Pharmacology of local anesthetics Dr S. Parthasarathy MD DA DNB PhD FICA , Dip software based statistics

History Local anesthesia was accomplished by having the operator chew coca leaves and apply the mascerated pulp to the skin and wound edges while using a tumi knife to bore through the bone.

Cocaine – brachial plexus Animal epidural Freud , koller Reviews on cocaine

Other drugs ?? Pethidine ?? Phenergan ?? LA properties !!

Basic structure Three parts Lipophilic aromatic ring Hydrophilic amine Intermediate chain Ester or amide chain

Esters – amides Cocaine Procaine Chlroprocaine Tetracaine Lignocaine Mepivacaine Prilocaine Etidocaine Bupivacaine Ropivacaine

Esters Metabolism by pseudocholinesterase Short action usually PABA – possible allergic reactions Cocaine is hydrolyzed in the liver

Amide with ester bond – hydrolysis for inactivation Articaine Amide with ester bond – hydrolysis for inactivation

Aromatic ring – lipophilic Lipophilic means membrane liking – potency of the molecule Hydrophobic or lipophilic More – more potent

What does it mean ?? Procaine – 4 % solution Lignocaine - 2 % solution Bupivacaine – 0.5 % solution Aromatic ring – substitution – lipophilicity Molecular weight !!

Pharmacokinetics Onset

NH4+ B BH +

Local anesthetics are weak bases Means they are hydrogen acceptors NH3 ( tertiary amine ) will become NH4 + Unionized ---- Vs ----- ionized Unionized is lipophilic hence it has to be made as hydrochloride salts to make it as solution

Base = unionized = lipophilic part = membrane liking This part has to be more if the drug has to have a fast onset

Henderson hasselbach equation pKa – pH = log [BH+] / [B] pKa = pH + log [BH+] / [B] Both are equal --- pH = pKa If pKa is low , the lipid soluble portion is more

Onset =other factors Site Lipophilicity Strength of a solution Very potent

Explanation – physiological pH But if the pH is itself is low Acidic tissue Base is further less – no action in pus and inflamed tissue

If we add sodium bicarbonate Lipid soluble form will be more in the syringe If we add more NaHCO3 – precipitation Not water soluble !!

Carbonation Local anesthetics are made as HCl salts at a pH of 3-6 We don’t want that Make it as carbonate salt – higher pH Carbondioxide later = acidic inside = action inside

Duration

Protein binding bupi tetrac Lig

But high protein binding is one of the projected reasons for increased toxic effect of bupivacaine

Vasodilation when used without vasopressors, lidocaine shortens its own duration by dilating local vasculature, whereas mepivacaine and bupivacaine do not. Lignocaine vasodilates and shortens

The duration of action of the drug is also related to its structure, length of the intermediate chain joining the aromatic and amine groups.

Onset – pKa , but lipophilic and concentration also Potency – lipophilicity Duration =- protein binding and vascular actions

Order of ease of blockade Preganglionic – Pain – Temperature – Touch – Proprioception (pressure) – Motor. Why ?? Size and myelination !!

Autonomic Sensory Motor But dentist -

Chiral drugs – asymmetric carbon atom Mepivacaine, bupivacaine, ropivacaine, and levobupivacaine have been developed as a pure S enantiomers. less neurotoxicity and cardiotoxicity than racemic mixtures or the R enantiomers of local anesthetics, perhaps reflecting decreased potency at sodium ion channels

An asymmetric carbon atom (chiral carbon) is a carbon atom that is attached to four different types of atoms or groups of atoms.

Sodium channel

Minimum concentration for blocking nerve fiber conduction is called Cm Nodes of ranvier 3 nodes – 6 mm of fiber to be blocked

sensory anesthesia sufficient for skin incision usually cannot be obtained without motor impairment, But if we have an LA , blocks pain but not others . --- great Bupi and ropi – more sensory but etidocaine – more motor – differential blockade

States of sodium channel Local anesthetics bind to sodium channels in open position from inside , block sodium entry , prevent depolarization – conductance Inactivated state Later resting state Use dependent block !!

Other actions Vasculature Anti arrhythmic action CNS action e,g. blunting intubation response Neuropathic pain

Distribution Lung extraction Skeletal muscle – maximum concentration Metabolized and excreted in the urine A unique systemic side effect associated with a specific local anesthetic is the development of methemoglobinemia after the administration of large doses of prilocaine

Amide local anesthetics N-dealkylation of the tertiary amine (e.g. lignocaine) produces a more water soluble secondary amine and renders it more susceptible to amide hydrolysis.

Local anesthetics may be combined in an effort to produce a rapid onset (chloroprocaine) and prolonged duration (bupivacaine) of action. The toxicity of combinations of local anesthetic drugs is additive rather than synergistic.

Emla (a eutectic mixture of 2.5 % lidocaine and 2.5 % prilocaine) is a topical local anesthetic that penetrates intact skin and reaches an anesthetic depth of up to 5 mm. The onset of effect is approximately 1 h. When the effect takes place, the vessels in the skin show vasoconstriction initially, followed by vasodilation when higher concentrations are reached IV access in children

Summary Local – history – cocaine Three portions Esters and amides Onset , duration and potency Metabolism and excretion Nerve fibre size, myelination and sensitivity Sodium channel