Local anesthetics
Local anesthetics (LA)
• cause temporary loss of sensation in a limited area
(absence of pain sensation) by local reversible inhibition of
sensory neurons
• other senses are often affected as well
- sensitivity of nerve fibres to LA:
vegetative > sensory > motoric nerve fibres
• in sensory fibers the perception of heat is blocked first, later
the perception of pain stimuli, and then the touch also
• at higher concentrations the loss of muscle power can be
achieved as well (e.g.local anesthetic regional nerve blockade)
Sensitive nerve system
• types of somatosensory nerve fibres - signals from skin
receptors and from skeletal muscles and joints, etc.
• protopathic perception (sensing pain, pressure, heat, or cold
in a nonspecific manner)
• epicritic perception (permits the discrimination and the
topographic localization of the finer degrees of touch and
temperature stimuli)
• and proprioception (sense of the movements and position of
the body independent of vision)
LA - mechanism of action
• penetration into sensitive nerve fibres
• blockade of voltage-gated sodium channels responsible
for fast depolarization along nerves
• binding on the inner side of the nerve membrane, and
preventing Na+ ions flow
other effects:
• vasodilation (sympathetic nerve fibres blockade)
• class I antiarrhythmic drugs (influence on Na+ channels
in myocardium)
LA - chemical structure
• amphiphilic substances:
• aromatic group is lipophilic
• nitrogen group is hydrophilic (ionizable)
- connected via ester or amide bond
(ester-type and amide-type of LA; exception - benzocaine)
• LA are weak bases, pKa = 8-9
• their efficacy depends on pH – ionized/non-ionized
• higher pH = increased efficacy– more molecules are nonionized
= increased penetration to nerve fibres
• low pH = less effective, e.g. in tissues with inflammation
LA - pharmacokinetics
• absorption - depends on drug concentration, on the
site of administration, dose, blood perfusion and
physical-chemical properties of drug
• distribution – in the whole body, deposits in adipose
tissues, amides strong binding to plasma proteins
• biotransformation – plasmatic esterases are
involved (fast, ester LA) or hepatic metabolism via
CYP (slower, amide LA)
• excretion of metabolites - kidneys
Vasoconstrictory agents
• additives for lowering systemic toxicity
• compensation of vasodilation induced by LA
• shortening time of onset
• increased duration of analgesia (delayed diffusion of LA)
in acral parts with caution – risk of ischemic necrosis
adrenaline, ev. noradrenaline, derivatives of vasopressin
LA - administration routes
delivery techniques
• topical (surface) anesthesia - transdermal penetration of LA
- solution, gel, cream
- mucosa, cornea, esophagus, respiratory tract, decubitus
- often used in urology (catheterization) and before other
painful instrumental procedures
• infiltration anesthesia
subcutanous, submucosal, intraarticular
- blocks nerve conduction near their site of administration
- low concentrations of LA and vasoconstrictory agents
- often used for minor surgical and dental procedures
LA - delivery techniques
• conduction anesthesia
- peripheral - local anesthetic nerve block
single treatments, multiple injections over a period of time,
or continuous infusions
- central - always without a vasoconstrictory agent
• epidural anesthesia
• subarachnoideal anesthesia (spinal)
LA - delivery techniques
central conduction anesthesia <contd>
• epidural anesthesia
- postoperative analgesia, analgesia in obstetrics
- regional anesthesia (cervical, thoracic, or lumbar)
• subarachnoideal anesthesia (spinal block)
- intrathecal administration of LA, must be injected
below L2 to avoid piercing the spinal cord
- limited to procedures involving most structures below
the upper abdomen.
- without vasoconstrictory agent
• intravenous regional anesthesia (Bier block)
- trimecaine 1%
- lidocaine 0,5 %
- for surgical procedures on extremities
- quick onset and inhibition of motor functions
- exsanguination of the limb (elevation + tourniquets)
- procedures max. up to 2 hrs (risk of ischaemia)
- no postoperative analgesia
LA - delivery techniques
Ester type of LA
cocaine
• medical use from 1884
• natural compound, isolated from leaves of
Erythroxylon coca
• central psychostimulant with high risk of addiction
• for surface anesthesia
• today rarely for LA for paracentesis – Bonain‘s
solution IPP (precription with blue stripe)
Ester types of LA
procaine
• the oldest sythetic LA (1905)
• slow onset, short duration
• for infiltration and conduction anesthesia
tetracaine
• fast onset
• high systemic toxicity – only for surface anesthesia
of oral cavity and throat (combined with
chlorhexidine)
benzocaine ethyl ester of p-aminobenzoic acid (PABA)
• only for topical anesthesia of oral cavity, ear and throat
(available in combination with antiseptics, OTC drugs)
Amide types of LA
trimecaine
• universal, for all types of local anesthesia
• used also as the class I antiarrhythmic drug
lidocaine (syn. xylocaine and lignocaine)
• universal LA for surface, infiltration and
conduction anesthesia
• class I antiarrhythmic drug
in patents treated with betalytics, Ca2+ channel blockers
and in patients with epilepsy doses of trimecaine and
lidocaine must be halved
Amide type of LA
mepivacaine
• in dentistry, in patients with KI of catecholamines
articaine
• used in dentistry
• fast onset, long effect
bupivacaine
• all typer of local anesthesia
• cardiotoxic
levobupivacaine
• lower cardiovascular toxicity and neurotoxicity
Amide type of LA
ropivacaine
• amide type of anesthetic
• for all types of anesthesia except subarachnoidal
prilocaine
• surface anesthesia EMLA
• spinal anesthesia for short surgical procedures
cinchocaine (dibucaine)
• surface (topical) anesthesia
• (spinal anesthesia)
LA - according to their efficacy
• weak
procaine, benzocaine
• intermediate
trimecaine, lidocaine
• strong
tetracaine, articaine, bupivacaine, ropivacaine
Toxic effects of LA
CNS
Excitation
Inhibition
tonic-clonic seizures
Areflexia
Respiratory failure
Coma
Cardiovascular
system
Hypotension
Arythmia
Bradycardia
Alergic
symptoms more in esters than in amides, anaphylactic
reaction
Vasoconstrictor
toxicity
local hypoxia up to necrosis (acral parts), celkově
restlessness, tachycardia, hypertension
Methemoglobinaemia
because of metabolite (o-toluidine)
cumulation
Alergic and anaphylactic reaction to LA
symptoms:
• pruritus
• urticaria
• swellings
• anaphylactic shock- restlessness, anxiety, breathlessness,
vomiting
• Quincke‘s oedema – without inflammation, fast onset in face,
affecting lips, face and throat ( suffocation!!)
therapy:
• adrenaline 1mg in 10 ml of saline i.v.
• oxygen and infusion 5% glucose with noradrenaline
• hydrocortisone i.v.
• antihistamines
• in case of respiratory failure, keep free airways, artificial
respiratory ventilation
Systemic toxic reaction to LA
symptoms: (most often till 15 min from LA administration):
• restlessness, hand tingling, hot or cold, nausea, vertigo, cold
sweat
• tachypnoe
• tremor, fasciculations, seizures
• tachycardia, increased blood pressure in the beginning with the
subsequent decrease, unconsciousness, bradycardia
• in the final phase respiratory and cardivascular failure
therapy:
• lay down patient, oxygen in respiratory insufficiency
• thiopental or diazepam i.v. in seizures
• slow adrenaline i.v. if critical decrease of BP
• resuscitation in respiratory and cardiac failure