Local Anaesthetics: Features, Development and Applications

An Ideal Local Anaesthetic:

An ideal local anaesthetic should qualify four principal qualities: it should be selective and effective for action and safe and stable for use.

Selective:

It should selectively block the function of sensory nerves (reversible paralysis) to produce local analgesia.

Effective:

It should be effective whether applied topically or upon injection. Onset of action should be rapid. Duration of action should be adequate; neither too short nor too prolonged to extend recovery period. High potency is desirable so that smaller amounts can be used.

Safe:

It implies requirements such that:

(i) It should not damage the tissue at therapeutic concentrations i.e. irritancy be negligible,

(ii) It should be slowly absorbed from the site into systemic circulation so that its action is prolonged and systemic toxicity is minimized,

(iii) Once absorbed into circulation it should be rapidly detoxified,

(iv) It should produce low systemic toxicity, and

(v) Anaesthesia should not be preceded by sensory nerve stimulation (unlike aconite or phenol) nor followed by hyper-aesthesia.

There is none that qualifies all the criteria. However, commonly employed local anaesthetics such as lidocaine and procaine fulfill most of the criteria at recommended concentrations. Other agents differ from these mainly with respect to relative potency, duration of action and toxicity.

General Indications:

BOVINES:

General anaesthesia is considered as a risky procedure for bovine species; common problems encountered include anorexia, bloat, regurgitation, salivation, radial paralysis and hyperthermia. Thus, the surgeons heavily rely upon nerve blocks, infiltration or other forms of regional anaesthesia for bovine surgery.

Emergencies:

Local anaesthesia is most suitable for emergencies such as accidents, natural catastrophes, war situations or when surgery can not be postponed without involving risks.

Minor Operations:

The technique is most suitable for minor operative procedures such as diagnostics, catheterizations, or minor surgical procedures (see applications).

Obstetrical Practice:

Local anesthesia is considered highly safe procedure for dam and neonate, so is a preferred techniques for gynaecological and obstetrical practices.

Field Conditions:

It is the method of choice for field conditions as it involves less cost, less labour, less materials and less trained personnel. It ensures quicker patient disposal with ensured safety. Post-operative supervision is not normally required.

Patient Conditions:

It can be conducted on weak and debilitating animals that are at high risk for general anaesthesia. It is considered safer for geriatric surgery, and with patients suffering from cardiovascular, pulmonary or other systemic complications.

Major Operations:

The method can be adapted to nearly all major surgical operations except those pertaining to organ/tissue transplantations, complicated operations concerning cardiovascular system or visceral organs and neurosurgical operations. The skill of the surgeon is required for the success of any operative procedure attempted with local anaesthetics.

Classification of Local Anaesthetics:

1. On the Basis of Chemical Features:

I. Amino-group Containing Agents (Common Category):

(i) Esters:

Contain esteric linkage; most are benzoic acid esters e.g., cocaine, procaine, chloroprocaine, tetracaine, hexylcaine, benzocaine, butamben, proxymetacaine and benoxinate

(ii) Amides:

Contain amide linkage (longer acting than esters) e.g., Lidocaine, etidocaine, prilocaine, dibucaine, mepivacaine, rupivacaine, bupivacaine

(iii) Ketone:

Contain keto group in the intermediate chain Dyclonine

II. Non-amino Agents (Non-classical Local Anaesthetic Agents):

(iv) Alcohols:

Ethanol, isopropyl alcohol, phenol, eugenol, creosote, chlorobutol, salicyl alcohol, benzyl alcohol, menthol

(v) Alkyl Halides:

Ethyl chloride and methyl chloride.

2. On the Basis of Duration of Action:

(i) Ultra-short Acting:

Duration of action brief, less than or equal to 15 minutes. These include proparacaine and benoxinate.

(ii) Short Acting:

Duration of action is approx. an hour. These include procaine, chloroprocaine and cocaine.

(iii) Intermediate Acting:

Duration of action about one to four hours. These include lidocaine, mepivacaine and prilocaine.

(iv) Long Acting:

Duration of action about three to ten hours or longer. These include bupivacaine, ropivacaine, tetracaine, etidocaine, hexylcaine and cinchocaine.

Development of Local Anaesthetics:

A constant search for similar structures with better anaesthetic qualities, and high safety has been the principal driving force in the development of local anaesthetics.

The synthetic process began from Einhorn and his colleagues that developed procaine, and continues till date. Procaine and lidocaine are, respectively, prototype local anaesthetics representing ester and amide categories. Salient developmental aspects in historical perspective are briefly outlined (Table 8. 2).

Structure Activity Relationship:

The classic local anaesthetics have three structural features:

(i) An aromatic group for lipophilicity,

(ii) An amino group for hydrophobicity, and

(iii) Intermediate chain straight or branched containing ester, amide or ketone function.

These are considered minimal requirements for local anaesthetic action. As indicated earlier two structural features are common to nearly all agents with local anaesthetic action; a hydrophilic group (s) (such as amino, hydroxyl or chloride) and lipophilic group (s) (such as aromatic, heterocyclic or alkyl).

Hydrophilic and lipophilic groups enable the molecules to anchor into respective regions in the nerve membrane thereby altering contour of sodium ion-channels to block sodium conductance.

Local anaesthetic agents with long lipophilic side chains such as bupivacaine, dibucaine, tetracaine and etiodocaine penetrate into depths of the nerve membrane and exert more intense effects than molecules with shorter side chains such as procaine, chlorprocaine and lidocaine.

Alkylation of aromatic ring (e.g. lidocaine) or chlorination of aromatic ring (e.g. chloroprocaine) appears to enhance potency. Thus, lidocaine and chloroprocaine are more potent than procaine.

Type of linkage in the intermediate chain affects duration of action: esters are rapidly hydrolysed so short acting than amides.

Structural rigidity also affects membrane penetrating ability of local anaesthetics; cocaine with rigid structure penetrates better than procaine that has flexible structure.

Increased lipophilicity increases systemic availability of local anaesthetic, and their penetration into the brain; this tends to increase toxicity potential in parallel to increase in anaesthetic potency.

Table 8.3 contains some structural formulae of selected local anaesthetics; structural features can be compared with respect to relative potencies, relative toxicities and relative duration of action to appreciate structure activity relationship.

Pharmacokinetics of Local Anesthetics:

Pharmacokinetics of local anaesthetics determines their suitability for a particular route, durations of action, and possibility of developing systemic toxicity.

Absorption:

Cutaneous absorption is poor except when they are applied on inflammed or abraded areas. Mucosal absorption is good for all agents except procaine; procaine is poorly absorbed due to low lipid solubility. This renders procaine topically ineffective. Tetracaine is better absorbed from mucosal sites so useful as a topical anaesthetic.

Absorption following injection or infiltration is faster with all agents particularly those with vasodilator activity. The rate of absorption into systemic circulation depends upon the site of deposition: it is rapid from intercostal sites compared to epidural and brachial plexus sites.

Absorption of the drug molecules from the purulent sites is poor: local acidic pH reduces dissociation of the salt (generally used as hydrochlorides), and/or favour greater ionization leading to ion-trapping at local site.

Distribution:

Local anaesthetics are distributed widely. They tend to get concentrated intracellularly as pH gradient existing between extracellular fluid (about 7.4) and intracellular fluid (e.g. brain sap, 7.0) favours intracellular ion-trapping of the cationic base. The CNS may contain 3 to 4 fold, and lungs and kidneys 10 to 15 fold more drug than the blood. Heart and liver also accumulate the base significantly.

Amides are concentrated into tissues faster than esters as the esters tend to get hydrolyzed while in the circulation. Amide anaesthetics are extensively bound to plasma proteins particularly alpha-l-acid glycoproteins.

It is about 50% with prilocaine, about 80% with mepivacaine and lidocaine, while it is more than 90% with long acting local anaesthetics such as bupivacaine and etidocaine. The agents cross all barriers. Amides appear in fetal circulation within 1 to 3 minutes following epidural administration in humans. Fetal organs tend to accumulate drug at faster rate.

This is possibly related to two factors:

(i) Relatively acidic blood of fetuses favour base trapping, and

(ii) Relatively low fetal blood protein content increases free drug concentration for diffusion into cells. This would render neonates more susceptible to local anaesthetic toxicity if concentrations recommended for use are exceeded.

Biotransformation:

Esters are rapidly hydrolysed by non specific pseudocholinesterases in blood and tissues, mainly liver so are as a class short acting than amides. Chloroprocaine is hydrolyzed about 4-times faster than procaine, while tetracaine is hydrolyzed more slowly (rate about 1/3rd that of procaine). Hexylcaine is also slowly hydrolyzed than procaine. This makes chloroprocaine short acting and tetracaine and hexylcaine long acting than procaine.

Plasma t_1/2 for chloroprocaine in humans is about 25 seconds while that of procaine in horses about 25 minutes. Procaine metabolites include para-amino benzoic acid (PABA) and di-ethyl-amino-ethanol (partly active). PABA antagonizes sulfonamide action. Therefore, esters that release PABA (e.g. procaine, chloroprocaine and tetracaine) should not be used during sulfonamide therapy.

Amides are primarily metabolized by hepatic microsomal enzymes. Bio-transformations include one or more of the following processes: aromatic hydroxylation, de-alkylation and amide hydrolysis Lidocaine undergoes first de-alkylation followed by amide hydrolysis; de-alkylated metabolite mono-ethyl-glycine xylidide has significant local anaesthetic activity.

Prilocaine is rapidly hydrolysed to form 0-toluidine metabolite that causes methemoglobinemia. The clearance rate of some amides have been found in the following decreasing order: etidocaine, lidocaine, mepivacaine and bupivacaine. Plasma t_1/2 of lidocaine is shorter in sheep (about 30 min) than in humans (90 to 120 min). T_1/2 of bupivacaine is comparatively longer in humans, 120-150 minutes.

Excretion:

The renal excretion is the main elimination route for local anaesthetics. The excretory products include unaltered drug as well as its metabolites. Procaine appears as unaltered drug along with PABA. Lidocaine appears as such along with sulfated conjugate.

Bupivacaine appears as glucuronide conjugate. The urinary pH affects elimination of the base; acidic urine favours its rapid elimination by increasing its ionization and alkaline pH delays excretion by decreasing its ionization.

Mode of Action:

Local anaesthetics reduce or block excitability and conductivity of axolemma. The site of action is axolemma. The blockade of axonal function is due to blockade of voltage-gated sodium channels. The obstruction in sodium ion conductance across the axolemma appears to involve both specific as well as non-specific mechanisms.

Axolemmal function is critically dependent on operation of voltage-gated sodium ion channels that are abundant on its surface. Each channel consists of a glycoprotein complex composed of three sub-units; a large glycoprotein and two polypeptide chains. The protein surrounds a centrally located water-filled ion channel pore.

The channel contains two gates; m-gate and h- gate, m-gate is responsible for allowing sodium entry while h-gate is responsible for inactivating sodium ion conductance. The two gates are placed very closely such that when one gate is opened, the other gate gets closed.

At resting state the membrane is polarized with inside negative with respect to outside. At this stage m-gate is closed and h-gate is open. When membrane is stimulated m-gate opens and h-gate closes. This increases sodium ion entry into the interior leading to depolarization of the membrane.

Development of height of action potential is dependent on the number of sodium channels that are opened by the applied stimulus. Once action potential has developed, the membrane is completely depolarized. Voltage difference exists between stimulated site (now negatively charged at exterior surface) and adjacent un-stimulated site (carrying original positive charge at exterior surface).

The current flows. The voltage difference opens voltage-gated sodium channels at un-stimulated site thus leading to development of another action potential at un-stimulated site. The current flows to next step. The process is sequentially advanced forward in the direction of current flow. This constitutes propagation of action potential or nerve impulse.

Local anaesthetic molecules interact with membrane components at polar as well as at hydrophobic sites. The result is change in conformation or orientation of protein and/or lipid Molecules with consequent occlusion of sodium channel at critical sites or physically blocking passage of sodium ions across the channel.

Both ionized as well as un-ionized (neutral) drug molecules appears to be contributing to this blockade. Cationic species appear to bind specifically with anionic sites present in the middle of the sodium channels. Neutral species appear to diffuse to interior of the axolemma through lipid matrix and act from that side.

This is the model of specific mode of action of local anaesthetics i.e. specific interaction of cationic species with anionic sites within the channel, and direct blockade of the channel for sodium entry.

Non- specific mechanisms are related to:

(i) The drug molecules compete with Ca⁺⁺, Mg⁺⁺ and Na⁺ at anionic membrane sites ; calcium and sodium ion depots exist at membrane exterior and play critical role in membrane excitability, and calcium and magnesium ions are associated with membrane proteins at interior sites and are responsible for maintaining conformation of proteins : thus displacement of these ions from the sites tends to stabilize the membrane and reduce sodium entry;

(ii) Local anaesthetic molecules following their interaction with hydrophobic and hydrophilic membrane sites distort the membrane leading to its expansion, particularly at critical sites that choke the membrane channels thus blocking sodium conductance; higher pressure has been found to reverse the local anaesthetic effect partially, and higher concentrations of local anaesthetic molecules have been found to cause over distention, buckling and finally lysis of the nerve membrane; and

(iii) Lipid molecules form a rigid ring-like (crystalline) structure that controls sodium channel pore permitting sodium entry when in rigid form; drug molecules interact with these lipid molecules and change them from rigid state into flexible (fluidy) phase ; this leads to closure of sodium ion-channel.

It appears that non-specific mechanisms play crucial role in blocking sodium ion channels owing to following reasons:

1. Local anaesthetic molecules are capable of blocking not only sodium conductance but also conductance of potassium (at higher concentrations) as well as entry of glucose.

2. All excitable membranes are stabilized by local anaesthetics including those that are not critically dependent on voltage gated sodium channels such as smooth muscles as well as motor- end-plate.

3. At least 10% of all pharmacodynamics drugs selected at random possess some local anaesthetic activity this would suggest specific structural constraints are not critical for sodium channel blockade.

4. Alkyl halides produce axonal conduction blockade by apparently causing freezing of water molecules in axolemma; alcohols and phenols block conduction by membrane protein denaturation (at low concentrations) and precipitation (at higher concentrations).

5. Structural features of all classical and non-classical local anaesthetics including other drugs with significant local anaesthetic activity (chlorpromazine), propraolol, acebutolol, quinidine, quinine-urea complex) possess both hydrophobic regions (aromatic ring, and/or alkyl chains) and hydrophilic portions (amino, hydroxyl and/or halogens) thus are inherently capable of interacting simultaneously with polar as well as with non-polar regions of the membrane.

6. Benzocaine with pKa 2.5 and unable to ionize at tissues pH has also some local anaesthetic activity further suggesting cationic species is not critical for local anaesthetic action. Thus, it can be concluded that local anaesthetic molecules block sodium ion conductance by obstructing voltage-gated sodium ion channels directly and/or indirectly thereby preventing development and propagation of action potential along axolemma.

Toxicity, Complications and Control Measures:

Local:

Local damage consists of transient or permanent injury to tissues due to the irritancy. Recommended concentrations are practically non-irritant. The ratio of irritant to effective concentration for procaine is 150 and for lidocaine 25. Tetracaine is more irritant, 8-10 fold more than procaine. Nerve damage can result if high concentrations are deposited into nerves or very close to the nerves. Proparacaine causes a transient corneal roughening for 30 to 60 minutes.

Systemic:

Systemic toxicity is determined by the balance of rate of absorption to the rate of destruction of local anaesthetics. The toxicity is primarily due to CNS stimulation presumably due to inhibition of GABA-ergic synaptic function leading to restlessness, muscular tremors and convulsive seizures.

Death occurs rarely, and is due to respiratory failure. Neuro-stimulation is followed by depression of all CNS functions. Secondary toxic effects are related to depression of all excitable tissues including neuromuscular junction, myocardium and smooth muscles.

Cardiovascular, respiratory and skeletal muscle functions may be affected following epidural and/or spinal anaesthesia as a complication of the particular route. Blockade of adrenergic fibres (i.e.epidural or spinal use) reduces sympathetic tone (and all except cocaine and prilocaine possess appreciable direct vasodilator effect) to vascular system leading to hypotension.

Respiratory paralysis can result due to blockade of intercostal nerves and/or direct medullary centre paralysis that may happen if drug is administered near intercostal nerves and/or reaches them or medullary respiratory centre following spinal aesthesia. Posterior paralysis can result if high concentrations are deposited epidurally while attempting caudal block.

These constitute complications that may accompany local anaesthesia in domestic animals and humans. Hypotension, bradycardia and arrythmias may be observed in neonates delivered after epidural anesthesia.

Allergic Reactions:

Allergic dermatitis or typical asthmatic attack has been observed in humans with exclusively ester type local anaesthetics; some ester metabolite acting as a hapten. The occurrence is, however, rare.

Factors Affecting Systemic Toxicity:

1. Type of Drug:

Toxicity potential of a drug appears to be related to anaesthetic potential; thus highly potent drugs are also highly toxic. The average relative toxicity potential of some selected local anaesthetics is tabulated. Cocaine induced CNS stimulation is primarily related to potentiation of central biogenic amines as cocaine prevents reuptake of released biogenic amines at presynaptic sites.

Hyaluronidase can potentiate toxicity by increasing area of absorption, and hence rate of diffusion of local anaesthetic into systemic circulation. Adrenaline reduces toxicity by reducing absorption rate. It may lead to cardiac arrythmias if used in higher concentrations and is particularly dangerous to use with cocaine.

2. Species:

Susceptibility to convulsions is related to degree of CNS development; primates are more sensitive than domestic animals. Horses are more sensitive than swine. Ruminants particularly cattle appear to be least sensitive. Among birds, parakeets are extremely sensitive to lethal effects of procaine.

3. Route:

The toxicity is obviously greater if drug goes inadvertently into vein while it is intended for local deposition, or if tourniquet is loosely applied while attempting retrograde intravenous regional anaesthesia. MLD of procaine, cocaine and cinchocaine on subcutaneous use are, respectively, about 1/10, 1/8 and 1/4 of intravenous amounts.

It is a safe practice to ensure the drug is not deposited into the vein (as indicated by absence of blood tinge in the syringe upon pulling the plunger). Always tie the tourniquet properly and secure in place, and release slowly afterwards to ensure the drug does not enter the circulation abruptly.

4. Ambient Temperature:

Avoid infiltration of local aneasthetics into the tissues under high ambient temperatures; excessive absorption follows due to cutaneous vasodilatation. This is particularly true with thin skinned and very young animals e.g. puppies.

Control Measures:

Adherence to proper dosage and to proper anaesthetic technique along with consideration to the factors affecting toxicity would minimize chances of toxicity. Diazepam or short-acting barbiturates are useful to prevent or control convulsions. Barbiturates should not be used if respiration is depressed.

Barbiturates are known to raise MLD of local anaesthetics by 3-4 and diazepam raises convulsive dose by more than 2 fold. Atropine is useful in depressed cardiac activity. Ephedrine can be used to prevent anticipated hypotension or to restore blood pressure if hypotension has occurred.

Oxygen therapy in indicated in case of severe respiratory depression. Simultaneous use of phenothiazine’s is contraindicated. They potentiate hypotensive effects of local anaesthetics as well as their membrane stabilizing effects on excitable membranes.

Clinical Applications:

Clinical applications of local anaesthetics are primarily dependent on three factors:

(i) Availability in market,

(ii) Suitability for intended purpose i.e. topical or injectable, and

(iii) Duration of action required for an operative purpose.

At present only four local anaesthetics are available in Indian market viz., procaine, lidocaine, bupivacaine and benoxinate.

Procaine is widely employed in veterinary practice for all injectable uses. Lidocaine is a multi-purposes local anaesthetic for all types of uses. Bupivacaine is mainly used in medical practice but has a considerable potential for use in veterinary practice. Benoxinate is mainly used for ophthalmic (topical) anaesthesia for brief procedures.

Accordingly, these are the drugs of choice for clinical applications in veterinary or medical practices in India. Procaine, lidocaine, bupivacaine and tetracaine are also most widely used worldwide (Catterall & Mackie, 1996).

1. Topical Anaesthesia:

Scope:

Topical anaesthesia is used for several purposes:

(i) To relieve pain associated with inflammatory conditions of skin and mucus membranes such as minor burns, ulcers, fissures or pruritic conditions,

(ii) To relieve pain and spasms associated with anticipated procedures such as tonometery, removal of sutures, catheterization, endotracheal entubation or insertion of endoscopic instruments into body cavities (lubrication as well as anaesthetic),

(iii) Removal of foreign bodies from eye, nose, ear and throat.

(iv) To flush urethra to relieve spasms and facilitate removal of calculi, and

(v) To aid teat and laryngeal surgery in large animals.

Drug Choices:

2. Infiltration and Field Block:

Scope:

It is used for removal of small superficial tumours, debridement and suturing of wounds, tail amputation, vulval suturing, teat surgery, realignment of fractures, and for diagnostic and surgical procedures of the lower limb in horses. It is sometimes used for laparotomy and caesarean section in cattle or canine for simplicity with minimal risk of recumbency.

Drug Choices:

3. Conduction/Nerve Blocks:

Scope:

Chiefly used in large and small animals such as dogs are difficult for restraint. In cattle the agents are mostly used for ophthalmic (e.g. enucleation of eye) and paravertebral blocks. In horses mainly used for limb nerve blocks. Nerve blocks have been used for dehorning and dentistry. Brachial plexus nerve block has been used in canine for forelimb orthopaedic surgery.

Drug Choices:

4. Epidural Anaesthesia:

The technique is safer than spinal anaesthesia:

(i) Traumatic injury to spinal cord is avoided as duramater is not punctured, and

(ii) Drug diffusion to intercostal nerve sites is slower, and to medullary centres avoided as the space terminates at foramen magnum, thus respiratory failure is avoided.

Epidural anaesthesia includes three main types of blocks depending upon area or extent of anaesthetization required; anterior, posterior and lumbar blockade. All three types are used in cattle. Caudal block is preferred in horses as recovery is quicker.

In donkeys both anterior and posterior blocks have been used. Lumbosacral blockade is preferred in small ruminants, cats and dogs. Sheep has been recommended as an experimental model for screening epidural anaesthetics for use in humans.

Posterior blocks are indicated for obstetrical manipulations and for surgical operations of the tail, perineum, vulva, vagina, rectum and bladder. Anterior block is indicated for surgery of the hind-quarters, udder, uterus, penis, scrotum, abdomen and amputation of digit, udder of caesarean section. Lumbar epidural block has been used in cattle for caesarean section and rumenotomy. Techniques for various types of blockade and sites of administration have been briefly described.

Drug Choices:

5. Spinal Anaesthesia:

The technique is favoured in medical practice but not in veterinary practice:

(i) The vertebrae in domestic animals are more compressed so less flexible than human vertebrae, &

(ii) Domestic animals can not be made co-operative to enable safe introduction into spinal fluid without involving risk of damaging spinal cord. It is, however, used in sheep that is used as an experimental model for screening spinal anaesthetics for humans.

Lidocaine, 5 ml 2%, provides duration of analgesia for over an hour in sheep, Bupivacaine can be used 0.25%, 0.5% or 15 solution ( 2 ml/adult sheep) to provide analgesia, respectively, for 2.5, 4.4. and 5.9 hours.

In humans, lidocaine (100 mg), bupivacaine (20 mg) or tetracaine (12 mg) are used depending upon duration of anaesthesia required. Procaine is used for very short duration operations.

6. Retrograde Regional Anaesthesia:

The technique is applicable only on extremities where tourniquet can be applied to restrict drug (given intravenously) within the confines of the limb circulation. It is used in humans as well as in large ruminants.

It is contraindicated in equines owing to their high sensitivity to intravenously given local anaesthetics. Lidocaine is drug of first choice; 10-20 ml 2% (1 mg/kg body wt.) provides anaesthesia for up to 75 minutes in cattle. Procaine has been used as 12-15 ml (8 or 12%) on forelimb operations in ruminants.