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Basic of Anesthetics

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During graduate school I was asked to give this lecture for pharmacy students. Describes aspects of local and general anesthetics including intravenous and inhaled forms of the latter.

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Basic of Anesthetics

  1. 1. PHARM 539 Pcol III 12-6-2012 Kellie Jaremko 6th year MDPhD Student in Neuroscience Kellie.jaremko@jefferson.edu
  2. 2.  First identified in ~1800s  Cocaine was isolated in 1860 and in 1884 Carl Koller noted its numbing properties as a topical ophthalmic agent ▪ In 1905 Procaine the first synthetic LOCAL anesthetic was produced  Nitrous Oxide, diethyl ether, & chloroform all introduced into medical practice in the mid 1800s ▪ These allowed for the development of major surgical opportunities since they were no longer limited by pain and shock with use of GENERAL anesthetics
  3. 3. Peripheral Nerve Anatomy Local Anesthetics • Perineurium is the hardest for LAs to penetrate • Clinically higher concentration than in- vitro would predict gets to site of action • Blocking synaptic transmission in this order: small myelinated (Aδ fibers)  unmyelinated fibers (C fibers/ nociceptors)  myelinated large axons (sensory then motor nerves)
  4. 4. Prototypical Local Anesthetics Local Anesthetics (LA): Chemical Aspects  Aromatic Group:  Related to hydrophobicity  Increase by adding alkyl groups  Moderate hydrophobicity is ideal for a balance between  Permeability through membrane & binding to hydrophobic binding sites  Diffusion from membrane to binding site
  5. 5. Prototypical Local Anesthetics Local Anesthetics (LA): Chemical Aspects  Tertiary Amine Group:  Makes LAs weak bases with pKa ~ 8-10  At Physiological PH ~7.4 more protonated but some still neutral  Neutral: crosses membrane easier  Protonated: binds site of action more strongly dissociates slower  Benzocaine is atypical with no basic group
  6. 6. Prototypical Local Anesthetics Local Anesthetics (LA): Chemical Aspects  Ester vs. Amide Linking Group:  Esters rapidly hydrolyzed by non specific esterases in plasma and tissues; ultimately excreted by kidney  Amides are more stable with longer plasma half lives; metabolized by P450 enzymes in liver then cleared by kidneys
  7. 7. Local Anesthetic Binding to Different Conformations (States) of the Sodium Channel Local Anesthetics (LA): Mechanism of Action
  8. 8. Tonic and Phasic (Use-Dependent) Inhibition Local Anesthetics (LA): Mechanism of Action • Phasic block is especially helpful when local damage causes spontaneous nociceptor firing and application of LA inhibits this more than the tonic block of unaffected sensory/motor nerves at that site. • LAs can also interact with potassium channels, calcium channels, uncouple g-proteins and inhibit substance P, bradykinin and glutamate receptors
  9. 9.  Topical Anesthesia  Pain relief for mucous membranes or skin it is applied to  Infiltration Anesthesia  To numb skin or surface via an injection intradermally or subcutaneously  Due to acidic solution there is a sting at injection but combination with sodium bicarbonate can reduce this pain  Peripheral Nerve Block  Major (brachial plexus) vs. Minor (radial nerve)  Requires much higher dosage than would be needed for application to unsheathed nerve  Central Nerve Block  Epidural and Spinal (intrathecal)  Intravenous RegionalAnesthesia (Bier’s Block)  Use tourniquet above block to prevent systemic toxicity  Used for hand and arm surgery
  10. 10.  LA absorbed by local tissues and redistributed to systemic circulation  To limit this and subsequent toxicity vasoconstrictors (epinephrine or felypressin) are often applied to ▪ 1) Increase local concentration of LA for prolonged effects ▪ 2) Decrease amount of LA in systemic circulation and toxic effects ▪ NOT given at peripheral extremities where blood flow is limited so as not to risk hypoxia at injury ▪ Mepivacaine has less vasodilation and prilocane has none, therefore doesn’t require adjunct  GeneralToxicity Risks:  Local irritation at site of inject with possible damage to muscle cells from intramuscular injection  CNS effects: ▪ Initial excitation (due to blockade of inhibitory pathways) with possible convulsions & tremors  ▪ depression at higher levels of LA in CNS when all pathways depressed  Cardiac effects: ▪ Low doses= antiarrhythmics via reducing conduction velocity ▪ Dose-dependent decreases in cardiac contractility
  11. 11.  Only naturally occurring LA  Ester-linked  Medium onset and duration (~1hr plasma half-life)  Indications: for topical ophthalmic application, otolaryngology (ENT) procedures, or spray for upper respiratory tract anesthesia  Formulations & Dosage:  Flakes, crystals, 135mg tablets, premade topical solutions  Max safe dose is 200mg or 2-3mg/kg  Used in combination asTAC (with tetracaine & adrenaline)  Drug Interactions & Contraindications:  Dihydroergotamine (ergot alkaloid for migraines  increased blood pressure)  Phenelzine, Selegiline, (monoamine oxidase inhibitor antidepressantsevere hypertensive reactions can occur)  Epinephrine ( with other Las, EpiPen for anaphylactic allergic reaction, risk of life threatening cardiac arrhythmias)  Cons:  Highly addictive  Inhibits catecholamine uptake in CNS  Large cardiotoxic potential
  12. 12.  Long acting highly potent due to high hydrophobicity  Ester-linked  Released slowly from tissues so metabolized slowly  Generally a 1% solution given as an injection  Indications: for spinal and ENT (especially nose surgeries and topical (cornea) anesthesia  Drug Interactions:  Hyaluronidase (a spreading substance used to improve uptake of drugs given under the skin  shorter duration LA effects and increased systemic LA side effects)  Sodium Nitrite/Amyl nitrite/ sodium thiosulfate (treatment for cyanide poisoning but can also cause methemoglobin formation so together  methemoglobinemia)
  13. 13.  0.5% tetracaine + 1:200,000 epinephrine solution+ 11.8% cocaine  A few drops of solution can be applied directly to a wound (<10cm) prior to suturing a laceration followed by constant pressure for 10-20mins  Most effective in head, neck, and scalp injuries in pediatric emergency situations  Benefits include: ease of application, patient comfort during irrigation and suturing and avoidance of wound distortion present with injections of local anesthetics/
  14. 14.  Aka Novocain  1st synthetic LA  Ester-linked  Medium onset  short duration (<1 hr)  Low hydrophobicity:  Low tissue accumulation  Low potency  Indications: dental procedures but more rarely now (1% procaine hydrochloride solution), subarachnoid (spinal) block (10% procaine hydrochloride solution)  Drug Interactions:  Sodium Nitrite/Amyl nitrite/ sodium thiosulfate (treatment for cyanide poisoning but can also cause methemoglobin formation so together  methemoglobinemia)  Hyaluronidase  Prilocaine & lidocaine local anesthetics  PABA is a metabolite  Commonly found in sunscreen  Can be an allergen ~hypersensitivity  contact dermatitis  Blocks sulfonamide antibiotic efficacy
  15. 15.  Rapid onset with medium duration of action (1-2hrs)  Amide-linked  Low pKa so mainly neutral at physiological pH  Indications:Widely used for nerve blocks, at infiltration, spinal, epidural, and topical anesthesia  Also used intravenously for treating ventricular dysrhythmias  CNS adverse effects include tinnitus, drowsiness, twitching and possibly seizures  Drug Interactions:  Increased Risk of Seizures from combining with: ▪ Bupropion (antidepressant) ▪ Sodium Biphosphate (a bowel cleansing agent for constipation pre-op) ▪ Tramadol (pain reliever) ▪ Ionhexol and Metrizamide (iodinated contrast media)  Cleared by CYP450 enzyme in liver so increased blood levels both drugs and increased cardiac/CNS toxicity: ▪ Saquinavir, Amprenavir (antiretroviral drugs for HIV) ▪ Conivaptan (used to treat hyponatremia)  Dihydroergotamine  Sodium Nitrite/Amyl nitrite/ sodium thiosulfate  Other antiarrhythmic like Dronedarone and Dofetilide due to additive effect  Arbutamine(an ionotropica cardiac agent with lidocaine may cause ventricular arrhythmias)  Prilocaine is like lidocaine but has its own vasoconstrictive properties
  16. 16.  5 % lidocaine transdermal patch  12 hours on 12 hours off per any 24 hour period  Indications: ▪ Post- herpatic neuralgia or pain after Shingles (herpes zoster) ▪ Recent studies suggest it is beneficial ▪ Low Back pain ▪ Osteoarthritis knee pain
  17. 17.  A 5% oil emulsion containing 2.5% of each lidocaine and prilocaine  FYI: Eutectic Mixture= the melting point of the mixture is lower than the melting point of the individual ingredients ▪ Lidocaine and prilocaine are solids but in this mix in a non-aqueous solution there is a higher concentration of anesthetic possible.  Can be a cream or on a cellulose disk (patch)  Indications: local analgesia prior to catheterization or procedures involving genital mucosal membranes, pre-treatment for infiltration analgesia, lumbar puncture, venipuncture, dental procedures  NOT for ophthalmic use  Side Effects: same as for drugs individually plus  Paleness (37%) or redness(30%) at site  Burning sensation (17%)
  18. 18.  Slow onset but long duration of action (~2hrs)  Amide-linked  Has chiral center so enantiomers with levobupivacaine safer form  High risk of cardiotoxicity  Formulations: As an isotonic solution with sodium chloride ranging in concentration from 0.25%- 0.75% with or without epinephrine  Indications: Used for labor and post-operative anesthesia, dental & eye procedures  Not in children or handicapped due to increased self-inflicted post-operative injury  Drug Interactions:  Hyaluronidase  Propranolol (non-selective beta blocker  increased risk of side effects)  St. John’sWort
  19. 19.  The most commonly used local anesthetic in dentistry is lidocaine  Gaffen et. al. study of Ontario Dentists (2009) ▪ 37.3% used lidocaine with epinephrine ▪ 27% used articaine with epinephrine ▪ Articaine has been widely used in Europe and Canada although only approved in a 4% solution in US in 2000. Similar to prilocaine and both have increased risk of nerve paresthesia (“pins and needles” feeling)  Ngan et. al. (2001) also found among pediatric dentists in the US lidocaine was the preferred local anesthetic  Mepivacaine (2% solution, amide LA) is used when a vasoconstrictor cannot be given
  20. 20. 1) Resident AP is preparing a patient for a surgical procedure to resect liver cancer. Catheterization is required so AP reaches for the lidocaine cream. His attending recommends EMLA cream instead because of its: a) Decreased side effect profile b) Higher concentration of anesthetic properties per application c) More balanced pH to reduce the sting of application d) Ester-linkage and metabolism which bypasses the liver
  21. 21.  Designed to induce a reversible depression of the CNS where perception of all sensations are blocked  Loss of consciousness  Amnesia  Immobility  Analgesia  & with adjuvants: anxiolysis, muscle relaxation, & loss of autonomic reflexes  Inhaled versus Intravenous agents…
  22. 22.  Potency is one factor that determines progression through these stages  Inversely related to the Minimum Alveolar Concentration (MAC) or the partial pressure required in the alveoli to abolish a response to surgical incision in 50% of patients
  23. 23. The Meyer–Overton Rule & Lipid Solubility • λ (oil/gas) coefficient describes the solubility of a GA into lipids and is related to potency • MAC x λ (oil/gas) = a constant such that MAC= 1.3/ λ (oil/gas) • This led to the lipid hypothesis of how anesthetics worked: Anesthesia was achieved when a specific concentration of anesthetics were in the lipid membranes such that the bilayer fluidity was disturbed altering excitability  no proof of a mechanism so largely discredited
  24. 24. Actions of Anesthetics on (Ligand-Gated) Ion Channels • Potentiate action of Inhibitory Receptors • Mainly GABAA Receptors • Two-Pore Potassium channels (Not affected by intravenous anesthetics) • Inhibit excitatory receptors • NMDA Glutamate Receptors by Xenon, Nitrous Oxide and Ketamine
  25. 25.  When you first breathe in a specific amount of inhaled anesthetic that is administered (PI) it mixes with the residual volume of gas in the lungs so that the concentration at the alveoli (Palv) is less  With subsequent breaths Palv comes closer to equilibrium with PI  The λ (blood/gas) coefficient or solubility of an anesthetic in the blood determines the rate of induction/recovery  The lower the λ (blood/gas) coefficient the slower the absorption into the blood is so Palv will equal the PI sooner  Ventilation rate also affects the rate of absorption  Additionally due to optimized gas exchange at the alveoli Palv ~ Part  Tissue distribution of an anesthetic depends upon blood flow to the area of interest (cardiac output) since equilibration of the partial pressure of arterial anesthetic Part with the tissue can occur in the span of time the blood traverses the capillary bed
  26. 26.  Ventilation-Limited Anesthetics  High λ (blood/gas) coefficient  High rate of uptake prevents the rise of Palv  Slow Induction and recovery  Includes: diethyl ether, enflurane, isoflurane, halothane  Perfusion-Limited Anesthetics  Low λ (blood/gas) coefficient  Slow rate of uptake expedites the rise of Palv  Fast Induction and recovery  Includes: Nitrous oxide, desflurane, sevoflurane
  27. 27. Effects of Changes in Ventilation and Cardiac Output on the Rate at Which Alveolar Partial Pressure Rises Toward Inspired Partial Pressure • Increasing ventilation accelerates equilibration and induction • Increasing cardiac output slows equilibration • The effects of these cardiovascular changes are more substantial for anesthetics with high λ(blood/gas) coefficients like halothane • Fast inducers like nitrous oxide equilibrate so fast that changes are not felt to the same extent • λ(oil/gas) coefficients indicate an anesthetic’s fat solubility • Affects potency • Distribution kinetics: high lipid solubility causes slower recovery due to slow reversal and release from fat stores that have absorbed the drug
  28. 28.  High λ (blood/gas)  Slow induction  High λ (oil/gas)  1) high potency (low MAC) and 2) slow recovery with “hangover” effect  Non-irritating smell  Used in pediatrics but rarely  Toxicity:  Metabolites can result in fatal hepatotoxicity with an incidence of 1: 35,000 adults  Malignant Hyperthermia
  29. 29. • Due to inherited autosomal dominant mutation in gene for the Ryanodine Calcium Channel on the Sarcoplasmic reticulum • ~1/30,000 risk • Caused by halogenated anesthetics in these individuals • Uncontrolled release of calcium into muscle cells  constant contractions  tetany & heat production  death • Treated with Dantrolene that blocks calcium release from SR
  30. 30.  Lower λ (blood/gas)  Faster Induction  Lower λ (oil/gas)  Less Potent but less in fat so easier recovery  Metabolism & SubsequentToxicity:  isoflurane<enflurane< halothane  Enflurane:  Slight increased risk renal toxicity,  Risk of epilepsy-like seizures  Isoflurane:  Most widely used general anesthetic  Can be an irritant to respiratory tract  May precipitate myocardial ischemia in patients with coronary artery disease due to vasodilation
  31. 31.  Extremely low λ (blood/gas) Very Fast Induction  Very Low λ (oil/gas)  Such low potency (MAC~1 atm)MUST be combined with other agents  Very good recovery  Toxicity:  Safe at low doses  Enters and accumulates in gaseous cavities potentially expanding them so avoid in pneumothorax, obstructed intestines or in the case of an air embolus  Prolonged or repeated exposure (>6hrs) inactivates methionine synthase needed for DNA and protein synthesis  bone marrow depression, anemia ▪ AVOID in patients with B12 deficiency
  32. 32.  Lower λ (blood/gas)  Faster Induction than older agents  High λ (oil/gas)  Increased Potency  Desflurane:  Faster onset and recovery than isoflurane  Used for day-case outpatient surgery  Not metabolized much so decreased toxicity  Reparatory irritant  coughing and bronchospasm and increase sympathetic activity ▪ AVOID in ischemic heart disease  Sevoflurane:  More potent than desflurane  NO respiratory irritation  Small amount of metabolism (3%)  Can be chemically unstable if machinery contains carbon dioxide absorbents that can create a nephrotoxin but better machinery improving usage
  33. 33.  High λ (blood/gas)  Slow Induction  High λ (oil/gas)  High Potency  Easy to administer and control  Analgesic and muscle relaxant properties  VERY flammable & explosive  Post-operative nausea and vomiting  Irritant to respiratory tract  Obsolete in developed countries but still used where modern facilities are not available
  34. 34.  Much faster induction (seconds to minutes)  Not as reversible i.e.. Can’t clear by increasing ventilation of oxygen  Rapid metabolism but elimination from body is slow so not generally used to maintain anesthesia
  35. 35.  Fast onset (30s) and fast recovery  Possible to use as continuous infusion for short day procedures with less nausea than inhaled anesthetics  Risks andToxicity:  Pain at injection site  Cardiovascular and respiratory depression  Propofol Infusion Syndrome (1/300): when high doses have been given for a prolonged period, particularly to sick patients-especially children-in intensive care units. ▪ severe metabolic acidosis, skeletal muscle necrosis (rhabdomyolysis), hyperkalaemia, lipaemia, hepatomegaly, renal failure, arrhythmia and cardiovascular collapse
  36. 36.  Thiopental  A barbiturate  Causes unconsciousness in 20seconds and lasts only 5- 10minutes due to high lipid solubility.  Largely replaced by Propofol  Risk of precipitating porphyria  Etomidate  Fast onset and fairly fast recovery  Less cardiovascular and respiratory depression than thiopental  Can cause unpleasant excitatory effects during induction and pain at injection site, as well as adrenocortical depression
  37. 37.  Takes 1-2minutes for effects  Causes a dissociative amnesia: sensory loss, analgesia, and amnesia, without complete loss of consciousness  Increases Cardiac Output through increased sympathetic outflow  Indications: General anesthesia as an adjuvant, procedural sedation, (Non-FDA approved: bronchospasm and rapid sequence intubation i.e.. Emergency situations)  Toxicity &Warnings:  Unpleasant hallucinations, delirium, and irrational behaviors  May increase intracranial pressure soAVOID n patients with risk of cerebral ischemia  Drug Interactions:  Hydromorphone, oxycodone, and tramadol (pain killers that also depress CNS)  St. John’sWort  Non-selective MAOIs (phenelzine &selegiline; ancedotal hyper and hypo tension cases with general anesthetics)
  38. 38. 2) High anesthetic potency is associated with which chemical properties: a) High λ(blood/gas) coefficient and extreme hydrophobicity b) Low λ(oil/gas) coefficient and moderate hydrophobicity c) High λ(oil/gas) coefficient and moderate hydrophobicity d) High λ(blood/gas) coefficient and High λ(blood/gas) coefficient e) Low λ(oil/gas) coefficient and low hydrophobicity
  39. 39.  Know the general mechanism of action of each class of anesthetics  Local anesthetics bind to the intracellular side of sodium channels in all states except the resting state to block excitatory nerve transmission  General anesthetics must either decrease excitatory neuronal signals by blocking glutamate receptors (NMDAr) and/or increase inhibitory GABA activity  Know major drug interactions and adverse effects  Know what makes special drugs in each class and subtype good for complicated patients & situations  EX: when vasocontrictors are contraindicated or best anesthetics for short procedures etc.

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