Local Anesthetics

What are local anesthesia?

Local anesthesia: produce loss of sensation to pain in a specific area of the body without the loss of consciousness

Local anaesthetic agents can be defined as drugs, which are used clinically to produce reversible loss of sensation in circumscribed area of the body. Local anesthetics block pain sensation by blocking nerve conduction

 Structure activity relationships Local anesthetics (LAs) consist of a lipophilic and a hydrophilic portion separated by a connecting hydrocarbon chain :An ester (-CO-) or an amide (-NHC-) bond links the hydrocarbon chain to the lipophilic aromatic ring.
The hydrophilic group is usually a tertiary amine, whereas the lipophilic portion is usually an aromatic ring

The caine ending on each of these drug names tells you that they are local anesthetics.
Esters: procaine, cocaine, chloroprocaine, and tetracaine. Amides: lidocaine, bupivacaine

Structure activity relationships

Ester:

Procaine

Amide: Lidocaine

If the local anesthetic has two is in its name; its an amide

Lidocaine Prilocaine Bupivacaine Mepivacaine

Metabolism and excretion

Ester and amide anaesthetics differ in their metabolism. Esters are hydrolyzed in plasma by pseudo-cholinesterase. One of the by-products of metabolism is paraaminobenzoic acid(PABA), the common cause of allergic reactions seen with these agents They consequently have a short half life. Ester metabolites are excreted by the kidney.

Amides are metabolized by the liver amidases (N-dealkylation). This is a slower process, hence their half-life is longer .

Site of metabolism

Esters

Plasma

Amides

Mechanism of action
Local anesthetics reversibly bind to the voltage-gated Na+ channel, block Na+ influx, and thus block action potential and nerve conduction.

The local anesthetic prevents action potential generation & conduction by physically blocking sodium channels via two alternative mechanisms:
The uncharged species reaches the blocking site within the channel via the membrane (hydrophobic pathway), while the charged species reaches the site via the open channel gate (hydrophilic pathway).

The blockade prevents voltage-dependent Na+ conductance, which results in local nerve block.

Susceptibility to block by local anesthetics

types of nerve fibers
In general, small nerve fibers are more susceptible than large fibers; however,
the type of fiber degree of myelination fiber length and frequency- dependence are also important in determining susceptibility

Differential sensitivity of nerve fibers to local anesthetics: LAs block conduction in the following order: Small myelinated axons,small nonmyelinated axons,large myelinated axons (mediating postural,touch)

So the sensitivity to LA block decreases with increasing fiber size. High sensitivity for pain sensation mediated by small fibers & low sensitivity for motor function mediated by large fibers.

Relative size and susceptibility of different types of nerve fibers to LAs.

Fiber Type

Function

Diameter

Myelination

Conduction Velocity (m/s)

Sensitivity to Block

Type A Alpha Beta Gamma Delta Type B Type C Dorsal root Pain 0.4-1.2 0.3-1.3 None None 0.5-2.3 0.7-2.3 ++++ ++++ Proprioception, motor Touch, pressure Muscle spindles Pain, temperature 12-20 5-12 3-6 2-5 <3 Heavy Heavy Heavy Heavy Light 70-120 30-70 15-30 12-30 3-15 + ++ ++ +++ ++++

Preganglionic autonomic

Sympathetic Postganglionic

Order of sensory function block

1. pain 2. touch 3.temperature 4. deep pressure 5. motor

Recovery in reverse order

Frequency & voltage dependence of LA

Nerves with higher firing frequency and more positive membrane potential are more sensitive to local anesthetic block. This is because anesthetic molecules gain access to the channel more readily when the channel is opened.

Local Anesthetics
Activity of local anesthetics is a function of their lipid solubility, diffusibility, affinity for protein binding, percent ionization at physiologic pH.

Effect of lipophilicity
ANESTHETIC POTENCY Lipid solubility appears to be the primary determinant of intrinsic anesthetic potency. Chemical compounds which are highly lipophilic tend to penetrate the nerve membrane more easily, such that less molecules are required for conduction blockade resulting in enhanced potency. more lipophilic agents are more potent as local anesthetics

Diffusibility (how well the LA diffuses through tissue to its site of action) will also influences the speed of action onset.

pH influence LAs are weak bases Usually pKa at range 7.6 8.9 Decrease in pH shifts equilibrium toward the ionized form, delaying the onset action. Lower pH, solution more acidic, gives slower onset of action

The nonionized form can cross the nerve membranes and block the sodium channels.
So, the more nonionized presented, the faster the onset action.

Low pH
The pH of the tissue becomes relevant in conditions of infection or inflammation, in which the natural pH may be more acidic. This acidity results in a greater proportion of the ionized (charged) form of the anesthetic, thereby delaying or preventing the onset of action.

Prolongation of by vasoconstrictors
Local anesthetics are removed from depot site mainly by absorption into blood. Addition of vasoconstrictor drugs such as epinephrine reduces absorption of local anesthetics, thus prolonging anesthetic effect and reducing systemic toxicity. Epinephrine is included in many local anesthetic preparations.

Local anesthetics - vasoconstrictors

Ratios

Epinephrine is added to local anesthetics in extremely dilute concentrations, best expressed as a ratio of grams of drug:total ccs of solution. Expressed numerically, a 1:1000 preparation of epinephrine would be
1 gram epi 1000 ccs solution

1000 mg epi
= = 1000ccs solution

1 mg epi 1 cc

Local anesthetics - vasoconstrictors

Therefore, a 1 : 200,000 solution of epinephrine would be
1 gram epi 1000 mg epi

200,000 ccs solution

=
or

200,000 ccs solution

5 mcg epi
1 cc solution

contraindication for Adrenaline containing local anaesthetic agents:

Absolute contraindication (should never be used) for: 1.Vasoconstrictors should not be used in the following locations: Fingers, Toes, Nose, Ear lobes, Penis or other areas with a terminal vascular supply as the intense vasoconstriction may lead to severe ischemia and necrosis.
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2.Patient with severe hypertension , heart disease. (Cardiac dysrhythmias, angina pectoris)

Felypressin is preferred in patients with heart disease & hypertension.

Summary
Clinical Pharmacology The potency of Local Anesthetics, their onset and duration of action are primary determined by physicochemical properties of various agents Lipid solubility is the primary determinant of anesthetic potency pKa of Local anesthetics determines the onset of action The addition of vasoconstrictors, such as epinephrine or phenylephrine can prolong duration of action of local anesthetics, decrease their absorption (and the peak plasma level) and enhance the blockade.

Toxicity and side effects

1.Central nervous system Stimulatory effects: restlessness, tremor, convulsion. this may be followed by depression & death due to respiratory depression. 2. Cardiovascular system: Decreases the electrical excitability, conduction rate and force of contraction in myocardium. Causes dilation of blood vessels. 3. Allergic reactions

Ester Linked Local Anesthetics Procaine Tetracaine Cocaine

Cocaine Vasoconstrictive properties Toxicity & its potential for abuse have steadily decreased its clinical use. Procaine Low potency Slow onset

Amide-Linked Local Anesthetic

Lidocaine:xylocaine: lignocaine Produces faster& longer lasting anesthesia than does an equal concentration of procaine. It is alternative choice for individuals sensitive to ester-type LAs. It is also used as antiarrhythmic agent.

What does 1% Lidocaine mean?

The dilute preparations are presented as percentage (%)solutions of LA. A solution expressed as 1% contains 1g substance in each 100mls 1 g in 100 ml = 1000mg in 100 ml 10 mg in 1 ml The number of mg/ml can easily be calculated by multiplying the percentage strength by 10. Therefore a 0.25% solution of lidocaine contains 2.5mg/ml of solution (10 * 0.25=2.5 mg /ml)
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Benzocaine Has very low solubility that is used as a dry powder.it produces long lasting surface anesthesia.

Methods of LAs administration

1: Topical Anaesthesia LA may be applied to the skin, the eye, the ear, the nose and the mouth as well as other mucous membranes. most useful and effective: Lidocaine (i.e.gel 2%)

2: Infiltration Anaesthesia: provide anesthesia for minor surgical procedures. commonly used Amide LA are (Lidocaine, prilocaine. Local infiltration is used primarily for surgical procedures involving a small area of tissue (for example, suturing a cut). The LA is directly injected into tissues to reach nerve branches & terminals.

3:Spinal Anaesthesia: injection directly into the cerebrospinal fluid (subarachnoid space)
produces spinal anaesthesia. 4:Nerve block anesthesia :LA is injected close to nerve trunks to produce loss of sensation peripherally. Less LA needed than for infiltration anaesthesia.

 Factors affecting the selection of anesthetic technique:

1. Area to be anesthetized Depending on the type of bone( bone density) Maxilla and anterior mandibular region. (thin cortical layer) Infiltration anesthesia reach the nerve filament inside cancellous bone Posterior mandible( thick & dense cortical bone) Nerve block anesthesia

2. Duration of anesthesia Nerve block anesthesia produces a more profound &longer duration of action than inflitration anesthesia. 3.Age of the patient Older individuals have dense bone, it is more difficult for infiltration anesthesia to penetrate the bone.

Local Anesthesia
1. Local infiltration
-

type of injection that anesthetizes a small area (one or two teeth and asscociated areas) anesthesia deposited at nerve terminals

2. Nerve block
-

type of injection that anesthetizes a larger area anesthesia deposited near larger nerve trunks