LOCAL ANAESTHETICS

Local anaesthetics are drugs used to prevent pain by causing a reversible block of conduction along nerve
fibres.
Mechanism of action:
Most LA are weak bases (exist mainly in a protonated form at body pH). LA penetrate the nerve in a
non-ionized (lipophilic) form but once inside the axon, some ionised molecules are formed and these block the
Na+ channels preventing the generation of action potentials.
Uncharged agents (e.g.benzocaine) dissolve in the membrane and, whilst expansion of the membrane
might be expected to compress the Na+ channels, eventually blocking the passage of Na+ ions, it seems the
channels are blocked in an all-or-none manner. Thus, ionized and non-ionized molecules act in essentially the
same way, that is, by binding to a "receptor" on the Na+ channel. This "block" the channel largely by preventing
the opening of h-gates (i.e. by increasing inactivation).
Note: acidic pH in inflammation decreases the effect of LA !
Sensitivity of nerves to LA:
All nerve fibres are sensitive, in general, smaller-diameter fibres are more sensitive than large fibres.
LA block conduction in the following order: small myelinated axons, (e.g., A and C-fibres carrying nociceptive
impulses), non-myelinated axons, large myelinated axons a differential block can be achieved where the
smaller pain and autonomic fibres are blocked, whilest coarse touch and movement are spared.
Pharmacokinetic:
- ester-linked LA (e.g., procaine, amethocaine) rapidly hydrolysed by plasma cholinesterase short T0.5
note: procaine hydrolysed to PABA (folate precursor) which interferes with the antibacterial effect of
sulfonamides !
- amide-linked LA (e.g., lignocaine, prilocaine) metabolised mainly by N-dealkylation in the liver (metabolites
often active) longer activity
- benzocaine (low solubility, used only for surface anesthesia)
- cocain (high toxicity, used only for surface anesthesia)
EFFECTS OF LA ON OTHER PHYSIOLOGICAL SYSTEMS AND TOXICITY OF LA:
The toxicity of LA is related to the amount and speed of their absorption into the systemic circulation !
Vasoconstrictor ingredient (e.g., adrenaline, felypressin) is often added to LA with the aim to reduce the
absorption of LA into the systemic circulation.
Effects of vasoconstrictors:
- increase in the effect of LA (increased concentration)
- decrease in the toxicity of LA (decreased absorption)
- increase in the duration of the effect of LA
Vasoconstrictors must not be used for producing ring-block of an extremity (e.g. finger or toe) because they may
cause prolonged ischaemia and gangrene.
1
LA depress other excitable tissues if the concentration in the blood is sufficiently high, but their main
systemic effects involve the central nervous system.
/1/ CNS: the most dangerous
- stimulation of CNS (anxiety, restlessness, tachycardia, palpitation, tremor, twitching, visual disturbances,
agitation, convulsion) therapy: i.v. diazepam, thiopental
- depression of CNS and coma (respiratory and cardiovascular medullary centre) therapy: oxygenotherapy
Note: both phases are not essential (i.e., only excitation or depression may occur). Even cocaine, which has
central stimulant properties unrelated to its anaesthetic action, may cause death by respiratory depression.
/2/ Cardiovascular system:
- myocardial depression (reduction of contractility via the reduction of Na+ entry - effect opposite to that of
cardiac glycosides)
- "quinidine-like effect" - useful in dysrhythmias
- vasodilatation (directly via the vascular smooth muscle, indirectly via the decreased tone of the sympathetic
system) fall in blood pressure may be life-threatening
Exception: cocaine (inhibits noradrenaline re-uptake increased sympathetic activity with vasoconstriction,
increased arterial pressure, tachycardia ...)
/3/ Smooth muscle:
Slight spasmolytic activity (decrease in the tonus of smooth muscle)
/4/ Neuromuscular junction:
Decrease in the depolarisation and contraction (LA affect the postsynaptic ion transports).
UNWANTED EFFECTS:
/1/ Acute intoxication: resulting from actions on CNS and cardiovascular system - see above.
/2/ Hypersensitivity reactions:
usually allergic dermatitis, but occasionally also an acute anaphylactic reaction.
/3/ Toxicity of vasoconstrictor agents:
- ischemic tissue damage
- systemic toxicity (increase in BP, metabolic activity of sympathomimetic agents), important, e.g., in diabetes
mellitus, hypertension, hyperthyreosis ...
/4/ Specific to particular drugs
METHODS OF ADMINISTRATION
/1/ Surface anaesthesia:
Topical application to external or mucous surface. LA must be able to penetrate tissues. Relatively high
concentrations used, when large areas are anaesthetised - systemic toxicity may occur.
EMLA (eutectic mixture of LA - lignocaine and prilocaine) can produce anaesthesia on the skin.
/2/ Infiltration anaesthesia:
Injected directly into the tissues to act on local nerve endings, usually with a vasoconstrictor.
/3/ Nerve block:
Techniques range from infiltration of anaesthetic around a single nerve (e.g. dental anaesthesia) or nerve trunks
to epidural and spinal anaesthesia. In spinal anaesthesia (intrathecal block) a drugs is injected into the
cerebrospinal fluid in the subarachnoid space. In epidural anaesthesia, the anaesthetic is injected outside the
dura. Spinal anaesthesia is technically far easier to producee than epidural anaesthesia, but the latter technique
virtually eliminates the post-anaesthetic complications such as headache.
/4/ Intravenous regional anaesthesia:
2
Anaesthetic is injected intravenously into an exsanguinated limb. A tourniquet prevents the agent reaching the
systemic circulation.
CHEMISTRY
Commonly used local anaesthetics consist of liphophilic end (often an aromatic ring) and a hydrophilic end
(usually a secondary or tertiary amine) connected by an intermediate chain that incorporates an ester or amide
linkage.
GROUPS OF LA (according to their chemical configuration):
/1/ Cocain (natural substance)
/2/ Ester - linked LA (PABA derivatives)
/3/ Amide - linked LA
/4/ Other
ad 1) COCAINE
Cocaine is found in the leaves of Erythroxylon coca, a South American shrub, coca used for their stimulant
properties by natives of South America, particularly those living at high altitude in the Andes.
Freuds eperiments, Koller (ophthalmologist - first use)
Cocaine is a potent inhibitor of catecholamine uptake by noradrenergic nerve terminals, and strongly
enhances the effects of sympathetic nerve activity. This occurs also in the brain, and it is likely that its
psychomotor stimulant effect depends on this mechanism. The effect of cocaine closely resembles that of
amphetamine tolerance, abuse, acute poisoning !!!
Symptoms: euphoria, garrulousness, increased motor activity and a magnification of pleasure. Excessive
dosage: stereotyped behaviour, hallucinations, tremors and convulsions, followed by respiratory and vasomotor
depression. The peripheral sympathomimetic actions: tachycardia, vasoconstriction and an increase in blood
pressure.
Body temperature: increase (increased motor activity coupled with reduced heat loss).
Like amphetamine, cocaine produces no clear-cut physical dependence syndrome, but tends to cause depression
and dysphoria following the initial stimulant effect. Withdrawal of cocaine after administration for a few days
causes a marked deterioration of motor performance and learned behaviour, which are restored by resuming
dosage with the drug. There is thus a considerable degree of psychological dependence. The pattern of
dependence, evolving from occasional use through escalating dosage to compulsive binges, is identical to that
seen with amphetamines.
Pharmacokinetic:
Readily absorbed by many routes. The duration of action of cocaine: about 30 minutes after i.v. administration,
after oral or nasal administration T0.5 about 1 hour. Degraded by plasma esterases.
For many years, illicit supplies consisted of the hydrochloride salt, which could be given by nasal inhalation or
intravenously. The i.v. route produces an intense and immediate euphoria, but involves the danger and stigma of
using a syringe. Nasal inhalation produces a less dramatic sensation, and also tends to cause atrophy and necrosis
of the nasal mucosa and septum. Cocaine use increased dramatically when the free base form ("crack") became
available as a street drug. This can be smoked, giving a very rapid intense effect with less risk and inconvenience
than intravenous or nasal administration. The social, economic, and even political consequences of this small
change in formulation have been far-reaching.
Use: occasionally used only topically !!! mainly in ORL and ophthalmology, but has no other clinical uses. In
dentistry, the practicality of cocaine is severely limited by its regulation under the Controlled Substances Act and
by the fact that it can cause tissue necrosis after repeated applications because of an intense vasoconstriction.
The concentration of cocaine should not exceed 4%.
Unwanted effects: CNS, mucosal irritation, necrosis (eye, nasal septum), enhancement of sympathetic activity
3
AD 2) ESTER-LINKED LA
PROCAINE (2-die-thyl-4-aminobenzoate hydrochloride).
Commercial names: Novocain, Procaine
Indications: infiltration and nerve block local anesthesia (not effective for the surface anesthesia).
Procaine is rapidly metabolized by esterase enzymes and, since it is not metabolized by the liver, may be used
in patients liver dysfunction.
Procaine is not sufficiently effective without a vasoconstrictor for dental applications, and even with a
vasoconstrictor, it produces of sufficient duration only for routine operative procedures (medium duration).
Solutions: 0.25-0.5% for infiltration anesthesia
0.5-2.0% for nerve block
10% for spinal an. (without vasoconstrictor)
Because procaine is rapidly inactivated in the blood by esterase enzymes, it is one of the least toxic of currently
available local anesthetic. However, the incidence of allergy with para-aminobenzoic acid derivatives is
substantially greater than that seen with amide-type agents. Furthermore, patients with procaine allergy may also
be allergic to other esters, especially tetracain. Procain should not be used in patients taking sulfonamides (its
metabolite - para-aminobenzoic acid - can inhibit the action of sulfonamides).
Adverse effects: intoxication (both phases)
allergy
vasodilation
TETRACAIN (Amethocaine): Pontocain, Gingicain
About 10 times more toxic and more active than procaine, duration of its effects about 2 times higher.
Suitable for topical anaesthesia (eye - 0.5%, mucous membranes - 2%) and spinal an.
BENZOCAINE
Poorly soluble in water slow absorption, suitable for topical anaesthesia
Available in non-aqueous solutions, gels, and ointments at 5 to 22% concentrations. Benzocaine is poorly
absorbed and rapidly metabolized, producing only rare systemic reactions.
However, allergy can occur in patients sensitized to benzocaine or other para-aminobenzoic acid derivates.
Since one of the hydrolysis products of benzocaine is para-aminobenzoic acid, it can antagonize the actions of
sulfonamides.
BUTACAINE
Effective topical anesthetic of the ester-type (commercial name Butyn as a non-aqueous ointment containing 4%
butacaine base). The total dose should not exceed 200 mg (5 gm of ointment) in adults, since it is absorbed.
AD 3) AMIDE-LINKED LA
LIDOCAINE (lignocaine) - diethylamino-2,6-acetoxylidide
as a hydrochloride salt: Alphacaine, Lidocaine, Octocaine, Xylocaine, Dentacaine
Indications: All types of LA (infiltration and nerve block local anaesthesia, also used topically), most widely
used LA.
4
Antiarrhythmic agent.
Lidocaine produces anesthesia of only short duration when used without a vasoconstrictor, it is recommended
that it is routinely used with 1:100,000 epinephrine for dental procedures.
Duration of action of about 90 minutes.
Quickly absorbed, dealkylated in the liver, metabolites retain LA activity.
Toxicity: ventricular fibrilation or cardiac arrest (massive overdosage)
CNS effects (signs of central depressions, including drowsiness, sedation, and ataxia, although tremor
and/or convulsions may occur).
Lidocaine regarded as being the prototype local anesthetic drug (formerly the prototype was procaine). All other
local anesthetics are compared to the prototype. Lidocaine is intermediate in toxicity: twice as toxic as procaine
but much less toxic than more potent agents, e.g., tetracaine. The total dose of lidocaine with 1:100,000
epinephrine should not exceed 350 mg (or 5mg/kg body weight).
Precautions: Do not use lidocain in patients with known hypersensitivity to amide-type local anesthetic.
Preparations containing vasoconstrictor must be used with caution in patients with cardiovascular disease.
Lidocain may be contraindicated in patients with severe liver disease.
PRILOCAINE (2-propylamino-o-propionotoluidide hydrochloride).
Commercial name: Citanest.
Indications: Prilocaine can be used for infiltration and nerve block local anesthesia.It is not suitable for topical
use.
The onset and duration of action of prilocaine is more rapid and longer than that of lidocaine (in
infiltrations, an onset action of less than 2 minutes).
Precautions and toxicity:
One of the metabolites of prilocaine is ortho-toluidine, which can produce methemoglobinemia. In adults,
significant levels of methemoglobin are produced only by high doses, therefore, there is little risk of
methemoglobinemia when prilocain is used for routine procedures.
Alternative agents should be used in the debilitated, the elderly, children, or pregnant patients and in patients
with heart disease, an existing condition of methemoglobinemia, or respiratory difficulty.
Prilocaine is slightly less toxic and less potent that lidocaine. Prilocaine should not be used in patients with
known hypersensitivity to amide-type local anesthetic, must be used with caution also in patients with liver
disease.
TRIMECAINE (Czech origin: Mezokain)
Indications: All types of LA (infiltration and nerve block local anesthesia, also used topically), most widely
used LA.
Antiarrhythmic agent.
Quickly absorbed, dealkylated in the liver, metabolites retain LA activity.
Toxicity: ventricular fibrilation or cardiac arrest (massive overdosage)
CNS effects (signs of central depressions, including drowsiness, sedation, and ataxia, although tremors
and/or convulsions may occur). About twice as active as procain (but not twice as toxic). Similar to lidocaine.
BUPIVACAINE (Marcaine)
Long acting amide (duration greater than tetracaine, but the toxicity is similar). Bupivacaine has a slow onset
(up to 30 minutes) but a very long duration of action, up to 8 hours when used for nerve blocks. It is often used
in pregnancy to produce continuous epidural blockade during labour.
Cardiac toxicity.
5
Supplied at 0.5% with an epinephrine concentration of 1:200,000.
MEPIVACAINE (1-methyl-2,6-pipecoloxylidide hydrochloride).
Commercial names: Carbocaine, Mepivacaine.
Indications: for infiltration and nerve block local anesthesia, not used topically.
Since mepivacaine can produce acceptable depth and duration without a vasoconstrictor, it may be useful in
patients in whom vasoconstrictors are contraindicated. More rapid in onset and somewhat more prolonged
action than that of lidocain.
Precautions: Do not use mepivacaine in patients with known hypersensitivity to amide-type local anesthetic.
Preparations containing vasoconstrictor must be used with caution in patients with cardiovascular disease.
Mepivacaine may be contraindicated in patients with severe liver disease.
Toxicity: equal to that of lidocaine.
When significant plasma levels are reached, central nervous system excitation can occur, which may terminate in
convulsions and post-seizure respiratory depression.
Dosage: Maximum total dosage should not exceed 5 mg per kilogram of body weight when levonordefrin is
present or about one-half that amount with no vasoconstrictor.
AD 4) FURHER LA
DIBUCAIN (cinchocaine): Nupercainal
Quinoline derivative, very potent but very toxic. Pronounced vasodilatation.
Use: Only topical.
DYCLONINE HYDROCHLORIDE
Differs sufficiently from other local anesthetic structures so that it may be useful in cases of allergy to other
agents. Commercial name Dyclone as a 0.5% or 1% aqueous solution. The total dose should not exceed 200 mg,
since it is absorbed.
Use: topical anesthesia
LOCAL ANESTHETIC IN DENTISTRY
LA are used in dentistry to reversibly abolish the sensation of paining a lokalized area of the oral cavity. There
are currently available many local anaesthetic preparations, although they can be placed generally into one of
two main chemical groups, the esters and the amides. Within each of these two categories, individual local
anesthetic agents may differ with respect to potency, toxicity, duration of action, vasoconstrictor requirements, or
type of vasoconstrictor used in the solution.
The modern dental practice should be stocked with an appropriate variety of injectable and topical anesthetic
agents, as well as emergency drugs. This armamentarium should include both ester- and amide-type agents,
agents that can be used without vasoconstrictor, agents that contain reduced amounts of vasoconstrictor, longacting
agents, and agents that do not contain paraben preservatives. When medical complications are expected,
the patient s physician should be consulted.
SPECIFICS OF LOCAL ANESTHETIC USE IN DENTISTRY
Indications for use:
1.Topical anesthesia of mucous membranes may be administered to increase patient comfort during the local
anesthetic injection.
2.Local anesthesia by nerve block or infiltration should be given prior to all operative procedures where pain is
expected.
3.Nerve block may aid in diagnosis of some pain syndromes.
6
4.Topical anesthesia of mucous membranes may be used for temporary relief of surface oral lesions.
SELECTION OF LOCAL ANESTHETIC AGENT:
Patient factors include the following:
1.Good health history to identify allergy, cardiovascular disease, endocrine disease, current medications, or prior
psychogenic reactions to local anestetic injection.
2.Use caution in the following:
a. Allergy
(1) avoid anesthetic to which patient is allergic
(2) consider possibility of allergy to preservatives
(3) always follow-up on patient report of allergy
(4) always be prepared for unexpected allergic reaction
b. Cardiovascular disease
(1) consult physician
(2) reduce or eliminate vasoconstrictor
(3) be prepared to handle emergency
c. Endocrine disease (e.g., hyperthyroidism)
(1) consult physician
(2) reduce or eliminate vasoconstrictor
d. Current medications: possible interactions of local anaesthetic with:
(1) sulfonamides (ester-type agents)
(2) anticholinesterase agents (esters and amides),such as diisopropylfluorophosphate (DFP), echothiophate, or
stigmine drugs used for glaucoma or myasthenia gravis
e. Current medications: possible interactions of vasoconstrictors with:
(1) monoamine oxidase (MAO) inhibitors
(2) tricyclic antidepressants
(3) guanethidine
f. Liver impairment (decreased metabolism of amides)
g. Genetic cholinesterase deficiency: impaired ester metabolism
TOXICITY
1.Allergy:
a. rush
b. itching
c. urticaria
d. bronchospasm (difficulty in breathing)
e. hypotension
2.Psychogenic reaction:
a. loss of colour
b. dizziness
c. rapid, thready pulse
d. cold sweat
3.Vasoconstrictor:
a. nervousness, palpitations
b. talkativeness, elevated blood pressure
c. anxiety
4.Local anesthetic:
a. nervousness
b. excitement
c. muscle twitching
d. tremors
e. convulsions
7
8