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The Pharmacology of Local Anesthetic Agents (LA):

- Local anesthetic agents can be defined as: drugs which induce reversible loss of sensation in a circumscribed area of the body.

There are 2 types of anaesthesia: 1- General anaesthesia (GA): reversible loss of consciousness induced by our hypnotic drugs. 2- Local anaesthesia (LA): reversible loss of sensation which depends on: *the type of the LA, and *the duration of action. So you should know the type of LA agent you use, the duration of action, the dose and safety, we'll talk about it.

In general, the molecule of LA agents consists of: 1. A tertiary amine attached to an 2. Aromatic ring by an 3. Intermediate chain.

Now, there are 2 classes of local anesthetic drugs defined by the nature of the intermediate chain: 1. The ester LA agents include cocaine, procaine, and chloroprocainen 2. The amide LA agents include lidocaine, prilocaine, bupivacaine, etidocaine, mepivacaine.

OK, Esters and amides have the same tertiary amines and aromatic ring, they only differ in the intermediate chain and there is a big difference between them clinically.

This picture shows the chemical structure of Lidocaine and Procaine, now Lidocaine is very common in dentistry it's a sample of Amides and Procaine is a sample of Esters. Of them have the same aromatic group the same tertiary amines, the difference is in the intermediate point, and this is the difference chemically. There is a clear difference between them clinically, and we'll talk about it. Again as we said before we have 2 classes of LA defined by the nature of intermediate chain: 1. Ester LA agents include gents Cocaine, Procaine and clorprocaine, you will not deal with esters you'll deal with amides much more. 2. Amides LA agents include Lidocaine, dentists mainly use Lidocaine, and also we have prilocaine, bupivacaine, etidocaine, mepivacaine. Dont confuse yourself with these Names (that's what the dr said). You will mostly use Lidocaine.

The duration of action for Lidocaine is about 2-3 hours also we use Bupivacaine, we use it commonly and it has duration of action 6-8 hours or sometimes more depending on concentration and site of injection. Well see now the differences between Esters and amides and why we use Amides Mainly. * Esters are relatively Unstable in solution, Amides are relatively stable.

Stable in solution means when you dilute it, there will be No change in its structure for longer time. * Esters are rapidly hydrolyzed in the body by plasma cholinesterase (and other esterases) and that will affect the duration of action and make it very short. Amides are slowly metabolized by hepatic amides which is good.

* Esters: One of the main breakdown products is Para-amino benzoate (PABA) which is associated with allergic phenomena and hypersensitivity reactions Amides: hypersensitivity reactions to amide local anesthetics are extremely rare.

In slide #5 this picture shows Sodium channels now we already know that always when there is action potential in the body it will pass from Brain through nerves now action potential will be induced and that will open the sodium channels, so sodium will influx and potassium will go outside. Thats called action potential And it will go through nerve terminals to its target which is Muscles, and Order them to contract.... Ok, this is the Normal situation Now, what about Sensation? How do you feel pain? When you put your hands on something Hot for example you will immediately move it, this happened according to action potential, when the brain recieved the sensation it will send you order to move your hand. (So we had sensation and motor orders) all of this was through sodium channels.

Ok, the principle of Local anaesthesia is blocking the sodium channels. When Sodium channels is blocked>>>> No action potential>>> no feeling of pain, (there is stimulation but without neurotransmitters)

Mode of action: Here there is an important subject we'll talk about, as we said before, after injection of tertiary amines base is liberated by the relatively alkaline pH of tissue fluids: Normally, when we inject the tissue normally it's alkaline.

In this equation: B.HCl + HCO3 <------> B + H2CO3 + ClB is the base HCo3 which is normally present in the tissue it will induce release of the base and Th H in HCl will move to HCO3 to give H2CO3. And the chloride ion cl- will be alone. Now this Base (B) is the part that Block the sodium channels,

If a patient came to your clinic and he was infected, what will you do? Will you start working directly? No, because of the acidic media when infected, the LA wont work. To void the diselimination of infection usually we give antibiotics to the patient, he will be sent home and then come back in a week

after taking the antibiotic course, the inflammation will be reduced by that we avoid diselimination of inflammation. The main point I want you to understand is : Don't give LA to an infected tissue because it won't work in an acidic media (infected tissue = acidic media) , LA only work on alkaline media, if there is no alkaline media there will be No release of the base and LA will not be effective.

Preparations of LA:
LA agents are usually acid (pH range 4.0-5.5) and contain 1. Reducing agent (e.g. sodium metabisulphite) to enhance the stability of added vasoconstrictors. 2. Preservative and a fungicide: for allergy which is very rare to have allergy to amides.

What does 1% Lidocain mean?

In General pharmacology any drug and mainly LA when you see 1% on the drug 1% means >>>> 10mg per 1ml So 2% means >>>> 20mg per 1ml The number of mg/ml can easily be calculated by multiplying the percentage strength by 10.

Why do we add vasoconstrictors to LA? Vasoconstriction of blood vessels will reduce the rate of absorption,

so the risk of toxicity will decrease especially when there is rich blood supply in specific sites, like skull; if someone had an injury in his head it will take long time to heal. WHY? Because of the rich blood supply. While in the hand for example, there is poor blood supply, it will heal faster. Bleeding differ from a site to another according to the blood supply in the area of injury. Increase blood supply--------->> will induce increase in reabsorption of LA and vice versa. Now, Adrenaline is the most common used vasoconstrictor with LA, adrenaline added to LA will enhance its potency and prolong the duration of action. Also the surgery itself will be in a bloodless field, for example, if you want to remove a nevus, you can use Lidocaine alone it will be OK, but if you added adrenaline to lidocaine it will reduce bleeding. we have to know the concentration of adrenaline, and how it is diluted, sometimes adrenaline already diluted and that's ok but the problem is when you need to dilute it in the clinic, it's very dangerous and you have to know the concentration and dilute it yourself, don't let anyone else do it. As we said LA block all sensation including sympathetic nervous system,

LA---->> block Na channels---->> relaxation---->> vasodilatation---->> increase bleeding in site of injection---->> reduce the duration of action.
So we add adrenaline (vasoconstrictor).

Usually the concentration of adrenaline we use is 1: 200000 The table in slide#10 shows the most common LA and its safety dose, this table is important you should memorize it especially Lidocaine, now why did we increase the dose of LA with adrenaline? Because it's a vasoconstrictor, it will decrease the absorption for safety to decrease toxicity. Toxicity does NOT come from LA itself even if you inject the same dose 3 times it will not do anything, the problem is in absorption, it's in the plasma level in the circulation, that is toxicity. And toxicity will not be locally it will inter the circulation and then to CNS and CVS, so that, we need to know the dose. Now, 3 mg\kg of lidocaine?? What does that mean? A child patient came to your clinic, his weight is 20 kg, you will use lidocaine 1% without adrenaline, how many ml are you allowed to use? As we said 1% means 10mg\1ml ok? Lidocaine without adrenaline means the dose is 3mg\kg (in the table slide#10). Now the child weighs 20 kg that means the dose is 20kg*3mg\kg = 60mg 10mg ----->> 1 ml 60mg------>>?? 60mg\10mg = 6ml. If in the same example we used lidocaine with adrenaline it will be. 7mg\kg * 20 kg = 140 mg

140mg\10mg = 14ml

The adrenaline that we use is 1:200000, it means 1g in 200000ml. 1g=1000mg. so 1g in 200000ml = 1000mg in 200000ml = 1mg in 200ml = 0.1mg in 20ml. In the same way, 1: 80000 will equal 0.1mg in 8ml. you need to know how to dilute the solution when it comes nondiluted, off-course you are not going to use 200000ml to put -shwayyet- lidocaine on them. Calculate it, it will be 0.1mg \20ml that's going to be easy to use (20ml), you bring a syringe with 20ml lidocaine and add 0.1mg adrenaline, it's simple :) Now adrenaline always comes in 1mg for 1ml that mean the percentage is 0.1%. Its a standard anywhere in the world you'll get adrenaline percentage of 0.1%. 10mg in 1ml ------->>> 1% 1mg in 1mk--------->>> 0.1% So the ampule comes in 1ml if I want 0.1mg in 20ml for example, I'll take the adrenaline ampule (1ml) and dilute it in 10cc of Normal Saline, then take 1ml from the solution and add 20cc lidocaine to that 1ml of adrenaline------>> 20cc lidocaine + 1ml adrenaline. Thats it: D

Contraindication for Adrenaline containing local anesthetic agents:

You should know that sometimes you can't use adrenaline with LA,

why? There is Absolute Contraindication (when adrenaline should never be used with LA) for: 1. infiltration around end-arteries: for example I want to remove a nevus, Ill do infiltration for the skin around the nevus, now in the region where I did the infiltration, with LA there will be vasoconstrictor, and the blood supply maybe impaired, no problem in this case because the blood supply in the body start in aorta and the branches of aorta end with arteries then arterioles then capillaries just like a tree, so the region of nevus will have blood supply from more than one site it may receive blood supply from another site (here it's ok Im not afraid of any problem)

The problem is in the end-arteries like for example: ring block of fingers (LA like a ring to anaesthetise the whole finger) what will happen now? Maybe there will be No blood supply to the finger because I blocked it with LA, no blood supply induce ischemia, so in these cases we should never use adrenaline (absolute contraindication), if you used it and (la sama7a Allah) you had a problem ---- 100% you'll be JAILED O_O! (la feeha laf wla dawaran) . - the other absolute contraindication: 2. Intravenous regional anaesthesia (IVRA): You'll not use it as dentists but we'll talk about it in general, sometimes when doing a surgery to the hand like the carpel tunnel surgery, instead of using General anaesthesia you put a canula in the hand and then squeezing by something like rubber, a big rubber, you squeeze the hand untill it drains all the blood inside it, after that you put a tourniquet on the hand with a pressure over 300mmHg, then No more blood supply will be there.. will that lead to ischemia??? YES,

there might be ischemia but the Limbal peripheries can stand ischemia u to 2.5 - 3 hours. so till 2 hours I can impair the blood supply for hands and legs (extremities), but centrally like kidney, brain and heart, can they stand ischemia? they NEVER do, the brain can just stand ischemia for 3 min after that death will occur, because the nerve cells will not regenerate (death is death). Now as I said in the intravenous regional anaesthesia when we squeeze the hand, the veins became empty, We inject the LA inside them. (no blood in the viens but LA only) and the patient will feel Numbness all over the hand instead of blood there is LA. in these cases adrenaline is contraindicated, why? because if any leak occurred, there will be huge amount of adrenaline within the circulation, So, we talked about absolute contraindications of adrenaline: 1. infiltration around end-arteries. 2. intravenous regional anaesthesia (IVRA).

Now the Relative contraindications, this is more important to you as dentists because it include patients with severe hypertension, and adrenaline use with these patient will cause hypertension and tachycardia, when you have patient with sever hypertension you may take BP reading if its Normal (controlled) then you can use adrenaline but if it's uncontrolled (e.g. BP= 150\100) it's better not to give him adrenaline that's the meaning of relative contraindication, you are the one who decide to give or not, according to the patient condition. another relative contraindication is General anaesthesia with halothane:

in anaesthesia we were using previously something which is called Halothane, halothane is given by inhalation, it cause sensitivity to the heart, so the heart will be more sensitive to adrenaline, that's why we don't use halothane with adrenaline (this is not important that much to you).

Clinical Uses of Local Anesthetics

1. Topical Anesthesia: like the spray we use when we feel pain, it's locally work on the mucous membrane. 2. Infiltration anaesthesia: doing infiltration on the surgical field (site) when you want to work on specific teeth you infiltrate the tissue that surround it, while working on the gingiva you do incision and infiltration on the site of incision. 3. Intravenous regional anaesthesia (IVBA). 4. Peripheral nerve blockade. 5. Extradural Anaesthesia. 6. Spinal anaesthesia 7. Tumescent anaesthesia. these are the routes of administration of LA, we'll talk about each one in details. 1. Topical anaesthesia: you can apply it 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%) and prilocaine(i.e.EMLA) , now why gel and why EMLA cream? I mean if I use the LA that's used in the clinic and I spray it regionally, it will not work, because it's ionized, it won't work except by injecting into

tissue. So. it's used externally on the mucous membrane or skin we use gels or EMLA cream that is made in a way to be absorbed locally. sometime, if you want to be a gentle dentist you can use topical LA before injecting the regional needle, to block nerves then it will not be painful because nerves will be blocked that's the idea of topical anaesthesia. 2. Infiltration anesthesia: provide anaesthesia for minor surgical procedures. commonly used Amide LA are (Lidocaine prilocaine, mepivacaine and Bupivacaine)., The site of action is at unmyelinated nerve endings and onset is almost immediately.

3. Intravenous regional anaesthesia (IVRA): I've already talked about, but you should know that it's not adrenaline which is not allowed with lidocaine, here we must not use anything with lidocaine (y3ne la adrenaline wla 3'airo). the main 2 types of amide LA as we said : 1. lidocaine which is very common. 2. bupivacaine (longer acting) you don't use it in the clinic as a dentist but you may make a mix of lidocaine and bupivacaine, lidocaine will work immediately for surgery and bupivacaine is added so the patient will rest overnight because it's duration of action 8-9 hours. Bupivacaine has very long acting duration but it's problem is if it's entered the circulation it will induce irreversible combination with sodium channel in CVS. if it induced cardiac arrest there will be irreversible resistance for CVR, so it's contraindicated to use

bupivacaine or etidocaine in IV general anaesthesia. 4. Peripheral Nerve Blockade: Regional anesthetic procedures that inhibit conduction in fibers of the peripheral nervous system. It can be divided into: Minor nerve blocks involve the blocking of single nerve entities such as the inferior alveolar nerve, mental nerve, ulnar or radial nerve. go to a specific nerve supplying the site of surgery, like when you work on the first molar for example you should know the nerve supply for that region to inject the LA there and block the sensation (reversible loss of sensation in the nerve) it differ from infiltration because we infiltrate at the site of surgery but the nerve block is not in site of surgery, you make block a nerve in a finger to work in another region and that's the Minor nerve block. Major nerve blocks involve the blocking of deeper nerves or trunks with a wide dermatomal distribution (e.g. brachial plexus blockade). Brachial plexus blockade: a patient is having a surgery in his hand and his health status cannot stand general anaesthesia we do brachial plexus block for him, brachial plexus is a group of trunks (4 trunks) everyone has its own branches of nerve supply to the whole arm and hand, so the brachial plexus is the whole nerve supply to the upper limbs. so we block the brachial plexus. The commonly used LA agents are: Lidocaine, prilocaine, mepivacaine, and bupivacaine. 5. Extradural anaesthesia: like labor needle ( ) if you heard about it, it's commonly known, it means that we inject the

needle in skin between the vertebrae in the ligmintum flavum, beneath ligamintum flavum will be the Dura mate, there are 3 layers that cover the brain and spinal cords: pia mater, dura mater and arachnoid mater. Between the first 2 layers there is CSF (Cerebrospinal fluid) which protect the brain and spinal cord ( ). If trauma or injury occurred, CSF will absorb it for protection. now while injecting the needle we don't reach the CSF we just stop between the CSF and the ligaminum flavum, in that area there is negative pressure, you'll feel resistance while injecting and pushing the Saline because of negative pressure, them a sudden loss of resistance occur, then you feel that the syringe going inside without making pressure on it that mean it reached the epidural space. Now all the nerves that supply lets say from the neck region to down. All of these nerves branch from spinal cord; we have vertebrae inside it the spinal cord which is protected by vertebrae (). That means inside the vertebrae we have all nerves that supply the whole body so they come from the spinal cord. These layers when you give lidocaine or bupivacaine in this layer we don't give high concentration because if the concentration is high it will completely block the nerves, motor and sensory nerves and we don't want the motor nerves to be blocked, we just seek the sensory nerves blockade we need the motor nerves to be active so the pregnant woman will still have the force to push during delivery. So that we give her low concentration. Lower concentration will just affect the small in diameter nerves which is sensory and sympathetic nerves, the motor nerves will not

be blocked because it has bigger diameter and need higher concentration to be blocked OK? So this is about extradural anaesthesia which is used in labor, 6. Spinal anesthesia: it differ from epidural in which: in epidural I control the concentration and blockade but in spinal anaesthesia. I inject the needle directly in the CSF which contain 2-3cc of LA and this will induce complete Blockade (sensory, motor and sympathetic from umbilicus to downward, we use it in surgeries which is below umbilicus like a surgery in prostate or leg and the patient has COPD, he can't stand general anaesthesia we use the spinal block, there will be complete block from let's say umbilicus downward. 7. Tumescent Anesthesia A technique most commonly employed by plastic surgeons during liposuction procedures.

Toxicity from Local Anesthetic Drugs

Toxicity depend on the blood level, to be toxic the LA should be huge concentrated in the blood. Focus in this Note: YOU Should NEVER does any injection of LA before Aspiration. Even if you changed the needle you have to do aspiration again to avoid intravascular injection. Now when excessive blood levels occur usually due to: 1. Accidental rapid intravenous injection. 2. Rapid absorption, such as from a very vascular site i.e. mucous membranes. Intercostals nerve blocks will give a higher blood level than subcutaneous infiltration, whereas plexus blocks are associated with the slowest rates of absorption and therefore give the lowest blood levels. 3.Absolute overdose if the dose used is excessive, like in children you gave 10cc to a child of 5kg weight, this is

excessive, but in adults it rarely occur.

Signs and Symptoms of LA Toxicity

You gave the patient the LA intravascular, how would you know? As I told you the systems that will be affected in LA are CVS and CNS, why? Because they have Sodium channels and LA may block the sodium channels. CVS manifestation ( ) you'll not see the CVS manifestations unless you gave a huge amount of LA, for example if you gave 3-4cc of LA even if you give them directly to blood this will not affect the CVS but they will affect the CNS. If ( ) toxicity occurred you'll see the CNS manifestation (Brain excitatory effects before the depressant effect). At first, when you give LA and reach for example the brain, it should induce depression, blockade of nerves and depression, there is excitatory effect, and the patient will be irritant. So, CNS signs and symptoms: Early or mild toxicity: light-headedness (it may occur because of vasovagal attack or toxicity),dizziness, tinnitus, circumoral numbness (this sign is VERY important, it is a characteristic sign of LA if the patient told you that he feel of numbness around his lips you immediately know that you gave him an overdose), also confusion and drowsiness. Patients often will not volunteer information about these symptoms unless asked. After injecting the LA doesnt deal with patient as a machine or cushion, you should keep talking to him; ask him, how do you feel? Is it painful? Dont ask him do you feel numbness or

drowsiness? () ,, ask him indirect questions so you can visualize his status, i.e. If you ask him how are you? And he answered you normally: el7mdolellah, then its ok he is conscious and there is no confusion. Sever toxicity: it's rare to occur, if you inject 10cc of LA without aspiration and you have a BAD luck that made you inject it in a vein directly, it will cause tonic chronic convulsion (), leading to progressive loss of consciousness and Coma, if coma occurred the patient will sleep, airway obstruction will occur (tongue will block the airway), patient won't be breathing, which end to arrest and die. So you should be aware. CVS signs: as we said it need a huge plasma level to occur, the size of CVS signs depend on Adrenaline presence. If LA with adrenaline: we will see the signs of adrenaline toxicity which is tachycardia and hypertension. If LA without adrenaline: we will see the signs of LA toxicity which is bradycardia and hypotension. Sever toxicity: Usually about 4 - 7 times the convulsing dose needs to be injected before CV collapse occurs. And that's impossible in your occupation to deal with this huge amount of dose. Collapse is due to the depressant effect of the LA acting directly on the myocardium (e.g. Bupivacaine), myocardium (the muscle itself) received the muscle relaxant, it will cause sodium channel block to the heart itself which cause arrest.

Essential Precautions and Treatment

If toxicity occurred, what will you do? Precautions: Don't do any procedure unless you secure intravenous access, so secure intravenous access before

injection of any dose that. Always have adequate resuscitation equipment and drugs available before starting to inject. Treatment: while you're injecting the patient he became drowsy or he feel circumoral numbness, he had signs of toxicity what will you do? The first thing is STOP injection, because if you continued you'll increase the dose, after that you have to assess the patient and call for help while treating the patient. Ensure an adequate airway, if coma occurred you should be afraid of airway obstruction>>> apnea>> Obstruction>> hypoxia during 3 min >> brain hypoxia during 6 min you'll lose the patient. At least you should be able to deal with it, to assess airway.

Treatment of circulatory failure

If, he had cardiac arrest or bradycardia or hypotension, what shall you do? First, give him IV fluid, huge amount of IV fluid to support the circulation, even RTA patient when he come the first procedure we do is giving him IV fluid to support CVS. Also patients with hypotension and bradycardia we give them IV fluid. Another thing we give is vassopressor like ephedrine or adrenaline, why? To increase the blood pressure. In hypotension and bradycardia patients, arms and legs can stand complete blood supply cutting up to 3 hours as I told you before but what I concern about is the kidney, heart and brain, those are the vital organs, they can't stand it, that's why the first thing to do is Support the CVS, give the patient IV fluid if he is in the clinic and if you have adrenaline give him 0.2 mg of adrenaline to elevate his blood pressure if he is hypertensive or nearly arrested.

Treat arrhythmias. Start chest compressions if cardiac arrest occurs. Treat Convulsions with anticonvulsant drugs (Diazepam 0.20.4mg/kg, Thiopentone 1-4 mg/kg)

Done by: Safaa' R Shloul