14.local_anesthetics.docx

7/30/2019 14.local_anesthetics.docx

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Pharmacology lecture #14

Local Anesthetics

Done by: Ammar Aldawoodyeh


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Note: the script will include the whole slides.

Local Anesthetics

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

Local anaesthetic agents can be defined as drugs which are used clinically to produce

reversible loss of pain sensation in circumscribed area of the body and the area of application.

These drugs can block pain sensation (they can produce an analgesic effect) by blocking nerve

conduction and propagation of impulse, so they inhibit both generation and propagation of

action potential.

Their main mechanism of action is blocking Na channels, and you know that the entrances of

Na initiate action potential (neuronal depolarization).

Structure activity relationships

Local anesthetics (LAs) consist of:

1- Lipophilic (lipid soluble) portion: which is aromatic ring (benzene ring), we can alsocall it hydrophobic portion.

2- Hydrophilic portion: which is tertiary amine in which we have a nitrogen atomconnected to 3 alkyl groups, also we can call it lipophopic (hates lipids).

3- Connecting hydrocarbon chain: connecting between the lipophilic and the hydrophilicportions, it's either an ester (-COO-) or an amide (-NHCO-) bond links the hydrophilic

portion to the lipophilic aromatic ring.

So local anesthetics are either amide type or ester type depending on the connecting chain.

The caine ending on each of these drug names tells you that they are local anesthetics , all of

local anesthetic end by (caine).

E.g.: Esters type local anesthetic: procaine, cocaine, chloroprocaine, and tetracaine.

Amides type: lidocaine, bupivacaine.


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Ester

Amide

If the local anesthetic has two is in its name, its an amide, E.G.: Lidocaine, Prilocaine,

Bupivacaine, and Mepivacaine.

Now the structure-activity relationship is extremely important, in which the lipophilic group

indicates it's lipid solubility, and the intermediate chain will determine its duration of action

and the site of metabolism.

Metabolism and excretion

Ester and amide anesthetics differ in their metabolism, Esters type (COO) are hydrolyzed

(metabolized) in plasma and the tissues by pseudo-cholinesterase, one of the by-products that

will form their metabolism is paraaminobenzoic acid (PABA), the common cause ofallergic

reactions seen with ester type is caused by PABA.

Ester type consequently has a short half life (and duration of action) because they are rapidly

metabolized in the plasma, Ester metabolites are excreted by the kidney.

Amides are metabolized mainly in the liver by the liver amidases by N-dealkylation. This is a

slower process, hence their half-life is longer, so amide type have longer duration of action

compared to ester type, and they have low risk to produce allergic response.

Mechanism of action

Local anesthetics reversibly bind to the voltage-gated Na+ channel, block Na+ influx, and thus

block action potential and its propagation and nerve conduction.

This is done via two alternative mechanisms:


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1- The uncharged (unionized) species reaches the blocking site within the channel via themembrane (hydrophobic pathway) because they are lipid soluble.

2- while the charged species cannot penetrate the membrane, so instead they reach the siteof action via the opened channel gate (hydrophilic pathway).

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

Susceptibility to block by local anesthetics

Different nerve fibers have different susceptibility (sensitivity) to local anesthetic, and this

depends on:

1- Size of the nerve fibers: small nerve fibers are more susceptible (rapidly inhibited)than large fibers, so it has reverse relationship.

2- The type of fiber.3- Degree of myelination: presence of myelination will increase the fiber sensitivity.4- Fiber length5- Frequency of activation is also important in determining susceptibility, high frequency

nerve activation means that Na channels are opened more than Na channels of low

frequency nerve fibers, once this channels are opened this will increase the penetration

of local anesthetic, in which the hydrophilic portions or species (the charged one) can

easily or more penetrate through the opened channels.


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So LAs (local anesthetics) blockage conduction (or nerve susceptibility to LA) have the

following order:

Small myelinated axons will be inhibited faster than small non-myelinated axons, which

will be inhibited faster than large myelinated axons, and this is very important.

So: Small myelinated axon>small non-myelinated axons>large myelinated axons (mediating

postural, touch).

High sensitivity for pain sensation mediated by small fibers & low sensitivity for motor function

mediated by large fibers (I think this means that fibers that conduct pain are smaller than

those that mediate motility, and thus the pain is lost easily by LAs, while the motor

function is more hardly lost by LAs).

The table below is Not for memorization, just to show u the type of nerve fiber, it's function,

diameter, presence or absence of myelination, and sensitivity to block by anesthetic.

They found that B and C type of fibers are highly sensitive to LAs (++++), although they are

non-myelinated, but they have small size, now the function of these fibers is conduction of pain

sensation, and this is what we concerned about in LAs, so fibers of pain are highly susceptible

to LAs compared to other types of fibers.

For example alpha (one of type A fibers) susceptibility is (+) and its function is motor

control.


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You already know that myelinated fibers conduct impulses faster than non-myelinated, because

in myelinated the impulses jump from one node of ranvier to another, while in non-myelinated

the conduction is continuous.

So the Order of sensory function blockage will be:

1. Pain (the first one that will be blocked, again because pain fibers are small)

2. Touch3. Temperature4. Deep pressure

5. Motor (the last one).

Recovery in reverse order, so the motor will be recovered first and the pain will be recovered

last, and this is that we need because the most important one that we want to block rapidly is

pain and the last one we want it to recover is also pain.

Frequency & voltage dependence of LA Nerves with higher firing frequency and more

positive membrane potential are more sensitive to local anesthetic blockage. This is

because anesthetic molecules gain access to the channel more readily when the channel is

opened.

And this will limit the penetration of LAs

And this will enhance the penetration of LAs

and this will inhibit impulse formation


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ANESTHETIC POTENCY

Activity of local anesthetics depends on their lipid solubility, diffusibility, affinity for protein

binding, percent ionization at physiologic PH, and the PH of the media.

1- 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 fewer molecules are required for conduction blockade resulting in enhanced

potency.

More lipophilic agents are more potent as local anesthetics, so they provide more inhibition of

nerve conduction

2- Diffusibility (how well the LA diffuses through tissue to its site of action) will also influence

the speed of action onset, more diffusion gives more inhibition and this will increase its speed

of action.

3- pH influence (which the dentist should be concerned about): LAs are weak bases Usually

pKa at range (7.68.9), and because they are bases then decrease in pH shifts equilibrium

toward the ionized form and this means that they carry a charge and it's incapable to penetrate

the membrane and block Na channels, delaying the onset action.

So dentist before doing and dental procedure should notice is there is any inflammation

because this will make the media more acidic, this means the pH will be low, so the LAs will

be ionized because it's a weak base, and it will carry a charge and won't be able to penetrate the

lipid membrane so it won't produce it's effect properly and won't be able to block pain sensation

properly, so the dentist should prescribe anti-microbial agents and wait for 2-4 days until the

inflammation is relived.

So lower pH, solution more acidic, gives slower onset of action


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Prolongation of by vasoconstrictors

Local anesthetics are removed from depot site mainly by absorption into blood, thus Addition

of vasoconstrictor drugs such as epinephrine reduces systemic absorption of local

anesthetics, thus prolonging anesthetic effect (duration of action) and reducing systemictoxicity or effect (more localized effect), because if LAs minimally absorbed from the site of

action it will minimally leave the site of administration and minimally go to the blood stream in

which it will be metabolized by the liver or by plasma pseudocholinesterase.

The most common type of vasoconstrictors that is used with LAs is epinephrine, so it is

included in many local anesthetic preparations.

Local anestheticsvasoconstrictors Ratios

Epinephrine is added to local anesthetics in extremely dilute concentrations, best expressed

as a ratio of grams of drug: total ccs ofsolution, expressed numerically as 1:1000 preparation

in which 1:1000 means 1 gram epinephrine per 1000 cc or ml of solution, and this equals

1000 mg per 1000 cc and by removing the zeros we get 1 mg per 1 cc.

Again: 1g : 1000ml = 1000 mg : 1000 ml = 1 mg : 1 ml

Therefore, a 1 : 200,000 solution of epinephrine means 1 gram per 200,000 cc or ml, and this

equals 1000 mg : 200,000 cc which equals 1 mg : 200 cc which equals 5 microgram : 1 cc

Again: 1000 mg : 200,000 cc = 1 mg : 200 cc = 1000 microgram : 200 cc = 5 microgram : 1cc.

(now this was all what the Dr said and the slides included about epinephrine concentration, as u

read the first concentration was 1 mg : 1 cc and the second concentration was 5 microgram : 1cc

, and I think the second concentration is the one that is used in local anesthetic, because it's the

one which is extremely diluted, while the first concentration is just a normal concentration for

normal epinephrine preparations).

Contraindication for Adrenaline containing local anaesthetic agents

Absolute contraindication (should never be used) for:

1. Vasoconstrictors (in general not only epinephrine) should not be used in the following

locations:Fingers, Toes, Nose, Ear lobes, Penis or other areas with a terminal vascular supply

(limited blood 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,

heart failure, infective endocarditis): you know that epinephrine is a type of catecholamine,

so it may stimulate other adrenergic receptors in the heart and this will induce palpitation,

tachycardia, chest pain, tremor and restlessness, these ADRs (side effects) are seen if it's used as

vasoconstrictor with LAs.

The other alternative for epinephrine is Felypressin which is preferred in patients with heart

disease & hypertension, because it's non-catecholamine vasoconstrictor, so it will induce

vasoconstriction without stimulating adrenergic receptors (epinephrine is used because has

stronger effect but Felypressin will be alternative option if the patient has CV diseases)

Felypressin is an analog for vasopressin or ADH (anti diuretic hormone) which has 2 effects:

vasoconstriction effect by binding to V1 receptor and anti-diuretic effect by binding to V2

receptor in the kidney; however Felypressin lack the anti diuretic effect.

There is a summary in slide 34 it doesn't contain any new info except that we can use

phenylephrine as a vasoconstrictor with LAs.

Toxicity and side effects

LAs have 3 main side effects:

1. On the central nervous system: they may cause CNS excitation although they block Na channel

(and u know that blocking Na channel give inhibitory effect) and that's because they inhibit theinhibitory neurons and by that we get neuronal excitation (CNS excitation) which is characterized by:

restlessness, tremor and convulsion.

At higher dose they will inhibit both the excitatory neurons and the inhibitory neurons, and this

may be followed by depression & death due to respiratory depression.

2. on the cardiovascular system: you know that the cardiac conduction depends on Na and Ca

cations, so LAs by inhibiting Na channels one of their effects is reduction in cardiac

conduction and cardiac excitation and this will reduce the rate and force of contraction inmyocardium, they also Decreases the electrical excitability and Causes dilation of blood

vessels.

so they have negative inotropic and contropic effect but in some cases this can be positive

effect, one of these cases is when Lidocaine (which is an amide type of LAs) is used in

treatment of cardiac arrhythmias (ventricular arrhythmias) -which is seen following to

myocardial infarction- by inhibiting Na channels and reducing cardiac conduction.

3.Allergic reactions: which is seen in ester type LAs because of the by product PABA, and it's

characterized by dermatitis and my procedure or become as anaphylactic reaction.


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Ester Linked Local Anesthetics

1- Cocaine: the first type of LAs that was discovered, it's natural (from plants) and it haspowerful LA effect and in the same time vasoconstrictive properties with local action(so

if it was still used it should not be used with vasoconstrictor), cocaine Toxicity & itspotential for abuse and addiction have steadily decreased its clinical use.

Now why it has vasoconstrictive action is homework, I tried to answer it in the last page of

the script.

2- Procaine: Low potency so it's required in high dose and it has Slow onset of action,meanly because of its low lipid solubility.

3- Tetracaine.4- Benzocaine: Has very low solubility that it is used as a dry powder, it produces long

lasting surface anesthesia, it's just used in surface anesthesia.Amide-Linked Local Anesthetic

Lidocaine (other generic names: xylocaine, lignocaine):

Produces faster & longer lasting anesthesia than does an equal concentration of procaine

or ester linked LAs. It is alternative choice for individuals sensitive to ester type LAs; it is

also used as antiarrhythmic agent.

What does 1% Lidocaine mean? A solution expressed as 1% contains 1g substance in each

100mls or cc.

1 g : 100 ml = 1000mg :100 ml = 10 mg : 1 ml

So if u want to know how many mg per ml of Lidocaine is, just multiply by 10, for example

0.25% means 2.5 mg/ ml, so for any percent just multiply by 10 in order to convert it to mg/mlMethods of LAs administration

1- Topical anesthesia: 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: Benzocaine and

Lidocaine in the form of gel 2%.

We have also a drug called lignosol which is a type of Lidocaine in the form of spry, used for

toothache.

2-Infiltration Anesthesia: commonly used by dentists along with nerve block anesthesia, to provide

anesthesia for minor surgical procedures.


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now the infiltration anesthesia is used for minor procedures like suturing a cut, in which the local

anesthetic is injected directly to the tissue, to reach the nerve branches and terminals, and it's used for

dental extraction in the maxilla, cause the maxillary nerve as u know is a branch of the trigeminal

nerve, and it's difficult to be reached, so instead we use multiple injections (infiltration) directly to the

tissue. Commonly used Amide LAs by infiltration are Lidocaine and Prilocaine.

3-Spinal Anaesthesia: injection directly into the cerebrospinal fluid (subarachnoid space), between

L3-L4 or L4-L5 vertebra which is the end of the spinal cord in order not to injure it, and this will

induce loss of pain sensation to the lower area (abdomen, pelvic region and the legs) and the site of

injection, this technique is also called epidural anaesthesia cause it's administered to the epidural

space, and it can be used to suppress pain during labour, in which it will be local and there won't be

loss of consciousness.

4-Nerve block anaesthesia: another technique used by dentists in which LA is injected

close to nerve trunks to produce loss of sensation peripherally in the mandibular, 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) : in maxilla and

anterior mandibular region we have thin cortical layer, so we chose Infiltration anesthesia

because it will reach the nerve filament inside cancellous bone, but in the Posterior mandible

we have thick & dense cortical bone so we use nerve block anesthesia.

2-Duration of anesthesia: nerve block anesthesia produces a more profound & longer

duration of action than infiltration anesthesia.

3-Age of the patient: Older individuals have dense bone, it is more difficult for infiltration

anesthesia to penetrate the bone so we use nerve block anesthesia, and in some cases the

patient is child and have thin cortical bone so you'll use infiltration anesthesia.

So local infiltration (infiltration anesthesia) type of injection that anesthetizes a small area

(one or two teeth and associated areas) and anesthesia deposited at nerve terminals , and

nerve block type of injection that anesthetizes a larger area and anesthesia deposited nearlarger nerve trunksWhy cocaine have vasoconstrictor activity? I couldn't find the exact answer to this question but wiki says that cocaine

enhance the release of dopamine, and u remember from the first that dopamine acts on beta 1 receptor, which induce

rennin secretion that will convert angiotensinogen to angiotensin I which will be converted to angiotensin II in the lung

by ACE, and angiotensin II has a vasoconstriction effect, but still I'm not sure of this answer because this will give

systemic not local vasoconstriction :P

Done by: Ammar Aldawoodyeh

14.local_anesthetics.docx

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