Upload
lediep
View
214
Download
0
Embed Size (px)
Citation preview
Anesthetics; Drugs of Abuse & Withdrawal
1
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
1
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
2
Overview
Anesthe'cs – Local – Inhala=onal – NM Blockers & Malignant Hyperthermia
Drugs of Abuse (Pearls) Withdrawal
3
Anesthetics; Drugs of Abuse & Withdrawal
2
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
5
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
6
Anesthetics; Drugs of Abuse & Withdrawal
3
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)
9
Anesthetics; Drugs of Abuse & Withdrawal
4
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)
10
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)
11
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
Anesthetics; Drugs of Abuse & Withdrawal
5
Local Anesthe=cs Systemic Toxicity
• 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
13
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!
14
Local Anesthe=cs Systemic Toxicity
CNS Effects Determinants – Potency & Dose – Rate of injec=on – Drug interac=ons – Acid-‐base status
• Acidemia → ↓ protein binding → ↑ free drug • Hypercarbia
15
Anesthetics; Drugs of Abuse & Withdrawal
6
Local Anesthe=cs Systemic Toxicity
Bupivacaine significantly more Cardiotoxic
CC/CNS ([Cardio collapse/CNS Tox]) – Lidocaine = 7 (CNS tox more evident) – Bupivacaine = 3.7
16
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
17
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?)
18
Anesthetics; Drugs of Abuse & Withdrawal
7
Local Anesthe=cs Management
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)
19
Local Anesthe=cs Management
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
Anesthetics; Drugs of Abuse & Withdrawal
8
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
22
23
24
Anesthetics; Drugs of Abuse & Withdrawal
9
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
25
Inhala=onal Anesthe=cs
Improved Clinical Proper%es
26
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)
27
Anesthetics; Drugs of Abuse & Withdrawal
10
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
28
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
29
Inhala=onal Anesthe=cs Pharmacokine=cs
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
Anesthetics; Drugs of Abuse & Withdrawal
11
Inhala=onal Anesthe=cs Pharmacokine=cs
• 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
31
Inhala=onal Anesthe=cs
NITROUS OXIDE Advantages
• Mild odor • Absence of airway irrita=on • Rapid induc=on & emergence • Potent • Minimal respiratory & circulatory effects • Safe
32
Inhala=onal Anesthe=cs
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
Anesthetics; Drugs of Abuse & Withdrawal
12
34
35
Inhala=onal Anesthe=cs
Methionine & THF both required for DNA & myelin
synthesis!!!
NO → oxidizes cobalt in B12 → Inactive form
36
Anesthetics; Drugs of Abuse & Withdrawal
13
Inhala=onal Anesthe=cs
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)
37
Inhala=onal Anesthe=cs
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
38
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
Anesthetics; Drugs of Abuse & Withdrawal
14
Inhala=onal Anesthe=cs HALOTHANE
HALOTHANE HEPATITIS (1) Mild Dysfunc%on
– 20% of exposed pa=ents – Asymptoma=c – Modestly ↑ transaminases within days – Complete recovery
40
Inhala=onal Anesthe=cs HALOTHANE
(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)
41
Inhala=onal Anesthe=cs HALOTHANE
HALOTHANE HEPATITIS
Volatile Metabolites: Free Radicals
or Haptens
20% oxidative metabolism via CYP – trifluoroacetic acid
42
Anesthetics; Drugs of Abuse & Withdrawal
15
Inhala=onal Anesthe=cs • Enflurane – weakly associated • Immune form of hepa''s (all but sevoflurane)
Isoflurane, Desflurane Low Hepatotoxic Poten'al
43
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
44
Inhala=onal Anesthe=cs
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)?
45
Anesthetics; Drugs of Abuse & Withdrawal
16
Inhala=onal Anesthe=cs
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?
46
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)
47
Anesthesia Is GOOD!!!
48
Anesthetics; Drugs of Abuse & Withdrawal
17
49
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...)
50
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
51
Anesthetics; Drugs of Abuse & Withdrawal
18
Goldfrank’s 8th ed, page 1026
Excitation-Contraction coupling in skeletal muscle
Calcium Release Unit the intimate association of DHPR, RYR-1, & SR
52
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
54
Anesthetics; Drugs of Abuse & Withdrawal
19
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
55
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
Neuromuscular Blockers Complica=ons
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
Anesthetics; Drugs of Abuse & Withdrawal
20
Neuromuscular Blockers Complica=ons
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
58
Neuromuscular Blockers Complica=ons
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
59
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
60
Anesthetics; Drugs of Abuse & Withdrawal
21
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)
61
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
62
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%)
63
Anesthetics; Drugs of Abuse & Withdrawal
22
Neuromuscular Blockers
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)
64
Neuromuscular Blockers
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!
65
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
66
Anesthetics; Drugs of Abuse & Withdrawal
23
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
67
Neuromuscular Blockers
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
68
Neuromuscular Blockers
Unique Toxicity • Metocurine – con=nes iodine, hypersensi=vity and shellfish allergy
• Rapacuronium – fatal bronchospasm, withdrawn.
69
Anesthetics; Drugs of Abuse & Withdrawal
24
70
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)
71
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)
72
Anesthetics; Drugs of Abuse & Withdrawal
25
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
73
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
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
75
Anesthetics; Drugs of Abuse & Withdrawal
26
Drugs of Abuse/Withdrawal
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
76
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 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
78
Anesthetics; Drugs of Abuse & Withdrawal
27
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.
79
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
80
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
Anesthetics; Drugs of Abuse & Withdrawal
28
www.nida.nih.gov
Bufotenine
Indolalkylamines (Tryptamines)
82
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)
83
• 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.
84
Anesthetics; Drugs of Abuse & Withdrawal
29
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
85
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
86
Toads and Hallucina=ons
87
Anesthetics; Drugs of Abuse & Withdrawal
30
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
88
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.
90
Anesthetics; Drugs of Abuse & Withdrawal
31
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.
91
92
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
93
Anesthetics; Drugs of Abuse & Withdrawal
32
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
Anesthetics; Drugs of Abuse & Withdrawal
33
Drugs of Abuse/Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
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
Drugs of Abuse/Withdrawal
Gamma-‐Hydroxybutyric Acid
110
111
Anesthetics; Drugs of Abuse & Withdrawal
38
Drugs of Abuse/Withdrawal
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
Drugs of Abuse/Withdrawal
Inhalants
114
Anesthetics; Drugs of Abuse & Withdrawal
39
Slip em a Mickey!
115
Drugs of Abuse/Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
40
Drugs of Abuse/Withdrawal
• 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
Anesthetics; Drugs of Abuse & Withdrawal
41
Drugs of Abuse/Withdrawal
• 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
Drugs of Abuse/Withdrawal
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
Anesthetics; Drugs of Abuse & Withdrawal
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
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
Anesthetics; Drugs of Abuse & Withdrawal
43
Drugs of Abuse/Withdrawal
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
Drugs of Abuse/Withdrawal
Critical Care Toxicology 128
You are ge�ng sleepy…
129