5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

Local Anesthetics

Local anesthetics are important clinical drugs that you will continuously administer to your pa-tients in the future. And this necessitate you to know exactly what are the agents and the tech-nique involved in anesthesia. First, we’ll speak generally about the CNS, neurotransmitters, and some terms related to them, and apply it to local anesthetics.

-Quick introduction:

Neurotransmitters:

These are chemical substances that are responsible for the chemical communication across synapses, they are released between two neurons or between the neuron and the effector site. Scientists used to think that all the conduction that happens in the central nervous sys-tem is through electrical conduction aided by the ion channels and gap junctions between the neurons. Later on, one scientist found that there is a small space between the neurons which is the synaptic cleft, where some substances are released and when we block these substances we can stop the electrical signals or nerve impulses. The first neurotransmitter that was discov-ered is acetylcholine. From that moment on, they believed that some chemical substances do exist and they cause a change in the electric conductivity of the membrane and affect the ion channels and the membrane potential.

In the ANS we talked about the different steps that we can interfere with, and enhance or stop the signal accordingly, like synthesis, storage, release, and termination of action (degradation of acetylcholine).

Reproducibility is a term related to the receptor, each neurotransmitter has a receptor, it works through it and you can see its effect.

Regional distribution and localization: it is the distribution of nerves and receptors where the neurotransmitter can induce its effect. Vagus nerve is an autonomic nerve and it innervates the heart, because we have these neurons activating this part of the muscle, we have a particular action, and in the CNS we have certain receptors and neurons that activate certain ends in the brain. That’s why the areas where we have serotonin for example, are responsible for the mood, and the areas where we have acetylcholine are responsible for the intellectual activity. So the regional distribution of the nerve, determines the action of the neurotransmitter and the action of the drug.

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5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

This concept introduced a new way for treating some neurological conditions or diseases, by which you decrease the stimulation by dissecting parts of the nerve that supplements certain regions, so you interfered surgically rather than pharmacologically.

Neurotransmitters are either excitatory or inhibitroy, and the main excitatory neurotransmitter in the brain is glutamic acid, it is almost 90% excitatory, and the inhibitory one is GABA. Other neurotransmitters like acetycholine were not sorted exactly as excitatory or inhibitory neuro-transmitters, it depends on the receptor it works on and in which tissue it’s present. The excita-tory or inhibitory properties of these are not related to their chemical structure, this division was put in regard to the receptor of the neurotransmitter. So when GABA binds to its receptor, it induces an inhibitory signal. And for acetycholine, we can’t tell exactly because it depends on its location, it is excitatory in some regions and inhibitory in others. And this division is not used so much nowadays because there are many things that come inbetween.

Dopamine, epinephrine and norepinephrine are also present centrally.

Serotonin: it is associated with depression. We’ll talk about it more in the mood disorder. Other neurotransmitters; adenosine, nitric oxide and acetylcholine.

Nitric oxide: when it is released, it activates endothelial cells and causes vasodilation and be-cause it is secreted from neuronal cells we call it a neurotransmitter.

Neurohormones: hormones that are secreted in the brain, from the hypothalamus, and these control the pituitary gland.

Neuromodulators: are substances that do not directly activate ion-channel receptors but that, acting together with neurotransmitters, enhance the excitatory or inhibitory responses of the receptors, and by themselves they are not able to affect the ion conductance, they do not alter the membrane potential of the nerve or the muscle cells, they just modify or assess the neuro-transmitter in conduction. Examples: CO2, NH4 steroids, adenosine (although sometimes is sorted as a neurotransmitter rather than neuromodulator, but it’s in between and we put it more as a neuromodulator), and prostaglandins.

They come from outside the cell and affect its receptors.

Neuromediaters: such as cGMP cAMP. They come from inside the cell. These are proteins that without them we don’t have the action potential produced. These are signaling cascade pro-teins.

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5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

The brain is a special tissue and it has a special guard for it that allows small lipophilic com-pounds to enter the CNS (blood-brain barrier), other needed molecules like glucose are trans-ported into the brain tissue through special transporters.

-Local anesthetics:

Definition:

They are drugs that produce a reversible blocking of nerve impulses. Anesthetics work in a re-versible manner, and as we increase the concentration of the drug we inhibit more and more of nerve conduction, and this in part, could be related to the nerve itself, which as you all know have several classifications; myelinated and nonmyelinated. And we have types A, B, and C.

Local anesthetics have the ability to produce varying degrees of inhibition for sensory and mo-tor activity. For example, at first we’re going to lose the autonomic, then sensory, and then the motor. In relation to sensory, first we lose the pain, then we lose the sensation of the tempera-ture (First cold and then warm), later on we lose touch, pressure and finally the motor. This is referred to as “Differential blocking of the sensation”, so again it is the gradual and sequential block of the different types of nerves. This is achieved as you increase the concentration of the local anesthesia, you will see more and more of blocking sensation.

History:

Cocain; the abusive drug, was one of the first local anesthetics in 1800, they used it as a topical anesthetic to the eyes, then they used it for nerve blocking, but nowadays it is not used that much, because it has an abuse potential (abuse potential refers to a drug that is used in non-medical situations repeatedly for the positive psychoactive effects it produces. They induce se-dation, hallucinations, and mood changes). It is a natural product, and remember that cocain blocks norepinephrin reuptake, the result of that is constriction because we have more norepi-nephrine staying at the nerve terminals.

Procain is the first synthetic local anesthetic. Later on they discovered more and more drugs, we have lidocane, tetracaine….etc. These are also the prodrugs of the local anesthetics.

Types of local anesthetics and routes of administration:

1. Injection: local anesthetics given as a shot, by the needle. Injection agents: we have pro-caine, tetracaine, and lidocaine. Lidocaine is the most common and you need to remember its side effects; it decreases heart rate and contractility. And it also causes vasodilation in the

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5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

blood vessels. Centrally; too much of it causes depression of the CNS, they can decrease acetyl-choline release. and it also causes hypersensitivity reaction, it is mainly associated with ester local anesthetics but also can happened because of the preservatives(additives to local anes-thetics).

So to avoid these side effects with a patient allergic to lidocaine, we use alternatives to lido-caine, such as: atracaine, and luvicaine. They work through the same mechanism.

We have different kinds of injectional anesthesia, we have nerve block, infiltration, and we have special types of block; epidural block, spinal block, lumbar, caudal, systematic, and intra-venous extremity block

What you’ll use more is infiltration and nerve block.

Infiltration: it is mainly used for anterior teeth because the material reaches them more easily. You inject the local anesthetic around the area where you want to numb. So you don’t block the central nerve, you block the nerve terminals; you keep inserting the needle all around the tooth trying to block nerve terminals as much as you can. While in nerve block, you block the nerve that supply the whole part.

For the lower mandible it is thicker, we usually do not use infiltration for the posterior teeth, we use inferior alveolar block, so you block the entry of the inferior alveolar nerve. You dig with your finger until you feel the notch, and you insert the needle 2 mm behind, as illustrated in the picture.

The whole half of the lower mandible and half of the tongue will be anesthetized. This is some-times inconvenient for the patient so we use infiltration under other circumstances.

2. Topical: this can be achieved by, lidocain, tetracaine, benzocaine. Benzocaine is a topical anesthetic used in dentistry, with a banana taste, and usually used for kids. This drug anes-thetizes or numb the area where you’re going to puncture the mucosa, so you can carry on some procedures like infiltration, without having the patient feeling uncomfortable.

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5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

Tetracaine can be used for conjunctiva, nose, and throat.

Their onset of action is about twenty seconds and they don’t stay for long. But usually we don’t puncture after twenty minutes immediately, because they take somewhat longer than twenty seconds. But as a guide, you need to keep checking on the patient, prickle his mucosa with your probe, till he doesn’t feel anything.

There are topical anesthetics that are available in the markets:

-EMLA (abbreviation of eutectic mixture of local anesthetics): Combination of two; lidocaine and Prilocaine. Used a lot for topical anesthesia, and for minor skin procedures.

-TAP: tetracaine with adrenaline and procaine, and it’s mainly used for skin.

Features of ideal Local Anesthetic:

-Rapid onset and a sufficient duration of action. A long duration of action is so bothering for the patient as he stays anesthetized for long hours. So you need it to be just long enough to do your procedure and finish it.

-Non-irritating.

-Reversible effect.

-Doesn’t have systemic toxicity.

-Stable and water soluble.

Structural and chemical aspects:

The basic chemical structure of a local anesthetic molecule consists of 3 parts: 1. Lipophilic group (an aromatic ring).2. Hydrocarbon connecting chain, either an ester (-CO-) or amide (-HNC-) linkage. And this determines the classification of the local anesthetic.3. Hydrophilic group (a tertiary amine).

Let’s examine lidocaine structure for example:

It has an aromatic ring, which is the lipophilic part. And tertiary amine, the hydrophilic part, we need it for the drug to be soluble in the anes-thetic cartridge. And finally a hydrocarbon chain.

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5-12-2013 Pharmacology- Sheet 26 Rawan Al-Majali

The link between the aromatic ring and the hydrocarbon chain is what decides the local anes-thetic type. As I said we have amides and esters (If we have an amide linkage it is an amide lo-cal anesthetic and if we have an ester linkage it’s an ester local anesthetic). Lidocaine for exam-ple is an amide local anesthetic, because we have an amide bond in its structure between the aromatic ring and the hydrocarbon chain.

You have to know examples of Ester local anesthetics: cocaine, procaine, tetracaine, and benzocaine/ and Amides: Lidocaine, Mepivacaine, Bupivacaine and Ropivacaine.

Now let’s link the chemistry and structure of local anesthetics to their activity or potency. Since we’re dealing with a molecule that contains both hydrophilic and hydrophobic regions, then ionization, pH, and pKa are of important issues for us to determine which drug to use. Before going into this, just to remind what is pKa: it is the pH at which the ionized and non-ionized forms of the local anesthetic are equal.

The pH in our body is 7.4, and in general, local anesthetics are weak bases. When any weak base dissociates in an aqueous medium, we’ll have ionized and non-ionized forms, there’s al-ways an equilibrium between them. And only the non-ionized drugs are able to cross the mem-brane and get inside the cell, by diffusion through their lipophilic part. Once it’s inside the cell, it gets ionized, and again equilibrium is re-established. The ionized form is needed for the ac-tion of the local anesthetic inside the cell, it binds to the sodium channel and blocks it, as a consequence impulses are not propagated along the nerve so we get the sedation effect which we are looking for.

Local anesthetics work from the inside so we don’t need them to block the ion channels from outside.

Local anesthetics with a pKa closer to physiologic pH have a higher concentration of non-ion-ized base resulting in a faster onset (better ratio of ionized to non-ionized drug). On the other hand, a local anesthetic with a high pKa, will have more ionized forms, so we won’t have much of it entering the cell, which slows the onset. So the lesser the pKa (approximating to 7.4) the lesser is the ionization, thus more of the local anesthetic will get inside the cell.

If the region you’re applying the local anesthetic to, is acidic (because of an inflammation), you’ll have a longer onset of action; cause in this case the difference between pH and pKa val-ues is higher. So we can conclude that acidity lowers the effectiveness of the local anesthetic.

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As we said, extracellular anesthetic exists in equilibrium between charged and uncharged forms. Charged cations do not penetrate the membrane (it is written in the slides “charged cations penetrate poorly”, but the Dr. said what she mentioned is more accurate). And then in-side the cell we have re-equilibrium, the more active charged species bind to the receptor and block the channel.

Local anesthetic can also perfuse laterally in the plasma membrane and perform a stabilizing effect to the action potential. The most pronounced action of the local anesthetic is through blocking sodium channels and as you know sodium entry is necessary for the action potential, so when we block sodium entry we don’t reach the threshold, and we don’t have the action potential produced. And this is what local anesthetics do, they don’t allow the cell to reach the threshold.

And according to the differential blocking of the local anesthetics; C fiber type is blocked before B, and B is blocked before A. So if you want to arrange them according to local anesthetic sen-sitivity; C > B > A.

In relation to myelination, we have myelinated nerves affected more by local anesthetics be-cause we have more lipids which is easier for the local anesthetic to enter. (That was what Dr. Alia said, but according to the table, it’s clear that non-myelinated fibers are blocked first, and this is what you can tell from C fibers because they’re un-myelinated. Anyway she’ll look it up)

Metabolism:

The metabolism of local anesthetics is dependent upon their classification: ester vs. amide. Es-ter local anesthetics undergo hydrolysis in the plasma by pseudo-cholinesterase enzymes, re-sulting in a metabolite called PABA (para-aminobenzoic acid), which is responsible for the aller-gic reaction that some people have after local anesthetics. And the amide ones are metabo-lized in the liver, so we should take that into consideration with people who have liver prob-lems.

Mainly the excretion of amides is through the liver, so renal excretion of local anesthetics is very minimal.

Mechanism of action:

They cause local anesthesia through two ways; acting nonspecifically to stabilize the mem-brane, or specifically by blocking sodium channels and this is the most important mechanism.

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Adrenaline is one of the additives to local anesthetics, it prolongs the duration of action signifi-cantly more than doubling. If we didn’t put adrenaline we’ll anesthetize the patient for ten minutes for example, and the addition of adrenaline can reach thirty minutes or one hour. Ad-dition of epinephrine to the local anesthetics, increases the duration of the anesthesia 5-10 minutes for pulpal anesthesia to 60-90 mintues. And for soft tissue anesthesia, it is increased from 1-2 hours to 2-4 hours, so it can be doubling or more. It is good to have epinephrine un-less you see contraindications. The usual dose or concentration of adrenaline is 1:100,000 or 1:200,000, and they have a non-epi local anesthetic.

1:100,000 adrenaline is found in EpiPen, it is used with anaphylactic shock so this is not given in dental cartridge for the patient. (EpiPen is an autoinjector, used for severe allergic reactions or anaphylaxis, and contains a single dose of epinephrine).

For treatment of cardiac patient the maximum dose is 0.04 which is equivalent to two car-tridges of the 1:100,000. So it is kind of safe to give one cartridge for these patients. You’re go-ing to achieve a very good control of the pain, but two is not very safe. If you have a hyperten-sive patient it is okay, but a patient with atrial fibrillation, ventricular fibrillation or heart fail-ure, you have to try the non epinephrine local anesthetic. So just to fix it, 1:100,000 not present in the dental practice.

Other things that are added to the local anesthetics: preservatives, and antimicrobial preserva-tives, called Methylparaben, which is very similar to PABA. This is another cause of allergic re-action, in patients who have allergy to local anesthetics.

Regarding nerve conduction blockage, local anesthetics block or bind more readily to the Na+ channel when it is open or activated, so the nerves need to be in an excitatory state for the lo-cal anesthetic to work better. So it’s better to stimulate the nerve, which is usually done while inserting the needle, then the local anesthetics will go in and block the open channel. Most of the times the patient is already in pain so he has an already stimulated nerve, and the local anesthetic will work better.

Best of luck

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