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Pharmacology-1 PHL 211
2nd Term
2nd Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Local Anesthetics, Systemic Effects
 The unintentional intravascular injection of LA agents in dentistry can occur because of
high vascularisation in this area
 Toxicity of LAs is mostly related to their inhibitory effects on excitable cells such as
neurons, cardiac muscle, smooth muscle and skeletal muscle cells:
 CNS
• Following absorption, LAs cause stimulation of the CNS, producing restlessness and
tremors that may progress to convulsion. Central stimulation is followed by depression;
death usually is caused by respiratory failure
• Drowsiness is the most frequent complaint that results from the CNS actions of LAs
• Cocaine is addictive
• Both lidocaine and procaine may produce a loss of consciousness
 Peripheral nervous system
• LAs affect transmission at the neuromuscular junction and ganglionic synapse. These
effects are due to block of the ion channel of the cholinergic receptor by high
concentrations of the LAs
 Smooth muscles
• LAs depress contractions of intestine, vascular and bronchial smooth muscle
Local Anesthetics, Systemic Effects
 Cardiovascular system (CVS): Following systemic absorption, LAs act on the CVS:
1. LAs block cardiac sodium channels and thus depress cardiac electrical excitability,
conduction rate
2. With the exception of cocaine, LAs depress the strength of cardiac contraction and
cause arteriolar dilation, leading to systemic hypotension
• Cocaine differs from the other LAs: it blocks NE reuptake, resulting in vasoconstriction
and hypertension, as well as cardiac arrhythmias
3. Bupivacaine is more cardiotoxic than other LAs and may cause ventricular
tachycardia and even cardiovascular collapse. The S-enantiomer (levobupivacaine) is
equally efficacious and potent; however, it is less cardiotoxic. Ropivacaine is
slightly less potent than bupivacaine in producing anesthesia, but it is less
cardiotoxic than bupivacaine.
 Hypersensitivity to LAs
• Rare individuals are hypersensitive to LAs. The reaction may manifest itself as an
allergic dermatitis or an asthmatic attack
• Hypersensitivity seems to occur more frequently with LAs of the ester type and
frequently extends to chemically related compounds
Local Anesthetics,
Individual Drugs, Ester Type
 Cocaine
 It is an ester-type LA that occurs in abundance in the leaves of the coca shrub. It is
the first LA introduced into medical practice
 The clinically desired actions of cocaine are the blockade of nerve impulses (see MOA
of LAs before), as a consequence of its LA properties, and local vasoconstriction,
secondary to inhibition of local NE reuptake (other LAs do not)
 Toxicity and its potential for abuse have steadily decreased its clinical use
 Its high toxicity is due to reduced catecholamine uptake in both the CNS and PNS
 Procaine (Novocain)
 The first synthetic LA and the prototype of amino ester-type LAs
 It has been replaced by newer agents, and its use now is confined mainly to infiltration
anesthesia. This is due to its low potency, slow onset, and short duration of action
• While its toxicity is fairly low, it is hydrolyzed in vivo to produce para-aminobenzoic acid,
which inhibits the action of sulfonamides. Thus, large doses should not be administered
to patients taking sulfonamide drugs
• It has a very high potential to cause allergic reactions
 Tetracaine (Pontocaine)
It is a long-acting amino ester LA. It is more potent and has a longer duration of action
than procaine. Tetracaine may exhibit increased systemic toxicity (CNS and
cardiovascular) because it is more slowly metabolized than the other commonly used
ester LAs. Currently, it is widely used in spinal anesthesia when a drug of long duration
is needed and as LA to the eye. Tetracaine also is incorporated into several topical
anesthetic preparations
Local Anesthetics,
Individual Drugs, Amide Type
 Lidocaine (Xylocaine)
 Lidocaine is the prototypical amide LA. It is an intermediate-acting LA
 It produces faster, more intense, longer lasting, and more extensive anesthesia than does an
equal concentration of procaine. Lidocaine is an alternative choice for individuals sensitive to
ester-type Las. It is still the most widely used LA in America today
 Lidocaine is absorbed rapidly after parenteral administration. Although it is effective when
used without any vasoconstrictor, epinephrine decreases the rate of absorption, such that
the toxicity is decreased and the duration of action usually is prolonged
 The clearance of lidocaine is almost entirely due to liver metabolism
 The half-life may be prolonged two-fold or more in patients with liver dysfunction
 Toxicity. The side effects of lidocaine seen with increasing dose include drowsiness, tinnitus,
dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression
and arrest will occur. Clinically significant cardiovascular depression usually occurs at serum
lidocaine levels that produce marked CNS effects. However, Lidocaine is one of the least
cardiotoxic of the currently used LAs
 Clinical Uses. Lidocaine has a wide range of clinical uses as a LA which include:
Dental anesthetic
Topical application to relieve itching, burning and pain from skin inflammations,
It is used for infiltration anesthesia and for nerve block techniques including peripheral,
sympathetic, epidural, and spinal block anesthesia.
Lidocaine also is used as an anti-arrhythmic agent (only by the i.v. route; systemic effect)
Local Anesthetics,
Individual Drugs, Amide Type, cont.d
 Bupivacaine (Marcaine)
Bupivacaine is a widely used amide LA. It is a potent long-acting LA
 Its long duration of action plus its tendency to provide more sensory than motor block
has made it a popular drug for providing prolonged analgesia during labor or the
postoperative period
 Toxicity. Bupivacaine is more cardiotoxic than equi-effective doses of lidocaine.
Clinically, this is manifested by severe ventricular arrhythmias and myocardial
depression after inadvertent intravascular administration of large doses of bupivacaine
 Although lidocaine and bupivacaine both rapidly block cardiac Na+ channels during
systole, bupivacaine dissociates much more slowly than does lidocaine during diastole,
so a significant fraction of Na+ channels at physiological heart rates remains blocked
with bupivacaine at the end of diastole. Bupivacaine-induced cardiac toxicity can be very
difficult to treat
• The S-enantiomer (levobupivacaine) is equally efficacious and potent, however it is less
cardiotoxic
 Ropivacaine (Naropin)
It is slightly less potent than bupivacaine in producing anesthesia. It is less cardiotoxic
than equi-effective doses of bupivacaine. In clinical studies, ropivacaine appears to be
suitable for both epidural and regional anesthesia, with a duration of action similar to
that of bupivacaine. It seems to be even more motor-sparing than bupivacaine
Local Anesthetics,
Individual Drugs, Amide Type, cont.d
 Mepivacaine (Carbocaine)
Mepivacaine is an intermediate-acting amino amide LA
Its pharmacological properties are similar to those of lidocaine. Mepivacaine, however,
is more toxic to the neonate and thus is not used in obstetrical anesthesia
It has a slightly higher therapeutic index in adults than does lidocaine
Its onset of action is similar to that of lidocaine and its duration slightly longer (about
20%) than that of lidocaine in the absence of a co-administered vasoconstrictor
 Mepivacaine is not effective as a topical anesthetic
 Prilocaine (Citanest)
Prilocaine is an intermediate-acting amino amide LA. It is used in dentistry for infiltration
anesthesia and for nerve block anesthesia
It has a pharmacological profile similar to that of lidocaine. The primary differences are
that it causes little vasodilation and thus can be used without a vasoconstrictor if
desired, and its increased volume of distribution reduces its CNS toxicity
It is not used for obstetric analgesia because of risk of methaemoglobinaemia
from its o-toluidine metabolite (usually appearing after a dose of 8 mg/kg)
• methaemoglobinaemia can be treated by the i.v. administration of methylene blue (1 to
2 mg/kg)