Local anaethetics

outline
Introduction History mechanism of action and overview Classes of LA Properties of a good LA Clinical uses Adverse effects

defination
a local anesthetic is a drug that causes reversible local anesthesia The primary aim is to have a local analgesic effect-inducing absence of pain sensation Other local senses may be affected

introduction
The property of electrical excitability is what enables nerve cells to generate propagated action potential These are important for communication Initiation of action potential is dependent on voltage gated sodium channels which open when membrane is depolarized Local anaesthetics work by blocking sodium channels

 Channel function may be modified in 2 ways Blocking the channelreduces excitability Modification of the gating behaviorsome drugs facilitate opening(increase excitability while others inhibit opening ,reducing excitability)

history
Coca leaves have been chewed for their psychotropic effects for many years by south Americans They also knew that it had numbing effect on the mouth and tongue Cocaine was isolated in the 1860 A synthetic substitute ,procaine was made in 1905

chemistry
All contain an aromatic part linked by an amide or an ester to a basic side chain They are weak bases They are mainly and not completely ionized at physiologic PH Ability to penetrate nerves sheath and axon membrane is dependent on this The ester or amide linkage is critical for hydrolysis

Chemistry
The esters are rapidly inactivated by esterases Amides are more stable and have longer half lives

RECALL
Polarization: Charges are separated across the plasma membrane, so the membrane has potential. Any time the value of the membrane potential is other than 0 mV, in either the positive or negative direction, the membrane is in a state of polarization.

 the magnitude of the potential is directly proportional to the number of positive and negative charges separated by the membrane the sign of the potential (+ or -) always designates whether excess positive or excess negative charges are present, respectively, on the inside of the membrane. At resting potential, the membrane is polarized at -70 mV in a typical neuron.

 Depolarization: A reduction in the magnitude of the negative membrane potential; the membrane becomes less polarized than at resting potential. During depolarization the membrane potential moves closer to 0 mV, becoming less negative (for example, a change from -70 to 60 mV); fewer charges are separated than at resting potential.

M.O A
Local anesthetics bind reversibly to a specific receptor site within the pore of the Na+ channels in nerves and block ion movement through this pore. When applied locally to nerve tissue in appropriate concentrations, local anesthetics can act on any part of the nervous system and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction.

M.O A.
Thus, a local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. These effects of clinically relevant concentrations of local anesthetics are reversible with recovery of nerve function and no evidence of damage to nerve fibers or cells in most clinical applications.

M.O A
The application of a local anesthetic to a nerve that is actively conducting impulses will inhibit the inward migration of Na. This elevates the threshold for electrical excitation, reduces the rate of rise of the action potential, slows the propagation of the impulse, and if the drug concentration is sufficiently high, completely blocks conduction.

 The local anesthetics interfere with the the large, transient voltage-dependent rise in the permeability of the membrane to Na which is fundamental to the generation of the action potential. Almost all local anesthetics can exist as either the uncharged base or as a cation. The uncharged base is important for adequate penetration to the site of action, and the charged form of the molecule is required at the site of action

 The cation forms of local anesthetics appear to be required for binding to specific sites in or near the Na channels. The presence of the local anesthetic at these sites interferes with the normal passage of Na through the cell membrane by stopping a conformational change in the subunits of the voltage-gated Na channel.

FREQUENCY- AND VOLTAGE-DEPENDENCE OF LOCAL ANESTHETIC ACTION

The degree of block produced by a given concentration of local anesthetic depends on how the nerve has been stimulated and on its resting membrane potential. Nerves that are rapidly depolarizing are inherently particularly susceptible to the effects of local anesthetics. These frequency- and voltage-dependent effects of local anesthetics occur because the local anesthetic molecule in its charged form gains access to its binding site within the pore only when the Na+ channel is in an open state (depolarizing).

differential sensitivity of nerve fibers to local anesthetics

Peripheral nerve functions are not equally affected by local anaesthetics. Generally, treatment with local anesthetics causes the sensation of pain to disappear first, followed by loss of the sensations of temperature, touch, deep pressure, and finally motor function.

 This differential blockade is a result of a number of factors which include: Size of the nerve Presence and amount of myelin Location of particular fibers within a nerve bundle

 For conduction to be effectively blocked, the local anesthetic must exert its effects over the distance between several nodes of Ranvier. Since the smallest nerves (C fibers) have no myelin, they can be most easily blocked; thus, sympathetic functions often are blocked soon after a local anesthetic is applied to a particular nerve bundle.

 Small myelinated nerves have correspondingly short distances between nodes of Ranvier and therefore are often blocked next. These nerves sub serve temperature and sharp pain sensation. Larger nerves then become blocked, accounting for the loss of function up to and including motor innervations.

 In general, autonomic fibers, small

unmyelinated C fibers (mediating pain sensations), and small myelinated A fibers (mediating pain and temperature sensations) are blocked before the larger myelinated A, A, and A fibers (mediating postural, touch, pressure, and motor information

prolongation of action by vasoconstrictors

The duration of action of a local anesthetic is proportional to the time of contact with nerve. Sympathomimetic agents e.g. epinephrine are added to local anaesthetics to delay absorption of the anaesthetic from the site of injection.

 By slowing absorption, these agents these drugs reduce the anaesthetic systemic toxicity and keep it in contact with nerve fibres longer, thereby increasing the drugs duration of action.

 Administration of 1% lidocaine with epinephrine results in the same degree of blockade as that produced by 2% lidocaine without the vasoconstrictor. Epinephrine can have and - adrenergic effects and therefore caution is needed when LA with this amine is given to patients with hypertension or myocardial dysfunction.

 The use of vasoconstrictors in local-anesthetic preparations for anatomical regions with limited collateral circulation could produce irreversible hypoxic damage, tissue necrosis, gangrene therefore is contraindicated.

Classes of LA
ESTHERS COCAINE BENZOCAINE TETRACANE PROCAINE

AMIDES
LIDOCAINE BUPIVACAINE LEVOBUPIVACANE ROPIVACAINE ETIDOCAINE MEPIVACAINE PRILOCAINE BENZOCAINE Cinchocaine(dibucaine) ARTICAINE

PROPERTIES OF AN IDEAL LOCAL ANAESTHETIC AGENT

An important property of the ideal local anesthetic is low systemic toxicity at an effective concentration. Onset of action should be quick, and duration of action should be sufficient to allow time for the surgical procedure.

IdealLA.
The local anesthetic should be soluble in water and stable in solution. It should not deteriorate by the heat of sterilization, it should be effective both when injected into tissue and when applied topically to mucous membranes. Its effects should be completely reversible.

 Although the characteristics of an ideal local anesthetic are easily identiable, synthesis of a compound possessing all these properties has not been accomplished. The compounds used clinically fall short of the ideal in at least one aspect. However, the judicious choice of a particular agent for a particular need will permit the practitioner to employ local anesthesia effectively and safely.

CLINICAL USES

Topical anesthesia-1 Local anesthetics are used extensively on the mucous membranes in the nose, mouth, tracheobronchial tree, and urethra. The vasoconstriction produced by some local anesthetics, cocaine especially, adds a very important advantage to their use in the nose by preventing bleed-ing and inducing tissue shrinkage

 Caution should be exercised because when the tracheobronchial tree and larynx are anesthetized, normal protective reexes, which prevent pulmonary aspiration of oral or gastric uids and contents, are lost.

Infiltration Anesthesia-2
Infiltration anesthesia is the injection of local anesthetic directly under the skin The duration of infiltration anesthesia can be approximately doubled by the addition of epinephrine (5 g/mL) to the injection solution

 Epinephrine-containing solutions should not, however, be injected into tissues supplied by end arteriesfor example, fingers and toes, ears, the nose, and the penis. the resulting vasoconstriction may cause gangrene.

 The advantage of infiltration anesthesia and other regional anesthetic techniques is that it can provide satisfactory anesthesia without disrupting normal bodily functions. The chief disadvantage of infiltration anesthesia is that relatively large amounts of drug must be used to anesthetize relatively small areas.

Nerve Block Anesthesia-3

Injection of a local anesthetic into or around individual peripheral nerves or nerve plexuses results in greater areas of anesthesia Brachial plexus blocks are particularly useful for procedures on the upper extremity and shoulder. Intercostal nerve blocks are effective for anesthesia and relaxation of the anterior abdominal wall.

 Cervical plexus block is appropriate for surgery of the neck. Sciatic and femoral nerve blocks are useful for surgery distal to the knee.

 Other useful nerve blocks prior to surgical procedures include blocks of individual nerves at the wrist and at the ankle, blocks of individual nerves such as the median or ulna at the elbow, blocks of sensory cranial nerves.

 Local anesthetic is never intentionally injected into the nerve; this would be painful and could cause nerve damage. Instead, the anesthetic agent is deposited as close to the nerve as possible.

 Higher concentrations of local anesthetic will provide a more rapid onset of peripheral nerve block, but the potential for systemic toxicity and direct neural toxicity limits use of high concentrations.

Spinal Anesthesia-4
Spinal anesthesia follows the injection of local anesthetic into the cerebrospinal fluid (CSF) in the lumbar space. For a number of reasons, including the ability to produce anesthesia of a considerable fraction of the body with a dose of local anesthetic that produces negligible plasma levels, spinal anesthesia remains one of the most popular forms of anesthesia

 In most adults, the spinal cord terminates above the second lumbar vertebra; between that point and the termination of the theca sac in the sacrum, the lumbar and sacral roots are bathed in CSF. Thus, in this region there is a relatively large volume of CSF within which to inject drug, thereby minimizing the potential for direct nerve trauma.

Control of cardiac arrhythmias-5

Procainamide and lidocaine are two of the primary drugs for treating cardiac arrhythmias.

UNDESIRED EFFECTS OF LOCAL ANESTHETICS

In addition to blocking conduction in nerve axons in the peripheral nervous system, local anesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. Thus, they have important effects on the CNS, autonomic ganglia, neuromuscular junctions, and all forms of muscle.

 The danger of such adverse reactions is proportional to the concentration of local anesthetic achieved in the circulation. In general, in local anesthetics with chiral centers, the S-enantiomer is less toxic than the R-enantiomer.

Central Nervous System-1

Local anaesthetics given in initially high concentrations result in CNS stimulation (presumably due to suppression of inhibitory neurons), producing restlessness and tremor that may progress to clonic convulsions.

 Continued exposure to high concentrations results in general CNS depression and death results from respiratory failure secondary to medullary depression

 Airway control and ventilatory support are essential features of treatment in the late stage of intoxication. Benzodiazepines or rapidly acting barbiturates administered intravenously are the drugs of choice for both the prevention and arrest of convulsions

Cardiovascular System-2
Cardiac toxicity is generally the result of drug induced depression of cardiac conduction Following systemic absorption; local anesthetics decrease electrical excitability, conduction rate, and force of contraction. Most local anesthetics also cause arteriolar dilation. These effects may progress to hypotension and cardiac arrest.

Hypersensitivity-3
Some individuals are hypersensitive to local anesthetics, displaying allergic dermatitis or a typical asthmatic attack. Hypersensitivity seems to occur more frequently with local anesthetics of the ester type

 The ester-type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a small percentage of the patient population. Amides are not metabolized to paminobenzoic acid, and allergic reactions to amide local anesthetics are extremely rare.

 However , although the amides are essentially free of allergic responses, solutions of such agents may contain preservatives such as methylparaben that may provoke an allergic reaction. Local anesthetic preparations containing a vasoconstrictor also may elicit allergic responses due to the sulfite added as an antioxidant.

ESTERS
Cocaine Cocaine hydrochloride remains useful primarily because of the vasoconstriction it provides with topical use. Toxicity prohibits its use for other than topical anesthesia.

 Cocaine has a rapid onset of action (1 minute) and a duration of up to 2 hours, depending on the dose or concentration. Lower concentrations are used for the eye, while the higher ones are used on the nasal and pharyngeal mucosa.

 Epinephrine plus cocaine, although still used occasionally, is hazardous because the catecholamine potentiates the cardiovascular toxicity (e.g., arrhythmia, ventricular brillation) of cocaine.

 Cardiovascular effects are related to both central and peripheral sympathetic stimulation. Initial bradycardia appears to be related to vagal stimulation; this is followed by tachycardia and hypertension. Larger doses are directly depressant to the myocardium, and death results from cardiac failure

 Cocaine is readily absorbed from mucous membranes, so the potential for systemic toxicity is great. The CNS is stimulated, and euphoria and cortical stimulation (e.g., restlessness, excitement) frequently result. Over dosage leads to convulsions followed by CNS depression. The cortical stimulation it produces is responsible for the drugs abuse.

Benzocaine
Benzocaine is a PABA derivative used primarily for topical application to skin and mucous membranes. Its low aqueous solubility allows it to stay at the site of application for long periods. Its minimal rate of absorption after topical administration is associated with a low incidence of systemic toxicity. Benzocaine is contraindicated in patients with known sensitivity to ester-linked anesthetics or PABAcontaining compounds.

Chloroprocaine
Chloroprocaine hydrochloride is obtained from addition of a chlorine atom to procaine, which results in a compound of greater potency and less toxicity than procaine itself. This local anesthetic is hydrolyzed very rapidly by cholinesterase and therefore has a short plasma halflife. Because it is broken down rapidly, Chloroprocaine is commonly used in obstetrics. It is believed that the small amount that might get to the fetus continues to be rapidly hydrolyzed, so there may be no residual effects on the neonate.

Procaine
Procaine hydrochloride is readily hydrolyzed by plasma cholinesterase, although hepatic metabolism also occurs. It is not effective topically but is employed for inltration, nerve block, and spinal anesthesia. It has a relatively slow onset and short (1hour) duration of action. All concentrations can be combined with epinephrine. It is available in dental cartridges with Phenylephrine as the vasoconstrictor.

Tetracaine
Tetracaine hydrochloride is an ester of PABA that is an effective topical local anesthetic agent and also is quite commonly used for spinal anesthesia. Epinephrine is frequently added to prolong the anesthesia. Tetracaine is considerably more potent and more toxic than procaine and cocaine. It has approximately a 5-minute onset and 2 to 3 hours of action.

AMIDES
Lidocaine hydrochloride is the most commonly used local anesthetic. It is well tolerated, and in addition to its use in inltration and regional nerve blocks, it is commonly used for spinal and topical anesthesia and as an antiarrhythmic agent. Lidocaine has a more rapidly occurring, more intense,and more prolonged duration of action than does procaine.

Bupivacaine hydrochloride (Marcaine)

has long action, and some nerve blocks last more than 24 hours; this is often an advantage for post-operative analgesia. Its use for epidural anesthesia in obstetrics has attracted interest because it can relieve the pain of labor at concentrations as low as 0.125% while permitting some motor activity of abdominal muscles to aid in expelling the fetus

 The lower concentration minimizes the possibility of cardiac toxicity. Fetal drug concentrations remain low, and druginduced neurobehavioral changes are not observed in the newborn. Bupivacaine also is approved for spinal anesthesia and is approximately four times more potent and more toxic than mepivacaine and lidocaine. It can be used with or without epinephrine.

Levobupivacaine hydrochloride
is the S-enantiomer of Bupivacaine. It too has long action. Animal studies show that it has less CNS and cardiac toxicity than does Bupivacaine. It also is slightly more motor sparing than is Bupivacaine.

Ropivacaine
is a recently developed long- acting amidelinked local anesthetic. Its duration of action is similar to that of bupivacaine, but it is slightly less potent and requires higher concentrations to achieve the same degree of block. Its primary advantage over Bupivacaine is its lesser degree of cardio toxicity.

Etidocaine hydrochloride
although chemically similar to lidocaine, has a more prolonged action. It is used for regional blocks, including epidural anesthesia. It exhibits a preference for motor rather than sensory block therefore, its use in obstetrics is limited, although fetal drug concentrations remain low. It can be used with or without epinephrine.

Mepivacaine hydrochloride
is longer acting than lidocaine and has a more rapid onset of action (35 minutes). Topical application is not effective. It has been widely used in obstetrics, but its use has declined recently because of the early transient neurobehavioral effects it produces. Adverse reactions associated with mepivacaine are generally similar to those produced by other local anesthetics. It can be used with epinephrine (dental use only).

Prilocaine hydrochloride
is an amide anesthetic whose onset of action is slightly longer than that of lidocaine . Prilocaine is 40% less toxic acutely than lidocaine, making it especially suitable for regional anesthetic techniques. It is metabolized by the liver to orthotoluidine, which when it accumulates, can cause conversion of hemoglobin to methemoglobin

 Oxygen transport is impaired in the presence of methemoglobinemia. Treatment involves the use of reducing agents, such as methylene blue, given intravenously, to reconvert met hemoglobin to hemoglobin.

OTHER THERAPEUTIC USES OF LA

EPILEPSY NEURODEGENERATIVE DISEASES STROKE NEUROPATHIC PAIN MYOPATHIES