. aGer 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 frigh{ully 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 postsynap=c nico'nic (nAch) receptor at the NMJ → ↓ ac=va=on 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 Modula'on of postsynap'c 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! •  Fascicula=ons!! •  Succ not hydrolyzed efficiently by true AchE • Voltage-‐gated Na channel in peri-‐junc=onal region

– Prolonged inac=ve state → desensi=za=on block → Muscle= temporarily refractory to presyn Ach

release (phase I block) 53

Neuromuscular Blockers Modula=on of postsynap=c Ach receptor

Nondepolarizing (phase II block) •  Compe==vely inhibit effects of Ach •  Prevent muscle depolariza%on! •  One molecule of NDNMB binds to α site

– Compe==vely inhibits normal channel ac=va=on

•  DO NOT block voltage-‐gated Na channels on mus mem – So…Direct electrical s=mula=on of muscle contrac=on = possible

•  Also block nAch receptors on prejunc=onal nerves – Inhibits Ach-‐s=mulated Ach produc=on & release

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Neuromuscular Blockers Pharmacokine=cs

Highly water soluble (won’t cross BBB) Speed of onset -‐ 1/ molar potency

(The > affinity for receptor, the fewer molecules/Kg 7ssue required)

In general: small, fast contrac=ng muscles

•  Most suscep=ble (e.g. extraocular vs. large slow) •  Respiratory Sparing Effect

Recovery fastest for diaphragm and IC muscles

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Neuromuscular Blockers Complica=ons

Pa'ent Awareness

•  NMBs do not affect consciousness •  Pupillary light reflex preserved in healthy pa=ents

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


Control of Respira'on

Subparalyzing doses – Blunt hypoxic ven=latory response (HVR) – But not the ven=latory response to hypercapnia

Autonomic Side Effects Tubocurarine

– Blocks nAch rec at PNS ganglia → Tachycardia

– At SNS ganglia → ↓ sympathe=c response – Histamine release

HYPOTENSION! 57


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Autonomic Side Effects

•  Muscarinic receptors mostly unaffected •  Pancuronium

– Blocks PNS transmission at Cardiac M Recs (Atropine-‐like effect)

– Block of presynap=c M receptors at SNS terminals – ? Indirect NE-‐releasing effect at postgang fibers → Dose-‐ and injec'on rate-‐related increase in Heart Rate, BP, CO, and Sympathe'c Tone

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Autonomic Side Effects

Succinylcholine – Rarely: Dysrhythmias -‐bradycardia, junct & vent rhythms – Due to S=mula=on 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 Interac=ons

Poten%ate dura=on 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 ac=vity)

– OP or Carbamate Poisoning – Hepa=c Dz, Malnutri=on, Pregnancy – Phase II block (large doses over short period – 8mg/kg)

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Neuromuscular Blockers Succinylcholine TOX 2) Hyperkalemia

Exaggerated with myopathy or prolifera7on of extrajunc7onal Ach rec

Suscep'bility aper neuro injury begins in 4-‐7 days! Denerva=on

Head or SC injury, CVA, neuropathy Muscle pathology

Trauma, compartment syndrome, musc dystrophy Cri=cal illness Hem shock, neuropathy, myopathy, ICU > 1 wk

Thermal burn or cold injury Sepsis (x several days)

“Normal or RI Patients” 1 mg/kg raises [K] approximately 0.5 mEq/L

Assume cardiac arrest after Sucks is

due to hyperkalemia

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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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Succinylcholine TOX 4) Muscle Spasms

– Masseter Muscle Rigidity (MMR) » Pediatric Pa=ents: 0.3-‐1% (Succ + Halothane)

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

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Succinylcholine TOX 5) Malignant Hyperthermia

» Inherited hypermetabolic condi=on » 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 ↑)

Also Volatile Anesthetics!

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Malignant Hyperthermia

Signs and Symptoms of MH (First 30 Min) Tachycardia 90% Hypercarbia 80% Rigidity 80% Hypertension 75% Hyperthermia 70%

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

May be a late sign

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Malignant Hyperthermia Management

• Aggressive Suppor=ve Care volume, cooling, hyper K…

DANTROLENE

» Prior Mortality Rate = 70% (now < 5%!!!) » Par=ally 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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NDNMBs TOX •  Persistent Weakness

– Administra=on longer than 48 hours – Cri=cal illness associated (mul=factorial)

•  2.5-‐3.5 – fold increase in ICU mortality & ICU stay

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Unique Toxicity •  Metocurine – con=nes iodine, hypersensi=vity and shellfish allergy

•  Rapacuronium – fatal bronchospasm, withdrawn.

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Drugs of Abuse/Withdrawal

Tolerance •  Physiologic process: increasing drug concentra=ons required •  Ship in dose-‐response curve to the right •  Receptor modula=on (opioids), metab (barbs), or both (EtOH) •  “Cross Tolerance” Key to trea=ng W/D

Dependence •  Implies that cessa=on leads to withdrawal

Withdrawal •  Physiologic (autonomic instability, N/V/D, hyperac=vity, AMS) •  Psychological (emo=onal symptoms & craving)

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Hallucinogens •  Lysergamides

–  LSD –  Ergine

•  Indolalkylamines / Typtamine –  Psilocin & Psilocybin –  Dimethyltryptamine (DMT) –  5-‐Methoxy-‐DMT –  Bufotenine

•  Phenylethylamines – Mescaline – MDMA (Ecstasy) – Methcathinone (Khat, Jeff) – Methamphetamine

•  Tetrahydrocannabinoids – Marijuana –  Hashish

•  Belladonna Alkaloids –  Jimsonweed –  Deadly nightshade

•  Miscellaneous –  Salvia divinorum –  Ketamine –  Phencyclidine (PCP)

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Hallucinogens •  Many flavors •  Common ac=on -‐ CNS serotonin receptors (5-‐HT)

•  Affects many psychological & physiologic processes (Mood, personality, affect, appe=te, motor func=on, sexual ac=vity, temperature regula=on, pain percep=on)

•  > 14 known 5-‐HT receptor subtypes; Each with different effects & degrees of effect by different structures

•  Other neurotransmi�ers also contribute to effects

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Drugs of Abuse/Withdrawal Amphetamines

Primary mechanism of Tox release of catecholamines (DA, NE) from presynaptic terminals

& block reuptake by competitive inhibition

Methyl additions = ↑ CNS & duration

Now = Serotonergic

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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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Amphetamines Methamphetamine

•  CNS effect more substan=al (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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Amphetamines 3,4-‐Methylenedioxymethamphetamine (MDMA)

•  Entactogen (means touching within) – Euphoria, expands consciousness, Inner peace – Desire to socialize, heightened sexuality

•  One-‐tenth the CNS s=mulant effect •  Serotonergic (5-‐HT chemistry!) •  Hyponatremia

– Hypovolemic (dancing/swea=ng), Euvolemic (SIADH), Hypervolemic (water drinking)

•  Long-‐term neuropsychiatric effects 77

Other Phenylethylamines

Subs=tu=on at the para posi=on of the phenyl ring → ↑ hallucinogenic or 5HT effects. 2CB, Nexus,

Bromo

2CT-7, Blue Mystic

Mescaline

Goldfranks Toxicology

2006

Myristicin is also phenylethylamine based

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Peyote & Mescaline •  A spineless cactus •  Lophophora williamsii •  Disk-‐shaped bu�ons are cut from the roots, on the top of the cactus and dried

•  Peyote bu�ons -‐ round, fleshy tops of the cactus that have been sliced off and dried.

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Peyote & Mescaline •  Bi�er-‐tas=ng bu�ons

– Eaten whole – Dried → crushed into a powder → Τea

•  6-‐12 bu�ons (270-‐540 mg of mescaline) typical •  Equivalent to roughly 5 grams of dried peyote •  Legal use in the US -‐ Na=ve 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 hallucina=ons and radically altered states of consciousness

–  Usually pleasurable and illumina=ng –  Occasional -‐ Anxiety or revulsion –  Not physically addic=ve –  N/V & Diaphoresis open precede hallucina=ons –  Effects las=ng for up to 12 hours 81


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www.nida.nih.gov

Bufotenine

Indolalkylamines (Tryptamines)

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Lysergamides

•  LSD is the synthe=c 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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Lysergic acid diethylamide

Is an Indole

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

LSD Lysergic

Acid

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Psilocybin •  Found in Psilocybe, Panaelous, and Concocybe genera

•  Grow in Pacific Northwest and southern US; open in pastures

•  In the GI tract, is metabolized to Psilocin (ac=ve hallucinogen)

•  Effects same as LSD but dura=on is shorter; ~ 4 hours

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Toads and Hallucina=ons

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The Bufo genus

•  All species have paro=d glands on their backs that → various xenobio=cs (dopamine, epinephrine, serotonin)

•  Many species → bufotenine •  Only B. alvarius → 5-‐MeO-‐DMT

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Other Hallucinogen

Flavors •  PCP •  Ketamine

N

Piperidine 89

PCP •  Developed in 1950s •  Dissocia=ve anesthe=c •  Never approved for human use (Delirium & Bad agita=on as awoke from anesthesia)

•  Brain Effects – Disrupts NMDA receptor for glutamate – Glutamate receptors…

• Percep=on of pain • Cogni=on -‐ including learning and memory •  Emo=on

– Dopamine ac=on altered • Neurotransmi�er •  Euphoria and "rush" due to many abused drugs.

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Ketamine •  Dissocia=ve anesthe=c •  Made in 1963 to replace PCP •  Current Use -‐ Anesthesia and veterinary medicine.

•  “Street” K mostly diverted from veterinarians' offices.

•  Manufactured → Liquid. •  Illicit ketamine – Evaporiza=on → powder → Snorted or compressed into pills.

•  Versus PCP -‐ Much ↓ potency & ↓ Dura=on.

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Cocaine Deriva=on and Types

Leaf

Mechanical Hydrocarbon Cocaine Alkaloid

(benzoylmethylecgonine)

Cocaine HCl Salt in Solution

Extracted into Aqueous Phase Evaporated

white powder (cocaine hydrochloride)

•  Decomposes if heated •  Insufflated •  Applied to other mucous membrane • Dissolved in water

Dissolve in water

Add a strong base

Hydrocarbon Solvent

(Ether) extracts cocaine base

Evaporated w/ Heating Free-Base Liquid tobacco or marijuana

cigarette is dipped…dried…

Crack

Smoked Injected or Ingested

Dissolve in HCl

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N-Demethylation

Cholinesterase

Non-Enzymatic Hydrolysis

Norcocaine

Ecgonine Methyl Ester

Benzoylecgonine

Cocaine Metabolism

Goldfranks Toxicology 2006 Robert Hoffman Cocaine Chapter

94

Mechanism Cocaine blocks the Pre-Synaptic reuptake of biogenic amines

Serotonin Dopamine Neuronal Norepinephrine

Adrenal epinephrine

Locomotor Effects

Addiction Reward Seizures

Hypertension Tachycardia

Psychomotor agitation Hyperthermia Seizures

Cocaine → ↑ Cerebral Excitatory amino acids

Sedation → ↓ CNS & peripheral effects of biogenic amines 95

An important considera=on

for Treatment

96


33


Cocaine Withdrawal – Emo=onal component = YES

•  Intense craving

– Physical component = DEBATABLE • Washed-‐Out Syndrome

– Catecholamine Deple=on – Lethargy & Adynamic

97

98

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

99


34

No specific Receptor

100

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

101

Ethanol EtOH induced hypoglycemia due to high redox ratio!

Malnourished & Children Highest Risk!

102


35

Ethanol

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

103

Ethanol

104

Disulfiram Reac=ons

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 105


36

Withdrawal Pathophysiology

GABA Receptor Chloride Channel

GABA

Benzo Barb

Inside Cell → ↑ Negative (Hyperpolarized) Cell Firing ↓

Ethanol

Cl-

Cl-

Cl- Cl- GABA

Benzo Barb

Threshold Potential

Resting Potential

Acute EtOH Effects

Mem

bran

e Po

tent

ial

Action Potential

mV

-70

-30

-90

0

Time (ms) 1 2 3 4

New Resting Potential

107

Threshold Potential

Original Resting Potential

Chronic EtOH Effects

Action Potential

Mem

bran

e Po

tent

ial

mV

-70

-30

-90

0

Time (ms) 1 2 3 4

Resting Potential

Tolerance! (Cell Δ)

Suddenly Remove EtOH →

↓ In-Cell Cl- New Resting

Potential

Disinhibited

108


37

Ethanol/Seda've Hypno'c Withdrawal MILD

Tremor Tachycardia HTN Diaphoresis Anxiety

Seizures “rum fits” 6-48 hours after Single, Generalized, Brief, short postictal

Alcoholic Hallucinos. Visual or auditory Persecutory Within a few hours Independently? Clear Mentation Disturbing Delirium Tremens

24 hrs after Lasts 3-5 days Altered sensorium May=hallucinate (visual or tactile), Sz’s, psycomotor agitation. Autonom Instable 109


Gamma-‐Hydroxybutyric Acid

110

111


38


GHB Withdrawal – Poten=ally severe & life-‐threatening – Rapid development (within hours of use) – Agita=on, disorienta=on, hallucina=ons, HTN, tachycardia, hyperthermia, tremor, Sz

– Consistent with seda=ve-‐hypno=c W/D •  Treatment the same

112

Drugs of Abuse/Withdrawal Inhalants

113


Inhalants

114


39

Slip em a Mickey!

115


Cannabinoids Metabolites may be

detected in the urine of chronic

users for several weeks

W/D? Tremor Sweaty Fever Nausea Irritable Restless Sleepless Nervous

116

Drugs of Abuse/Withdrawal Nico'ne

– Ter=ary amine, colorless, bi�er, H2O soluble – Weakly alkaline (pKa=8.0-‐8.5) – Solanaceae family of plants

• Nico7ana tabacum • N. rus7ca (higher concentra=on,

Turkish tobacco) – Lobeline

•  Lobelia inflata (Indian tobacco) – Cys=sine (mescal beans) – Coniine

•  Lethal alkaloid in poison hemlock 117


40


•  Open biphasic; with nico=nic s=mula=on early ; followed by “loss of s=mula=on” due to receptor fa=gue

•  Note can have both sympathe=c and parasympathe=c signs and symptoms

•  Vomi=ng is #1 most common; occurs early. •  Death due to CV collapse and respiratory depression

118

Drugs of Abuse/Withdrawal Nico=ne Withdrawal

119

Opioids

120


41


•  2D6 polymorphisms affect clinical effects

•  Heroin – be�er BBB penetra=on bc of more hydrocarbon groups →the “Rush”

•  6-‐MAM –  Not natural; confirms heroin presence

– More potent than morphine

Opioids

121


Opioids Heroin (3,6-‐diacetylmorphine)

Hydrochloride salt – White or beige powder (insuffla=on) – H2O soluble = IV administra=on

Heroin base – More prevalent form – Brown or black – Rela=vely insoluble in H2O – Insuffla'on – Chasing the dragon

» Spongiform leukoencephalopathy 122

Dextromethorphan •  D-‐isomer of codeine analog levorphanol •  No analgesic, respiratory, or CNS effects at therapeu=c doses

•  Dextrophan is ac=ve metabolite → ↑

serotonin release → Affects NMDA receptor at PCP site (→ Hallucina=ons) → Sigma receptor effects

•  Toxicity: Hyperexcitable, lethargy, ataxia, diaphoresis, HTN, nystagmus, dystonia, seizures; occasionally opioid-‐like

Does Narcan work? Variable 123


42

Meperidine •  Meperidine → Nor-‐meperidine

•  Serotonin ↑ due to ↓ reuptake of the NT & ↑ release

•  Toxicity: twitches, tremors, myoclonus; seizures

T½ 3-4 hrs 15-30 hrs

The unique drug reaction compared to other opioids?

MAOIs potentiated: Agitation Irritability Hyperpyrexia Tachycardia Hypertension 124

Tramadol •  Analog of codeine •  Analgesia:

– Mu-‐agonism is 10% of codeine – NE and serotonin reuptake ↓ → pain modula=on

•  Narcan reverses seda=on and some ot the analgesia; but…its use has → seizures

•  Physical dependence has occurred

Toxicity - lethargy, tachycardia, agitation, seizures, hypertension.

125


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


43


Opioid Withdrawal –  Uncomfortable –  Generally not life-‐threatening –  Heroin W/D = 4 – 8 hours – Methadone W/D = 36 – 72 hours –  Psychological

•  Craving •  Dysphoria •  Anxiety •  Insomnia

Physiologic Tachycardia Tachypnea Diaphoresis

Tearing Yawning

Rhinorrhea Myalgias

Piloerection Abdominal pain

N/V/D

Not Delirium Seizures

CV collapse Hyperpyrexia

127


Critical Care Toxicology 128

You are ge�ng sleepy…

129

3.1 kleinschmidt anesthetics, doa wd kck edit of 2010 ... · anesthetics; drugs of abuse &...

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