Color Atlas of Pharmacology (Part 19): Local Anesthetics

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204 Local Anesthetics

Local Anesthetics

Local anesthetics reversibly inhibit im-

pulse generation and propagation in

nerves In sensory nerves, such an effect

is desired when painful procedures

must be performed, e.g., surgical or den-

tal operations

Mechanism of action Nerve im-

pulse conduction occurs in the form of

an action potential, a sudden reversal in

resting transmembrane potential last-

ing less than 1 ms The change in poten-

tial is triggered by an appropriate stim-

ulus and involves a rapid influx of Na*

into the interior of the nerve axon (A)

This inward flow proceeds through a

channel, a membrane pore protein, that,

upon being opened (activated), permits

rapid movement of Na+ down a chemi-

cal gradient ([Na*]exr ~ 150 mM, [Na*]int

~ 7 mM) Local anesthetics are capable

of inhibiting this rapid inward flux of

Nat; initiation and propagation of exci-

tation are therefore blocked (A)

Most local anesthetics exist in part

in the cationic amphiphilic form (cf p

208) This physicochemical property fa-

vors incorporation into membrane

interphases, boundary regions between

polar and apolar domains These are

found in phospholipid membranes and

also in ion-channel proteins Some evi-

dence suggests that Na*-channel block-

ade results from binding of local anes-

thetics to the channel protein It appears

certain that the site of action is reached

from the cytosol, implying that the drug

must first penetrate the cell membrane

(p 206)

Local anesthetic activity is also

shown by uncharged substances, sug-

gesting a binding site in apolar regions

of the channel protein or the surround-

ing lipid membrane

Mechanism-specific adverse ef-

fects Since local anesthetics block Nat

influx not only in sensory nerves but al-

so in other excitable tissues, they are

applied locally and measures are taken

(p 206) to impede their distribution

into the body Too rapid entry into the

circulation would lead to unwanted systemic reactions such as:

e blockade of inhibitory CNS neurons, manifested by restlessness and sei- zures (countermeasure: injection of a benzodiazepine, p 226); general paralysis with respiratory arrest after higher concentrations

e blockade of cardiac impulse conduction, as evidenced by impaired AV conduction or cardiac arrest (countermeasure: injection of epinephrine) Depression of excitatory pro-

cesses in the heart, while undesired

during local anesthesia, can be put to therapeutic use in cardiac arrhythmi-

as (p 134)

Forms of local anesthesia Local anesthetics are applied via different

routes, including infiltration of the tis-

sue (infiltration anesthesia) or injection next to the nerve branch carrying fibers from the region to be anesthetized (conduction anesthesia of the nerve, spinal anesthesia of segmental dorsal roots), or by application to the surface of the skin or mucosa (surface anesthesia) In each case, the local anesthetic drug is required to diffuse to the nerves concerned from a depot placed in the tissue or on the skin High sensitivity of sensory nerves, low sensitivity of motor nerves Im- pulse conduction in sensory nerves is inhibited at a concentration lower than that needed for motor fibers This differ- ence may be due to the higher impulse frequency and longer action potential duration in nociceptive, as opposed to motor, fibers

Alternatively, it may be related to the thickness of sensory and motor

nerves, as well as to the distance

between nodes of Ranvier In saltatory impulse conduction, only the nodal membrane is depolarized Because de- polarization can still occur after block-

ade of three or four nodal rings, the area

exposed to a drug concentration suffi- cient to cause blockade must be larger for motor fibers (p 205B)

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Local Anesthetics 205

Na'-enry_<“2Z¿ | Na+-channel

Peripheral nerve CNS Blocked Nat

Nat-channel

Conduction Restlessness,

respiratory Blocked paralysis Nat-channel

polar Cationic Uncharged

impulse amphiphilic | local `

Local conduction ‡ local - anesthetic application cardiac arrest apolar anesthetic

A Effects of local anesthetics

Local anesthetic

0.3-0.7 mm

1 ON OOM OOOO ™

C sensory and

B Inhibition of impulse conduction in different types of nerve fibers

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myelinated Aä-fibers are affected later

and to a lesser degree than are stimuli

conducted via unmyelinated C-fibers

Since autonomic postganglionic fibers

lack a myelin sheath, they are particu-

larly susceptible to blockade by local

anesthetics As a result, vasodilation en-

sues in the anesthetized region, because

sympathetically driven vasomotor tone

decreases This local vasodilation is un-

desirable (see below)

Diffusion and Effect

During diffusion from the injection site

(i.e., the interstitial space of connective

tissue) to the axon of a sensory nerve,

the local anesthetic must traverse the

perineurium The multilayered peri-

neurium is formed by connective tissue

cells linked by zonulae occludentes

(p.22) and therefore constitutes a

closed lipophilic barrier

Local anesthetics in clinical use are

usually tertiary amines; at the pH of

interstitial fluid, these exist partly as the

neutral lipophilic base (symbolized by

particles marked with two red dots) and

partly as the protonated form, i.e., am-

phiphilic cation (symbolized by parti-

cles marked with one blue and one red

dot) The uncharged form can penetrate

the perineurium and enters the endo-

neural space, where a fraction of the

drug molecules regains a_ positive

charge in keeping with the local pH The

same process is repeated when the drug

penetrates the axonal membrane (axo-

lemma) into the axoplasm, from which

it exerts its action on the sodium chan-

nel, and again when it diffuses out of the

endoneural space through the unfenes-

trated endothelium of capillaries into

the blood

The concentration of local anes-

thetic at the site of action is, therefore,

determined by the speed of penetration

into the endoneurium and the speed of

diffusion into the capillary blood In or-

der to ensure a sufficiently fast build-up

of drug concentration at the site of ac-

tion, there must be a correspondingly

large concentration gradient between

drug depot in the connective tissue and the endoneural space Injection of solu- tions of low concentration will fail to

produce an effect; however, too high

concentrations must also be avoided because of the danger of intoxication resulting from too rapid systemic absorp- tion into the blood

To ensure a reasonably long-lasting local effect with minimal systemic action, a vasoconstrictor (epinephrine, less frequently norepinephrine (p 84)

or a vasopressin derivative; p 164) is often co-administered in an attempt to confine the drug to its site of action As blood flow is diminished, diffusion from the endoneural space into the capillary blood decreases because the critical concentration gradient between endoneural space and blood quickly becomes small when inflow of drug-free blood is reduced Addition of a vasoconstrictor,

moreover, helps to create a relative

ischemia in the surgical field Potential disadvantages of catecholamine-type vasoconstrictors include reactive hyperemia following washout of the con- strictor agent (p 90) and cardiostimula- tion when epinephrine enters the systemic circulation In lieu of epinephrine, the vasopressin analogue felypressin (p 164, 165) can be used as an adjunc- tive vasoconstrictor (less pronounced reactive hyperemia, no arrhythmogenic action, but danger of coronary constric- tion) Vasoconstrictors must not be applied in local anesthesia involving the appendages (e.g., fingers, toes)

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Interstitium

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A Disposition of local anesthetics in peripheral nerve tissue

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Characteristics of chemical struc-

ture Local anesthetics possess a uni-

form structure Generally they are sec-

ondary or tertiary amines The nitrogen

is linked through an intermediary chain

to a lipophilic moiety—most often an

aromatic ring system

The amine function means that lo-

cal anesthetics exist either as the neu-

tral amine or positively charged ammo-

nium cation, depending upon their dis-

sociation constant (pK, value) and the

actual pH value The pK, of typical local

anesthetics lies between 7.5 and 9.0

The pk, indicates the pH value at which

50% of molecules carry a proton In its

protonated form, the molecule possess-

es both a polar hydrophilic moiety (pro-

tonated nitrogen) and an apolar lipo-

philic moiety (ring system)—it is amphi-

philic

Graphic images of the procaine

molecule reveal that the positive charge

does not have a punctate localization at

the N atom; rather it is distributed, as

shown by the potential on the van der

Waals’ surface The non-protonated

form (right) possesses a negative partial

charge in the region of the ester bond

and at the amino group at the aromatic

ring and is neutral to slightly positively

charged (blue) elsewhere In the proto-

nated form (left), the positive charge is

prominent and concentrated at the ami-

no group of the side chain (dark blue)

Depending on the pK,, 50 to 5% of

the drug may be present at physiologi-

cal pH in the uncharged lipophilic form

This fraction is important because it

represents the lipid membrane-perme-

able form of the local anesthetic (p 26),

which must take on its cationic amphi-

philic form in order to exert its action

(p 204)

Clinically used local anesthetics are

either esters or amides This structural

element is unimportant for efficacy;

even drugs containing a methylene

bridge, such as chlorpromazine (p 236)

or imipramine (p 230), would exert a

local anesthetic effect with appropriate

application Ester-type local anesthetics

are subject to inactivation by tissue es-

terases This is advantageous because of the diminished danger of systemic in-

toxication On the other hand, the high rate of bioinactivation and, therefore,

shortened duration of action is a disad- vantage

Procaine cannot be used as a surface anesthetic because it is inactivated fast-

er than it can penetrate the dermis or mucosa

The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the C- atom adjacent to the nitrogen group Ar- ticaine possesses a carboxymethyl group on its thiophen ring At this posi-

tion, ester cleavage can occur, resulting

in the formation of a polar -COO- group, loss of the amphiphilic character, and conversion to an inactive metabolite Benzocaine (ethoform) is a member

of the group of local anesthetics lacking

a nitrogen that can be protonated at physiological pH It is used exclusively

as a surface anesthetic

Other agents employed for surface anesthesia include the uncharged poli- docanol and the catamphiphilic cocaine, tetracaine, and lidocaine

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<— [H*] Proton concentration

Io

60 F A Te \ 4 40

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40Ƒ — +60

pH value —>

Ability to penetrate

barriers and cell membranes

A Local anesthetics and pH value

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210 Opioids

Opioid Analgesics—Morphine Type

Source of opioids Morphine is an opi-

um alkaloid (p.4) Besides morphine,

opium contains alkaloids devoid of an-

algesic activity, e.g., the spasmolytic pa-

paverine, that are also classified as opi-

um alkaloids All semisynthetic deriva-

tives (hydromorphone) and fully syn-

thetic derivatives (pentazocine, pethi-

dine = meperidine, |1-methadone, and

fentanyl) are collectively referred to as

opioids The high analgesic effectiveness

of xenobiotic opioids derives from their

affinity for receptors normally acted

upon by endogenous opioids (enkepha-

lins, 8-endorphin, dynorphins; A) Opi-

oid receptors occur in nerve cells They

are found in various brain regions and

the spinal medulla, as well as in intra-

mural nerve plexuses that regulate the

motility of the alimentary and urogeni-

tal tracts There are several types of opi-

oid receptors, designated u, 4, «, that

mediate the various opioid effects; all

belong to the superfamily of G-protein-

coupled receptors (p 66)

Endogenous opioids are peptides

that are cleaved from the precursors

proenkephalin, pro-opiomelanocortin,

and prodynorphin All contain the ami-

no acid sequence of the pentapeptides

[Met]- or [Leu]-enkephalin (A) The ef-

fects of the opioids can be abolished by

antagonists (e.g., naloxone; A), with the

exception of buprenorphine

Mode of action of opioids Most

neurons react to opioids with hyperpo-

larization, reflecting an increase in K*

conductance Ca?* influx into nerve ter-

minals during excitation is decreased,

leading to a decreased release of excita-

tory transmitters and decreased synap-

tic activity (A) Depending on the cell

population affected, this synaptic inhi-

bition translates into a depressant or ex-

citant effect (B)

Effects of opioids (B) The analge-

sic effect results from actions at the lev-

el of the spinal cord (inhibition of noci-

ceptive impulse transmission) and the

brain (attenuation of impulse spread,

inhibition of pain perception) Attention

and ability to concentrate are impaired There is a mood change, the direction

of which depends on the initial condi- tion Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (float- ing sensation) and sense of well-being (euphoria), particularly after intrave-

nous injection and, hence, rapid build-

up of drug levels in the brain The desire

to re-experience this state by renewed administration of drug may become overpowering: development of psychological dependence The atttempt to quit repeated use of the drug results in with- drawal signs of both a physical (cardio- vascular disturbances) and psychological (restlessness, anxiety, depression) nature Opioids meet the criteria of “ad- dictive” agents, namely, psychological and physiological dependence as well as

a compulsion to increase the dose For these reasons, prescription of opioids is subject to special rules (Controlled Sub-

stances Act, USA; Narcotic Control Act,

Canada; etc) Regulations specify, among other things, maximum dosage (permissible single dose, daily maximal dose, maximal amount per single prescription) Prescriptions need to be is- sued on special forms the completion of which is rigorously monitored Certain opioid analgesics, such as codeine and tramadol, may be prescribed in the usu-

al manner, because of their lesser po-

tential for abuse and development of dependence

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Opioids 211

Proopiomelanocortin Proenkephalin

B-Lipotropin 8

Sel

B-Endorphin

A Action of endogenous and exogenous opioids at opioid receptors

Mediated by opioid receptors

i

7

Dampening effects

Pain sensation

Analgesic 1

Vagal centers,

Chemoreceptors

of area postrema

Oculomotor

center

(Edinger's nucleus)

Mood

alertness

system

Smooth musculature

stomach

— spastic

constipation

Antidiarrheal

Ureter

bladder

bladder sphincter

Respiratory center

Cough center

Antitussive

B Effects of opioids

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212 Opioids

Differences between opioids re-

garding efficacy and potential for de-

pendence probably reflect differing af-

finity and intrinsic activity profiles for

the individual receptor subtypes A giv-

en sustance does not necessarily behave

as an agonist or antagonist at all recep-

tor subtypes, but may act as an agonist

at one subtype and as a partial ago-

nist/antagonist or as a pure antagonist

(p 214) at another The abuse potential

is also determined by kinetic properties,

because development of dependence is

favored by rapid build-up of brain con-

centrations With any of the high-effica-

cy opioid analgesics, overdosage is like-

ly to result in respiratory paralysis (im-

paired sensitivity of medullary chemo-

receptors to COz) The maximally pos-

sible extent of respiratory depression is

thought to be less in partial agonist/

antagonists at opioid receptors (pentaz-

ocine, nalbuphine)

The cough-suppressant (antitussive)

effect produced by inhibition of the

cough reflex is independent of the ef-

fects on nociception or respiration

(antitussives: codeine noscapine)

Stimulation of chemoreceptors in

the area postrema (p 330) results in

vomiting, particularly after first-time ad-

ministration or in the ambulant patient

The emetic effect disappears with re-

peated use because a direct inhibition of

the emetic center then predominates,

which overrides the stimulation of area

postrema chemoreceptors

Opioids elicit pupillary narrowing

(miosis) by stimulating the parasympa-

thetic portion (Edinger-Westphal nu-

cleus) of the oculomotor nucleus

Peripheral effects concern the mo-

tility and tonus of gastrointestinal

smooth muscle; segmentation is en-

hanced, but propulsive peristalsis is in-

hibited The tonus of sphincter muscles

is raised markedly In this fashion, mor-

phine elicits the picture of spastic con-

stipation The antidiarrheic effect is

used therapeutically (loperamide, p

178) Gastric emptying is delayed (py-

loric spasm) and drainage of bile and

pancreatic juice is impeded, because the

sphincter of Oddi contracts Likewise,

bladder function is affected; specifically bladder emptying is impaired due to in- creased tone of the vesicular sphincter Uses: The endogenous opioids (metenkephalin, leuenkephalin, B-endorphin) cannot be used therapeutically

because, due to their peptide nature,

they are either rapidly degraded or ex- cluded from passage through the blood- brain barrier, thus preventing access to their sites of action even after parenter-

al administration (A)

Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord The opioids heroin and fentanyl are highly lipophilic, allowing rapid entry into the CNS Because of its high potency, fentanyl is suitable for transdermal delivery (A)

In opiate abuse, “smack” (“junk,”

“jazz,” “stuff,” “China white;” mostly

heroin) is self administered by injection (“mainlining”) so as to avoid first-pass metabolism and to achieve a faster rise

in brain concentration Evidently, psy-

chic effects (“kick,” “buzz,” “rush”) are

especially intense with this route of administration The user may also resort to other more unusual routes: opium can

be smoked, and heroin can be taken as

snuff (B)

Metabolism (C) Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and elim- inated renally Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity The extent to which the 6-glucuronide con- tributes to the analgesic action remains uncertain at present At any rate, the activity of this polar metabolite needs to

be taken into account in renal insuffi- ciency (lower dosage or longer dosing interval)

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Opioids 213

Met-Enkephalin Morphine Fentanyl fie Cry

N

Œ} Gy)Hay)Cre ác) Cee 3, mí

6

(A)

HạC~C~Ø o O-C—CH,

A Bioavailability of opioids with different routes of administration

heroin

Intravenous

"Mainlining" Morphine-6-|

| glucuronide

Morphine-3- glucuronide

Bronchial

mucosa

e.g., opium

smoking

|

B Application and rate of disposition

Tiêu đề	Local anesthetics
Chuyên ngành	Pharmacology
Thể loại	chapter
Năm xuất bản	2000

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