Pharmacology of local anesthetics

Pharmacology of local anesthetics

The objectives

1. Define a local anesthetic (LA) 
2. Know the molecules of each class of local anesthetic  
3. Know the pharmacodynamic properties of local anesthetics
4. Know the vasoconstrictor agents   

Plan

• Introduction 
• Physicochemical properties
• Mechanism of action
• Pharmacodynamic properties
• Pharmacokinetic properties
• Practical use 
• Vasoconstructors 
• Conclusion

I. Introduction

Definition

• Local anesthetics are defined as a drug substance that selectively and reversibly blocks nerve conduction (sensitive, sensory, sympathetic, parasympathetic and motor) without nerve damage or loss of consciousness.
• At the molecular level these drugs act by slowing the rate of depolarization of nerve fibers and the entry of sodium

Historical 

•  The first local anesthetic was cocaine used by Koller in 1884.  
•  Cocaine, which is an ester of benzoic acid, is no longer used  

As a local anesthetic.

• These substances, discovered more than a century ago, are divided into two distinct chemical families:  

• aminoesters (tetracaine, procaine, etc.)  

• and aminoamides (lidocaine, bupivacaine, etc.).

Physicochemical properties  

ALs are composed of 3 elements: 

• A lipophilic pole : aromatic structure responsible for the anesthetic properties (fixation, diffusion, activity)  

• An intermediate chain : conditions the metabolism (duration of action, toxicity) 

• A hydrophilic pole : amine derivative conditioning hydrosolibility and protein fixation

Chemical structure of AL

Pharmacology of local anesthetics

Classification :  

Reminder on the action potential

The permeability of membranes to ions changes depending on the transmembrane potential. 

     – At rest, potassium permeability is increased

          – When the nerve impulse arrives, depolarization increases sodium permeability. The membrane potential goes from –70 to +35 mV.  

        – This phenomenon spreads along the nerve

        – Repolarization results from a decrease in the permeability of sodium channels and an excretion of sodium from the intracellular environment to the extracellular environment. 

Mechanism of action of ALs 

• In situ, ALs exist in ionized form ALH+ and non-ionized form AL.  
•  The non-ionized form AL (free form, not bound to proteins) diffuses and crosses the cell membrane, but it is the ionized form ALH+ which binds to the sodium channel on the intracellular side and blocks it. 
• The affinity of ALH+ is higher for the inactivated and open state of the channel, i.e. the depolarized state.  
•  The block is therefore favored by a high frequency of nerve stimulation.

Pharmacology of local anesthetics

                                                                                                                             – AL enters the nerve in non-ionized form                                                                                                                                                                                                                                                      

                                                                                                                            – binds to the sodium channel, in ionized form

                                                                                                                           – Blocks PA conduction, and increases                  

                                                                                                                              Refractory period   

ALs block small unmyelinated fibers more easily than large myelinated fibers;  

• thus, the block installation timeline is as follows:  

• B fibers (sympathetic system) → C and Aδ fibers (thermoalgic sensitivity)  

           → Aβ (epicritical sensitivity) → Aα fibers (motor skills); the block regresses in the opposite direction. 

The pharmacological action of AL depends on its solubility in fluids, its binding to proteins, and its pka 

1. liposolubility: the activity of an AL depends on its passage through nerve membranes and therefore on its liposolubility, 
2. Protein binding The higher the plasma protein binding rate, the longer the duration of action of the AL. This fixation reduces the quantity of AL available to act on the nerve but constitutes a functional reservoir gradually releasing the AL. 
3. Pka : ALs are weak bases with Pka between 7.8 and 8.9. Those whose Pka is closest to the physiological pH (≈ 7) diffuse most quickly across the nerve membrane due to their low ionization potential.

Pharmacokinetics

1. Plasma half-life 

• It is very variable but generally brief. 

• It is not related to the duration of the effect which depends on the nature of the tissue where the drug is administered but also on the simultaneous use of adrenaline

2. Metabolism  

 depending on the chemical structure  

• Esters (procaine, tetracaine) are hydrolyzed in the plasma by pseudo-cholinesterases and give rise to para-aminobenzoic acid which is undoubtedly the cause of allergic reactions to AL  

• Amides  

– They are metabolized by liver amidases.  

– Liver failure and also certain medications are accompanied by a sometimes considerable extension of half-life and a prolongation of pharmacological effects 

   3- Resorption

• ALs all tend to diffuse from their point of application.  
• The extent and speed of resorption depends on the vascularization of the tissue.  
• Thus, after local application the plasma concentrations obtained may be identical to those observed after intravenous injection.  
• This unintended diffusion explains the predictable adverse effects
•  Resorption may vary with age due to changes in vascularity or the amount of fat in the epidural space. In older children and adults , resorption of local anesthetics after subcutaneous injection is very rapid. 

  4- Distribution : 

• Blood concentration depends on the amount of product administered, the rate of 
  vascular resorption, tissue distribution, metabolism (biotransformation) and elimination of the product.

5-Factors modifying the activity of ALs

Injection site:

• Acidosis decreases diffusion and increases toxicity. 
• Addition of a vasoconstrictor prolongs the duration of action, decreases the rate of resorption and toxicity

      Metabolism: 

– Hyperthermia increases metabolism and elimination of amide agents

– Severe hepatic insufficiency, decreased hepatic flow increase the duration of action and toxicity of amides.  

– Pseudocholinesterase deficiency increases the duration of action and toxicity of esters.
– Renal failure prolongs the action of ALs 

– Heart failure, shock, beta-blockers and ventilation increase the toxicity of local amide anesthetics. 

Pharmacology of local anesthetics

Pharmacodynamics

1. On the central nervous system: 

      At low concentrations ,  

• ALs can cause dizziness, lightheadedness, and drowsiness.  
• Anticonvulsant activity is also noted by inhibition of sodium flows in epileptogenic foci.
  At medium concentrations ,  

Psychomotor agitation, chills, tremors of the extremities appear. 
          At high concentrations ,  

– ALs depress CNS activity with sedation, impaired consciousness and respiratory depression.  

    2-  On the Lung : 

No effect on thoracic mechanics 

no effect of lidocaine, mepivacaine and bupivacaine on responses to hypoxia/hypercapnia 

2. On the Heart : 

In low doses:  

– ALs behave like antiarrhythmics (class I) whose action predominates at the level of depolarized fibers and therefore arrhythmogenic foci. 

This accounts for the use of lidocaine in the treatment of ventricular arrhythmias in myocardial infarction or digitalis poisoning.  At high doses :  

– effects on conduction (prolongation of the PR interval and widening of the QRS complex), sinus bradycardia and a negative inotropic effect  

3. Peripheral vascular effects:  

• They are observed especially with amidated derivatives (example: lidocaine). 

-At low doses vasoconstriction occurs  

– At high doses, peripheral vasodilation is noted which, combined with negative inotropic properties, contributes to the drop in blood pressure in AL overdoses. 

4.  On Muscles : Decreased neuromuscular transmission at high doses 
5. On the digestive tract : Spasmolytic action on the biliary tract, nausea, vomiting of central origin.

MAIN LOCAL ANESTHETICS: Use

Pharmacology of local anesthetics

              VASOCONSRICTORS: 

1.  Definition : 

Vasoconstrictors, also called sympathomimetics, are similar to sympathetic nervous system mediators and are classified into two families: 

1. catecholamines: 

• adrenaline (epinephrine): 

Is the most used product; adrenaline compensates for the depressive action of  

local anesthetics on the heart and circulation by acting on α, β1 and β2 adrenergic receptors and the entire sympathetic system 

• Used at concentrations of 1/100000 (1mg/100ml) or 1/200000 (2mg/100ml) 

• noradrenaline (norepinephrine): has 9 times more side effects than adrenaline. 

b- Non-catecholamines: Neo-cobefrin, neo-synephrine, and felypressin.
2 – Mode of action of Vaso-constrictors : 

They act in 3 different ways: 

 -By direct action: on adrenergic receptors (case of adrenaline and 
noradrenaline) 

-by indirect action: by simulating the secretion of Noradrenaline. 

 -Either by combining the two at the same time. 

3- Indication of vasoconstrictors : 

– indicated especially for oral surgery procedures while: 

-reducing bleeding 

-and increasing the duration of the act 

-Used for all local and loco-regional anesthesia techniques but is not always essential. 

4- Pathologies contraindicating vasoconstrictors associated with AL: 

-Pheochromocytoma (tumor very rich in adrenaline 
and noradrenaline) constitutes an absolute contraindication
. -Irradiated bone: beyond [40 GY] 

-Arrhythmic patient: cardiac risk. 

5- Pathologies not contraindicating vasoconstrictors associated with AL: 

-Stabilized hyper and hypothyroid patients 

-Stabilized hypertensive subject 

-In coronary heart disease 

-in asthmatics except those dependent on corticosteroids due to sulfites or Asthma attacks could be provoked by minimal doses of less than 1 mg; these doses can be 
reached in dental anesthesiology, in the case of multiple procedures

Conclusion

Good knowledge of pharmacology and the rules of good clinical practice make locoregional anesthesia a safe, effective technique with rare contraindications. 

Pharmacology of local anesthetics

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Pharmacology of local anesthetics