Local Anesthetics Drugs

Local Anesthetics


• Local Anesthetics

• Classification of local anesthetics

• Mechanism of Action

• Structure Activity Relationships of Local Anesthetics

• Various Local anesthetics drug profile

Local Anesthetics

• Local anesthetics (LAs) are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body

• They block generation and conduction of nerve impulse at

• All parts of the neuron where they come in contact, without causing any structural damage

Comparative features of general and local anesthesia

Classification of Local anesthetics

• Benzoic Acid derivatives; Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine, Piperocaine

• Amino Benzoic acid derivatives: Benzocaine, Butamben, Procaine, Butacaine, Propoxycaine, Tetracaine, Benoxinate

Lidocaine/Anilide derivatives: Lignocaine, Mepivacaine, Prilocaine, Etidocaine.

• Miscellaneous: Phenacaine, Diperodon, Dibucaine

• Injectable anaesthetic

• Low potency, short duration

• Procaine

• Chloroprocaine

• Intermediate potency and duration

• Lidocaine (Lignocaine)

• Prilocaine

• High potency, long duration

• Tetracaine (Amethocaine)

• Bupivacaine

• Ropivacaine

• Dibucaine (Cinchocaine)

• Surface anaesthetic

• Soluble Insoluble

• Cocaine Benzocaine

• Lidocaine Butylaminobenzoate

• Tetracaine Oxethazaine

• Benoxinate

Mechanism of Action of Local anesthetics

• LAs block nerve conduction by decreasing the entry of Na+ ions during upstroke of action potential (AP).

• As the concentration of the LA is increased, the rate of rise of AP and maximum depolarization decreases causing slowing of conduction Finally, local depolarization fails to reach the threshold potential and conduction block ensues

• The LAs interact with a receptor situated within the voltage sensitive Na+ channel and raise the threshold of channel opening

• Na+ permeability fails to increase in response to an impulse or stimulus

• Impulse conduction is interrupted when the Na+ channels over a critical length of the fiber are blocked

A model of the axonal Na+channel depicting the site and mechanism of action of local anaesthetics.

• The Na+ channel has an activation gate (‘m’ gate) near its extracellular mouth and an inactivation gate (‘h’ gate) at the intracellular mouth.

• In the resting state the activation gate is closed

• Threshold depolarization of the membrane opens the activation gate allowing Na+ ions to flow in along the concentration gradient within a few msec, the inactivation gate closes and ion flow ceases

• The channel recovers to the resting state in a time-dependent Manner

• The local anaesthetic (LA) receptor is located within the channel in its intracellular half.

• The LA traverses the membrane in its unionized lipophilic from (B), reionizes in the axoplasm and approaches the LA receptor through the intracellular mouth of the channel

• It is the cationic form (BH+) of the LA which primarily binds to the Receptor

• The receptor has higher affinity or is more accessible to the LA in the activated state compared to the resting state.

• Binding of LA to its receptor stabilizes the channel in the inactive state and thus reduces the probability of channel opening

Structure Activity Relationships of Local Anesthetic

• The structure of most local anesthetic agents consists of three parts

(a) A lipophilic ring that may be substituted

(b) A linker of various lengths that usually contains either an ester or an amide

(c) An amine group that is usually a tertiary amine

The Aromatic Ring

• The aromatic ring adds lipophilicity to the anesthetic and helps the molecule penetrate through biological membranes

• Substituents on the aromatic ring may increase the lipophilic nature of the aromatic ring

• An SAR study of para substituted ester type local anesthetics showed that lipophilic substituents and electron-donating

• Substituents in the para position increased anesthetic activity

• The lipophilic substituents are thought to both increase the ability of the molecule to penetrate the nerve membrane and increase their affinity at the receptor site

• Electron-donating groups on the aromatic ring created a resonance effect between the carbonyl group and the ring, resulting in the shift of electrons from the ring to the carbonyl oxygen

• As the electronic cloud around the oxygen increased, so did the affinity of the molecule with the receptor

• When the aromatic ring was substituted with an electron withdrawing group, the electron cloud around the carbonyl oxygen decreased and the anesthetic activity decreased

The Linker

• The linker is usually an ester or an amide group along with a hydrophobic chain of various lengths

• When the number of carbon atoms in the linker is increased, the lipid solubility, protein binding, duration of action, and toxicity increases

• Esters and amides are bioisosteres having similar sizes, shapes, and electronic structures

• The similarity in their structures means that esters and amides have similar binding properties and usually differ only in their stability in vivo and in vitro

• For molecules that only differ at the linker functional groups, amides are more stable than esters and thus have longer half-lives than esters

• Plasma protein binding may be more prevalent for the amide anesthetics as well, contributing to the increased half-life

• The nature of the substituents on the aromatic ring can affect the electronic nature of the linker and can contribute to the drug’s potency and stability

• Substituents on the aromatic ring may also confer a steric block to protect the linker from metabolism.

• The binding affinity and stability of the anesthetic molecule is affected by the linker as well as the functional groups on the aromatic ring

• Ester groups are more susceptible to hydrolysis than amide functional groups because of the prevalence of esterases in the blood and the liver

• The para-aminobenzoic acid (PABA) metabolite, common to the ester class of drugs, is believed to be responsible for the allergic reactions some patients have experience with local anesthetics

The Nitrogen

• Most local anesthetics contain a tertiary nitrogen

• Quaternary anesthetics applied to the external side of the nerve membrane do not penetrate and cannot access the local anesthetic binding site

Local Actions

• The clinically used LAs have no/minimal local irritant action and block sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic synapse and receptors (non-selectively)

• Structures which function through increased Na+ permeability

• They also reduce release of acetylcholine from motor nerve endings Injected around a mixed nerve they cause anesthesia of skin and paralysis of the voluntary muscle supplied by that nerve


methyl (1R,2R,3S,5S)-3- (benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate

• A stimulant drug obtained from the leaves of two Coca species native to South America, Erythroxylum coca and Erythroxylum novogranatense

• Cocaine is the only local anesthetic with vasoconstrictive properties. This is a result of its blockade of norepinephrine reuptake in the autonomic nervous system.

• It is applied to certain areas of the body (for example, the nose, mouth, or throat) to cause loss of feeling or numbness.


• Hexylcaine is a local ester-class anesthetic.

• Hexylcaine hydrochloride, also called cyclaine (Merck) or osmocaine, is a short-acting local anesthetic.

• It acts by inhibiting sodium channel conduction.


• Meprylcaine (also known as Epirocaine and Oracaine) is a local anesthetic with stimulant properties that is structurally related to dimethocaine.

• Meprylcaine has a relatively potent inhibitory action on the monoamine transporter and inhibits the reuptake of dopamine, norepinephrine and serotonin.


• Cyclomethycaine is a local anesthetic.

• Used for pain on damaged skin,mucous membrane of rectum and urinary bladder


• Piperocaine is a local anesthetic drug developed in the 1920s

• Used as its hydrochloride salt for infiltration and nerve blocks.

• In eye lotion


• It is not water soluble but is ideal for topical applications.

• The onset of action is within 30 seconds and the duration of drug action is 10 to 15 minutes

• Benzocaine is used for endoscopy, bronchoscopy, and topical Anesthesia

• Benzocaine is available as a 20% solution topical spray, in a 1% gel for mucous membrane application

• 14% glycerin suspension for topical use in the outer ear

• Toxicity to benzocaine can occur when the topical dose exceeds 200 to 300 mg resulting in methemoglobinemia

• can be directly applied to wounds and ulcerated surfaces and remain in contact with the affected skin or mucous membrane


• It is more efficacious than benzoate

• Butamben is anesthesia of mucus membranes other than the eyes.

• Butamben is a lipophilic local anesthetic of the ester class,

• Produces a differential nerve block of long duration,

• Used to provide prolonged analgesia for patients with terminal malignancy.


• Local anaesthetics which are derivatives of p-aminobenzoic acid

• Veterinary use


• Used in 1950s

• Combined with procaine to accelerate its onset of action and provide longer lasting anaesthetic effect


• Topical use

• To reduce pain or discomfort caused by mild skin irritations such as sunburn or minor rashes


• Enoxinate or BNX, is an ester-type local anesthetic,

• Which is used especially in ophthalmology and otolaryngology.

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