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PHARM 539 Pcol III
12-6-2012
Kellie Jaremko
6th year MDPhD Student in Neuroscience
Kellie.jaremko@jefferson.edu
 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
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)
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
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
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
Local Anesthetic Binding to Different Conformations (States) of the Sodium Channel
Local Anesthetics (LA): Mechanism of Action
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
 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
 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
 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
 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)
 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/
 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
 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
 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
 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%)
 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
 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
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
 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…
 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
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
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
 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
 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
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
 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
• 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
 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
 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
 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
 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
 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
 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
 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
 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)
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
 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.
Basic of Anesthetics

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Basic of Anesthetics

  • 1. PHARM 539 Pcol III 12-6-2012 Kellie Jaremko 6th year MDPhD Student in Neuroscience Kellie.jaremko@jefferson.edu
  • 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. 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. 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. 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. 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. Local Anesthetic Binding to Different Conformations (States) of the Sodium Channel Local Anesthetics (LA): Mechanism of Action
  • 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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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. 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.
  • 22.  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…
  • 23.  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
  • 24. 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
  • 25. 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
  • 26.  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
  • 27.  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
  • 28. 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
  • 29.  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
  • 30. • 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
  • 31.  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
  • 32.  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
  • 33.  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
  • 34.  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
  • 35.  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
  • 36.  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
  • 37.  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
  • 38.  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)
  • 39. 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
  • 40.  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.

Editor's Notes

  1. 1. Local anesthetics (LAs) are injected or otherwise applied outside the peripheral nerve epineurium (the outermost sheath of connective tissue containing blood vessels, adipose tissue, fibroblasts, and mast cells). 2. LA molecules must cross the epineurium to reach the perineurium, another epithelial membrane, which organizes nerve fibers into fascicles. The perineurium is the most difficult layer for local anesthetics to penetrate, because of the tight junctions between its cells. 3. LAs then pass through the endoneurium, which envelops the myelinated and unmyelinated fibers, Schwann cells, and capillaries. Only LAs that have passed through these three sheaths can reach the neuronal membranes where the voltage-gated sodium channels reside. Clinically, a high concentration of local anesthetic must be applied because only a fraction of the molecules reach the target site.
  2. Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
  3. Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
  4. Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
  5. 1st figure: Local anesthetic action. An injected local anesthetic exists in equilibrium as a quaternary salt (BH+) and tertiary base (B). The proportion of each is determined by the pKa of the anesthetic and the pH of the tissue. The lipid-soluble base (B) is essential for penetration of both the epineurium and neuronal membrane. Once the molecule reaches the axoplasm of the neuron, the amine gains a hydrogen ion, and this ionized, quaternary form (BH+) is responsible for the actual blockade of the sodium channel. The equilibrium between (BH+) and (B) is determined by the pH of the tissues and the pKa of the anesthetic (pH/pKa). A. The sodium channel is composed of one polypeptide chain that has four repeating units. One region, known as the S4 region, has many positively charged amino acids (lysine and arginine). These residues give the channel its voltage dependence. At rest, the pore is closed. When the membrane is depolarized, the charged residues move in response to the change in the electric field. This results in several conformational changes (intermediate closed states) that culminate in channel opening. After about 1 ms (the channel open time), the 3–4 amino acid “linker region” plugs the open channel, yielding the inactivated conformation. The inactivated conformation returns to the resting state only when the membrane is repolarized; this conformational change involves the return of the S4 region to its original position and the expulsion of the linker region. The time required for the channel to return from the inactivated state to the resting state is known as the refractory period; during this period, the sodium channel is incapable of being activated. B. The binding of local anesthetic (LA) alters the properties of the intermediate forms assumed by the sodium channel. Sodium channels in any of the conformations (resting, closed, open, or inactivated) can bind local anesthetic molecules, although the resting state has a low affinity for LA, while the other three states have a high affinity for LA. LA can dissociate from the channel–LA complex in any conformational state, or the channel can undergo conformational changes while associated with the LA molecule. Ultimately, the channel–LA complex must dissociate, and the sodium channel must return to the resting state to become activated. LA binding extends the refractory period, including both the time required for dissociation of the LA molecule from the sodium channel and the time required for the channel to return to the resting state.
  6. A. In tonic block, depolarizations occur with low frequency, and there is sufficient time between depolarizations for equilibrium binding of local anesthetic (LA) molecules to the various states of the sodium channel to be reestablished. When a depolarization occurs, resting channels (which have low affinity for LA) are converted into open channels and inactivated channels (both of which have high affinity for LA). Thus, there is an increase in the number of LA-bound channels. Once the depolarization ends, there is enough time before the next depolarization for equilibrium between LA molecules and sodium channels to be reestablished, and virtually all of the channels return to the resting and unbound state. B. In phasic block, depolarizations occur with high frequency, and there is not sufficient time between depolarizations for equilibrium to be reestablished. After each depolarization, a new baseline is established that has more LA-bound channels than the previous baseline, leading eventually to conduction failure. Because high-frequency stimulation of nociceptors occurs in areas of tissue damage, phasic (use-dependent) block causes actively firing nociceptors to be inhibited more effectively than nerve fibers that are only occasionally firing. The frequency dependence of phasic block depends on the rate at which LA dissociates from its binding site on the channel.
  7. pi
  8. The deepening anesthetic state can be divided into four stages, based on observations with diethyl ether. The analgesia of stage I is variable and depends on the particular anesthetic agent. With fast induction, the patient passes rapidly through the undesirable “excitement” phase (stage II). Surgery is generally undertaken in stage III. The anesthesiologist must take care to avoid stage IV, which begins with respiratory arrest. Cardiac arrest occurs later in stage IV. During recovery from anesthesia, the patient progresses through the stages in reverse.
  9. Molecules with a larger oil/gas partition coefficient [λ(oil/gas)] are more potent general anesthetics. This log–log plot shows the very tight correlation between lipid solubility [λ(oil/gas)] and anesthetic potency over five orders of magnitude. Note that even such gases as xenon and nitrogen can act as general anesthetics when breathed at high enough partial pressures. The equation describing the line is: Potency = λ(oil/gas)/1.3. Recall that Potency = 1/MAC.
  10. Anesthetics potentiate the action of endogenous agonists at inhibitory receptors, such as GABAA and glycine receptors, and inhibit the action of endogenous agonists at excitatory receptors, such as nicotinic acetylcholine, 5-HT3, and NMDA glutamate receptors. At GABAA receptors, anesthetics both decrease the EC50 of GABA (i.e., GABA becomes more potent) and increase the maximum response (i.e., GABA becomes more efficacious). The latter effect is thought to be due to the ability of anesthetics to stabilize the open state of the receptor channel. At excitatory receptors, anesthetics decrease the maximum response while leaving the EC50 unchanged; these are the pharmacologic hallmarks of noncompetitive inhibition.
  11. The rate of equilibration of the alveolar partial pressure with the inspired partial pressure can be affected by changes in ventilation (A) and cardiac output (B). Increasing ventilation from 2 L/min (dashed lines) to 8 L/min (solid lines) accelerates equilibration. On the other hand, increasing cardiac output from 2 L/min (dashed lines) to 18 L/min (solid lines) slows equilibration. Both effects are much larger for more blood-soluble gases, such as halothane and diethyl ether, which have rather slow induction times. For nitrous oxide, the rate of equilibration is so fast that any changes caused by hyperventilation or decreased cardiac output are small. The dashed horizontal line represents 63% equilibration of Palv with PI; the time required for each curve to cross this line represents τ{Palv→PI}.