The document provides a comprehensive overview of local anesthetics, including their historical development, mechanisms of action, and various types such as topical, infiltration, peripheral nerve blocks, and central nerve blocks. It details the chemical structure, pharmacokinetics, and potential side effects or toxicity associated with different local anesthetics, also touching upon general anesthetics and their characteristics. Additionally, specific indications, drug interactions, and contraindications for various agents are discussed, emphasizing their clinical relevance in surgical and procedural settings.

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

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.