Local Anesthetics

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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-) (- 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 procaine cocaine,,

chloroprocaine, and tetracaine chloroprocaine, tetracaine..  Amides:

lidocaine lido caine,, bupivacaine bupivacaine

 

Structure activity relationships 

Ester:

Procaine

Amide: Lidocaine

 

If the local anesthetic has two “i”s in its name; it’s 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 metabolized by the liver  amidases (N-dealkylation). This is a slower process, hence their half-life is longer .

 

Site of metabolism

Esters

Amides

Plasma

 

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 

12-20

Heavy

70-120

+

Beta

motor  Touch, pressur pressure e

5-12

Heavy

30-70

++

Gamma

Muscle spindles

3-6

Heavy

15-30

++

Delta

Pain, temperature

2-5

Heavy

12-30

+++

Preganglionic autonomic

<3

Light

3-15

++++

0.4-1.2

None

0.5-2.3

++++

0.3-1.3

None

0.7-2.3

++++

Type A   Alpha

Type B 

Proprioception,

Type C  Dorsal root

Pain

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 local anesthetics anesthetics is 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 y  Diffusibilit

(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 – 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

areinto removed mainlyanesthetics by absorption blood.from depot site

 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 cc’s of solution. Expressed numerically, numerically, a 1:1000 preparation of  epinephrine would be 1 gram epi 1000 cc’s solution  solution 

=

1000 mg epi

1 mg epi

= 1000cc’s solution  solution 

1 cc

 

Local anesthetics - vasoconstrictors Therefore, a 1 : 200,000 solution solution of epinephrine epinephrine would be 1 gram epi 200,000 cc’s solution

1000 mg epi =

or  5 mcg epi 1 cc solution

200,000 cc’s solution

 

contraindication for Adrenaline containing local anaesthetic agents:  Absolute

contraindica c ontraindication tion (should (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. 32

 

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 phenylephri ne can prolong duration of action of local anesthetics,, decrease their absorption (and the peak anesthetics 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  Procaine  • Tetracaine  Tetracaine  • Cocaine  Cocaine 

 

 Cocaine

Vasoconstrictive properties Vasoconstrictive Toxicity & its potential for abuse have steadily decreased its clinical use.  Procaine

Low potency Slow onset

 

Amide-Linked Local Anesthetic 

Lidocaine:xylocaine: ne:  Lidocaine:xylocai

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)

12/3/2012  

 Benzocaine

Has very low solubility that is used as a dry powder.it produces long lasting surface anesthesia.

39

 

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 anesthetized Depending on the type of bone( bone density) Maxilla and anterior mandibular region. (thin cortical layer) Infiltration anesthesia 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

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