Local anaesthetics
●drugs used for pain relief (desensitization) in site of proceeded
intervention (e.g. surgical)
© Oldřich Farsa 2019
Kinds of local anaesthesia
1. superficial – on skin and mucous membranes, borders of wounds – determined at the rabbit
cornea
2. infiltration – injection to subcutaneous a submucose region – determined in guinea pigs
3. periferial nerve block – targeted to a particular nerve – determined at isolated rat nervus
ischiaticus
4. epidural – injection at surface of dura mater and
5. spinal (subarachnoidal) – injection into spinal cord; both (4. and 5.) to produce anesthesia
for major surgery (e.g., abdomen) or childbirth
Epidural Spinal
General mechanism of action
●reversibly block leading of nervous impulses through nervous axons and other cells
with excitable membranes using Na+
channels for generating of action potential
●binding to receptor – sodium channel in cell membrane in its open form from the
internal (cytoplasmic) side (In contrast, a number of highly polar toxins (e.g.,
tetrodotoxin TTX and saxitoxin ScTX) block the Na+
channel from the outer surface of
the neuronal membrane)
●effect depends on pH: minimal in acidic media (weak bases dissociated in acidic
media, poor permeation into Na+
channels)  poorly active in a tissue where is
inflammation
●
increased extracellular Ca2+
concentration antagonizes their effect due to increase of
superficial potential on a membrane
Polar toxins blocking the Na+
channel from the outer surface of the neuronal membrane
tetrodotoxin (puffer fish; several
genera of Tetraodontidae family)
●log P = -6.210
saxitoxin (shell fish; edible moluscs of
various genera; the toxin itself is produced
by planctonic protozoa Gonyaulax catenella
and consumed by moluscs)
Unwanted effects - toxicity
●generally smaller in less stable esters
●CNS: sleepiness, photodysphoria, failures of vision and hearing, convulsions; early
symptoms: insensitivity of tongue, metalic taste
●peripherial NS: temporary neuropathies
●
and vessels: decrease of contraction strenghth, ECG changes, dilation of arteriols,
decrease or reflection increase of pressure
●alergies: esters (4-aminobenzoic acid is alergene)
Cocaine – prototype = „lead compound“ of local anaesthetics
H
H
N H
H
O
O
CH3
O
CH3
O
●contained in leaves of coca shrub Erythroxylon coca, isolated by Niemann 1860, Koller begun
its clinical usage 1884 in ophtalmology, structure elucidated by Willstätter (1898) including total
synthesis
●additional 30 years the only one local anaesthetic
●centrally-stimulating effects, strongly addictive; today again only in ophthalmology
●comparative standard for evaluation of activity of (novel) local anaesthetics
●the suffix -caine of INN names of all local anaesthetics originated from cocaine
General structure of local anaethetics – SAR (structure-activity relationships) =
common „building principle“ of local anaesthetics
X
R
1
Y
Z N
R
2
R
3
n
I II III IV
Region I: electron-donor substituent
Region II: lipophilic aromatic ring
Region III: linking chain
Region IV: basic substituent – tertiary amino group
R1
,R2
,R3
: alkyls (R2
+R3
can be connected a saturated ring)
X: typically NH
Y-Z: COO, CONH, NHCO, NHCOO
Classification of local anaesthetics according to their structures
1. Esters
2. Amides
3. Anilides
4. Carbamates
1. 4-aminobenzoic acids esters
NH2
O O CH3
NH2
O O
N
CH3
CH3
R
benzocaine
●the simpliest
●
very weakly basic  used as free base
●stomatology
●Benzocainum PhEur
R = H procaine
●Alfred Einhorn 1905
●hydrochloride
●poorly soluble salt with benzylpenicilline
for depot i.m. administration
●Procaini hydrochloridum PhEur
R = OC4
H9
oxybuprocaine
●Oxybuprocaini hydrochloridum PhEur
●lower effect of antibacterial sulfonamides (resources of 4-aminobenzoic acid)
1. 4-aminobenzoic acids esters
O
N
CH3
CH3
O
NH
CH3
tetracaine
●topical, infiltration and spinal anaesthesia
●topically in ophthalmology
●slow onset of action and its longer lasting than in procaine (the longest among esters)
●about 10x more toxic and effective than procaine
2. Amides
●mnemotechnic rule of pronounced „i“ - includes also anilides
procainamide
●amide isosteric analogue of
procaine
●also antidysrythmic effects:
the amide bond in more stable
than the ester one thus it can
be delivered into heart in
satisfactory concentration
●Procainamidi hydrochloridum
PhEur
N
N
N
CH3
CH3 CH3
O
OH
O
CH3CH3
CH3
NH
N
CH3
CH3
O
NH2
oxethacaine [INN] syn. oxethazaine
[USAN:BAN:JAN]
2,2'-[(2-hydroxyethyl)imino]bis[N-(1-
phenyl-2-methyl-2-propyl)-N-
methylacetamide]
●usage with antacids: Anacid
compositum®
OCH3
N
NH
N CH3
CH3
O
cinchocaine
dibucaine [USP]
●Meischer 1925
●inhibits pseudocholinesterase; used to detect abnormality of this enzyme
Faktu ® sup., ung. (+ policresulene) for treatment of hemorrhoids
SO O
OH
OH
SO O
OH
S
OH
O
O
CH3OH
CH3 CH3
OH
n
policresulene
2. Amides (continued)
3. Anilides
●also amides; in contrast to previous group isosteric change performed: „reversion“ of the
amide bond  N-phenyl amino acid amides
Acetanilides with a basic substituent
NH
O
CH3
CH3R
N
CH3
CH3
NH
O
CH3
CH3
N
R = H lidocaine
●prepared by Nils Lögfren 1943
●most frequently used; all ways of administration
●Lidocaini hydrochloridum monohydricum PhEur
●forms various hydrates
●
Xylocaine®
R = CH3
trimecaine
●
Mesocaine®
●also antidysrythmics
pyrrocaine
Syntheses of lidocaine a trimecaine
"Classical" - also in practical classes in MC
NH2
CH3
CH3
R NH
CH3
CH3
R
Cl
O
NH
CH3
CH3
R
O
N CH3
CH3
(C2H5)2NH
Ugi condensation
N
+
CH3
CH3
R C
+
H H
O
+ NH
CH3
CH3
NH
CH3
CH3
R
O
N CH3
CH3
R = H or CH3
ClCH2COCl
base
Anilides (continued)
CH3
CH3
NH
O H
N
R
CH3
NH
O
H
NH
CH3
CH3
R = CH3
mepivacaine
R = C3
H7
ropivacaine
●nearly ideal local anaesthetics:
●fast onset of action
●long lasting
●selective block of sensoric nerves
without motoric block
●minimal local irritability and no systemic
toxicity
R = C4
H9
bupivacaine
●slowest hydrolyzed
●cardiotoxicity
●(-)-enantiomer = levobupivacaine less
cardiotoxic but also less efficient and
with shorter time of activity
➢used in obstetrics
prilocaine
●fastest hydrolyzed compound in group of anilides
●Prilocaini hydrochloridum PhEur
●
AE: methemoglobinemia (o-toluidine: FeII
FeIII
)
4. Carbamates
NH O
H
NH
+
CH3
CH3
CH3
O
O
CH3
Cl
- O
CH3
NH
O
OH
H
N
carbisocaine trapencaine
syn. pentacaine
●also anti-ulcer effect