Section 2

 

Section 2: Local Anesthetics (LAs)  A. Review of neuronal physiology B. Ph Phys ysiico coch chem emiica call p pro rope pert rtiies o off L LAs As C. Side effects

 

Local Anesthetics (LAs) LAs are used used by a wide rrange ange of practit practitioners ioners (prior tto o sutur suturing ing a laceration, for example) as well as in more specific situations such as regional anesthesia practiced mainly by anesthesio anest hesiologis logists ts (intersca (interscalene lene block pri prior or to shoulder su surgery) rgery)..  An understanding of pain physiology as w well ell as the pharmacology of local anesthetics is needed by anyone using these drugs. Regional Regio nal anest anesthesia hesia in involve volves s the use of LAs at speci specific fic sit sites es along the neuraxi neuraxis s not only ffor or surgi surgical cal anes anesthes thesia, ia, but als also o for postoperative pain management. LAs can be used used alone o orr in conju conjuncti nction on wit with h other dr drugs ugs suc such h as epinephrine epinephrine or cl clonidi onidine ne when adj adjustm ustment ent of spe speed ed of onset onset,, duration of action, or depth of anesthesia is desired.

 

Section 2A: Neuronal Physiology How is pain transmitted and where do local anesthetics work? When a surgeon makes a cut, for example, nerves sensing a noxious stimuli in that area are stimulated, resulting in an impulse that is transmitted from that periphera perip herall site via nociceptive nociceptive affe afferent rents s to the centr central al nervous system where perception of pain occurs (link to slideare withthe pain pathway ). Nerve impulses are electrical and result of a propagated ionic current.

Local anesthetics work by blocking this current. How? First, a review of physiology of nerve conduction:

 

Like other cells, neurons maintain a resting potential through the active and passive diffusion of ions of about -70mV. The ionic concentration of sodium (Na+) is large outside the cell and low inside the cell whereas with potassium (K+) the opposite is true leading to a tendency of Na Na+ + to flow in and K+ to flow out. This ionic gradient is maintained by the Na-K ATPase pump imbedd imbedded ed in the neural membrane. The membrane potential is due to the relative impermeability of Na+ across the membrane compared to K+ which is selectively permeable leading to a relatively greater concentration of anions within the cell due to this passive and active diffusion. Unlike many other tissues, however, neuronal membranes contain voltage-gated sodium and potassium ion channels.  According to voltage-clamp studies using the Hodgkin-Huxley model, an action potential associated with with a nerve impulse initiallyflux in an to the transient increased permeability of the-90mV membrane to Na+ resultingresults in an inward of upward Na+ ionsswing and adue transient increase in the resting potential from to +60mV. It is thought that the action potential causes a change in the conformation of the nerve membrane resulting in the opening of the Na+ channel within the membrane causing the inward flux. The action potential ends with the closure of the Na+ channel and the inactivation of the transient Na+ conductance. The action potential is propagated to adjacent nerve membranes that reach threshold voltage and depolarize. Potassium ion outflow is permitted by the almost simultaneous opening of K+ channels by a similar mechanism as that resulting in the inward flow of Na+. http://hyperphysics.phy-astr.gsu.edu/hbase/biology/imgbio/actpot4

The resting membrane potential is restored by movement of the ions back to their initial intra- and extracellular  concentratio conce ntrations ns by the Na-K AT ATPase Pase pump.

 

How and where do local anesthetics exert their effect? The Sodium Channel LAs block conduction in all neurons neurons by impairing the function of the sodium sodium channels involved involved in action potential generation. The voltage-gated sodium sodium channel e embedded mbedded in the neuronal membrane is a membrane-bound protein composed of one large α-subunit and one or two smaller β-subunits. Most local anesthetics bind the α-subunit and block the channel from inside the cell. This prevents subsequent subsequent channel activation and influx of sodium sodium ions resulting in membrane membrane depolarization. The membrane is therefore stabilized and unaffected by further nerve stimulation. In other words, a noxious noxious stimuli is no longer propagated propagated as an impulse to the central nervous system and perceived as pain.

Image Imag e from Cattera Catterallll WA, Golden Golden AL, AL, Waxman SG. International Union of Pharmacology. Pharmaco logy. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmac Phar macol ol Rev. 2005 2005 Dec;57(4):3 Dec;57(4):39797409.

 

The Sodium Channel, continued . . .

Local anesthetics bind with greatest affinity when the Na+ channel is in the activated or inactivated state rather than in the resting state. The resti resting ng membrane potential is not altered but as the concentration of drug increases, the rate of firing declines as conduction slows and the rate of rise and the amplitude amplitude of the action potential dimi diminishes. nishes. Local anestheti anesthetics cs have their greatest effect when nerves are firing rapidly. The above blockade mechanism is true for ester and amide local anesthetics. However, benzocaine is believed to exert its effect via membrane expansion and Na+ channel distortion. Interestin Inter estingly, gly, bi biotoxi otoxins ns like tet tetrodot rodotoxin oxin alter th the e Na+ chann channel el extracell extracellularl ularly. y.

 

How do do LAs reach the iintrace ntracellula llularr binding binding s site? ite? LAs are weak weak bases bases and exist in the body o outsid utside e the neuronal membrane as a mixture of the uncharged base and charged cationic form (more on our friends Henderson and Hassel Hass elba bach ch la late ter) r).. The form that penetrates the hydrophobic cell membrane is the lipid-soluble, uncharged base form. Once inside inside the the cell, there is reequilibra reequilibration tion in acc accord ord wit with h the pKa of the drug drug and th the e catio cationic nic form form is the o one ne whic which h actua actually lly binds to an anionic site within the Na+ channel. In addition to the increased binding of LA to rapidly-firing neurons, nerve fiber (link back to prior slide) type determines LA sensitivity. Most simply, smaller diameter, unmyelinated fibers are most sensitive to LAs.

 

Section Sectio n 2B: Phy Physic sicoch ochemi emical cal Pro Proper pertie ties s of LAs Chemical Structure The chemistry of the most commonly commonly used LAs is most easily described described by dividing them into two categories categ ories:: ester- and amide-link amide-linked ed amines. amines.

Structure 1)

An aro aromati matic c gro roup up (b (be enzen nzene e ri ring ng)) at one end contributes to the lipophilic nature of the drug, allowing it to pass through nerve membranes to site of action at Na+ channel.

2)

The The hydr hydrop ophi hillic gr gro oup at the the other ther end end is a tertiary amine which becomes ionized in the presence of H+.

3)

The bond between the lipophilic and amine ends of the molecule is either an esterester- or amide-li amide-linkage nkage.. (Here lidocain lido caine e contains contains an amide-link amide-linkage age while procaine has an ester-linkage).

 

Chemical Structures of Common LAs

http://www.med-ed.virginia.edu/courseSites/display.cfm?keyID=181&click=0

 

Dr u g

Po t en c y an d L i p i d Solubility

pKa

Du r at i o n an d p r o t ei n binding

Bupivacaine (Marcaine)

++++

8.1

++++

Etidocaine (Duranest)

++++

7.7

++++

Lidocaine (Xylocaine)

++

7.8

++

Mepivacaine (Carbocaine)

++

7.6

++

Prilocaine (Citanest)

++

7.8

++

Ropivacaine Esters

++++

8.1

++++

Chloroprocaine

+

9 .0

+

Coccaine

++

8.7

++

Procaine

+

8.9

+

Tetracaine

++++

8.2

+++

 Amides

 

Section 2B: Physicochemical Properties of LAs LA s - Ch Chem emic ical al an and dS Str truc uctu tura rall R Rel elat atio ions nshi hips ps Chemical structure, Chemical structure, lipid lipid solubility, solubility, protein protein binding, binding, ionization ionization,, and chiral forms contribut contribute e and correlate to the potency, onset, duration of action, and toxicity of LAs.

Structure and Potency The structural differences between LAs is determined by substitutions to the aromatic ring, ring, the type of linkage of the intermediate chain, and the alkyl groups attached to the amine nitrogen. (Link to slide with structures.) The degree to which a LA is hydrophilic or lipophilic is determined by the size of the alkyl groups on on or near the ends of the molecule. molecule. Increasing the size of these groups increases increases the hydrophobicity, or or lipid solubility, solubility, of the molecule. Lipid solubility correlates correlates with potency in that, generally, both potency and lipid solubility increase with the total number of carbon atoms in the molecule. For example, etidocaine has three more carbon atoms than lidocaine at the amine amine end and is more potent potent and longer-acting longer-acting as a result. (Link to table) The measure of relative potency is affected by many factors f actors including nerve fiber characteristics (size, degree of myelination), frequency of nerve stimulation, and environmental factors like pH and electrolyte concentrations concentrations (hypokalemia (hypokalemia and hypercalce hyper calcemia mia antagonize antagonize blockade blockade). ).

 

Structure and Duration of Action Lipophilicity Lipophili city is also also associate associated d with longer longer duration duration of of action. action. All LA LAs s exist in large large part part bound to plasma and tissue proteins and the bound form is generally inactive but does serve as a reservoir.  Albumin and alpha1-acid alpha1-acid glycoprotein glycoprotein (AAGP) are the two major proteins that bind L LAs As in the body.  Albumin shows low-affinity low-affinity high-capacity binding binding while AAGP shows shows high-affinity low-capacity binding. The fraction of drug drug bound to plasma proteins correlates with with duration of LA activity activity presumably because the drug is cleared more slowly by blood flow. Highly lipophilic lipophilic drugs tend to bind more strongly strongly to AAGP and albumin and th therefore erefore have a lo longer nger duration of action. It has been been thought that the bond bond between the LA the the Na+ channel may be similar to that between the LA and plasma proteins such that greater protein binding in the plasma and tissues correlates to longer duration of binding to the Na+ channel and longer duration of anesthesia. Duration of action Duration action is also affected affected by the use use of epinephri epinephrine ne as a “chemical “chemical tournique tourniquet” t” causing causing local vasoconstriction and decreasing the elimination of the drug.

 

Ionization and Speed of Onset Ionization of the hydrophilic amino group is determined by the pKa of the LA and the pH of the medium. This then determines the amount amount of uncharged base form (that can pass through the nerve m membrane) embrane) and cation catio n form (that (that binds the Na+ chann channel) el) of drug present present in solution by the Henderson-H Henderson-Hassel asselbach bach equation: equation:

pH = pKa + log (base (base / cation) cation) Becaus Bec ause e LAs have have a pK pKa a greate greaterr than than 7.6 (link to table) table) (greater than physiologic pH of 7.4), 7 .4), they will exist in equilibrium at in to thephysiologic b ody with a body greater fraction present in thepresent cationicinform; this fractionbase decreases as the pKa gets closer pH. By increasing the fraction the uncharged, form, the onset-time will decrease as more more drug is able to cross neuronal membranes. In other words, drugs with with a lower pKa will generally generally have have a shorter ons onset et time. However, in vivo, vivo, the pKa is not always directly correlat correlated ed with speed of onset as it is with isolated fibers in vitro.. For e vitro exampl xample, e, c chlorop hloroprocai rocaine ne has a pKa of 9. 9.0 0 and a very very rap rapid id speed speed of onset (see table) which is thought to be due tto o the hi high gh percentage of chloroprocaine used (3%). Other factors factors such as speed of diffusion through tissues also plays a role. Other clinica clinicall implic implications ations of iioniza onization tion cha characte racteristi ristics cs exist. exist. The ten tendency dency to to be protonated protonated is affected affected when when the pH of the environment changes. For example, in inflammed or infected tissues, the pH tends to be lower due to lactic lactic acidosis. This then causes more of the LA to exist in the protonated form slowing the speed of onset. Commercially available preparations of LAs are water-soluble water-soluble hydrochloride salts with pH 6.0-7.0. If the solution contains epinephrine, however, be loweredRepeated as epinephrine at higher pHs. This slows the speed of onset onset as more ofthe thepH LAmust is protonated. dosingisofnot LAsstable also decreases effectiveness as salt forms of the drug exhausts the local buffering capacity of the tissue leading to refractoriness. Clinical Pearl: Some practitioner practitioners s add add sodium sodium bicarbona bicarbonate te to lidocaine and mepivacaine (not to bupivacain bupivacaine e or ropivacaine) to increase the amount of LA in the base form and increase speed of onset.

or ropivacaine) to increase the amount of LA in the base form and increase speed of onset.  

Chir Ch iral al Fo Form rms s Back in the days of biochemistry we learned learned that stereoisomers of molecules exist when when there is an asymmetric carbon present within the molecule. An asymmetric car carbon bon is one that has four distinctly different substitution substitution groups. In the image shown here, the the asymmetric carbons of the two enantiome enan tiomers rs of bupivac bupivacaine aine are shown shown with an asterix asterix.. The R and S isomers isomers are labeled labeled DextroDextroand Levobupivacaine, respectively. The importan importance ce of stereoiso stereoisomers mers of local local anesthetics lies in differences in potency and toxicity that exists between between different forms. Many commercial comme rcial drug drug preparati preparations ons of LAs are a mixture mixture of the R- and S-isomer S-isomers, s, also called called racemi racemic c mixtures. As a general rule, when when differences differences exist between isomers, the S form is less toxic and has a longer duration of action. For example, infiltration anesthesia with levobupiv levob upivacain acaine e shows longer longer duration duration of action action and lower systemic toxicity when compared with dextrobupivacaine.

 

Struc tr uctu ture re of Ropiva Ropiv acaine Ropivacaine was developed Ropivacaine developed solely solely as an an Senantiomer enant iomer due to to the the evidence evidence that levo le vobup bupiv ivac acai aine ne (t (the he S-en S-enan anti tiom omer er of bupivicaine) was less toxic.

Sidebotha Sidebo tham m DA. Schug Schug SA. Stere Stereoch ochemi emistr stry y in anaesthesia. [Review] [42 refs] [Journal Article. Review] Clinical & Experimental Pharmacology & Physiology. 24(2):126-30, 1997 Feb.

 

Differential Motor and Sensory Blockade Since local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. Nerve fibers differ significantly in their susceptibility to local anesthetic blockade on the basis of differenc differences es in size and degree degree of myelination myelination (link to slide). slide). Upon direct application of a local anesthetic to a nerve root, the smaller B and C fibers are blocked first, followed by those associated with other other functions, functions, and motor function function is is the last to be blocked. blocked. This is known as differential blockade. Depending on the concentration of LA around a nerve, nerve, it has been shown that some LAs LAs can provide sensory blockade without impairing motor response response as well. This is especially especially true for ropivacai ropivacaine ne and bupivacai bupivacaine, ne, but not for etidocaine etidocaine.. The inab inablity lity of etido etidocaine caine to produce differential motor-sensory impairment has been attributed to its high lipophilicity and ease ease of blocking blocking both both myelinat myelinated ed and unmyeli unmyelinated nated nerve fibers. fibers. Pearl: Sensory blockade Clinical Pearl: blockade without motor impairment impairment is desired desired in such fields as as obstetrics and and postoperative analgesia analgesia in which which low concentrations concentrations of bupivacaine bupivacaine and ropivacaine ropivacain e provide analgesia analgesia without without impairing impairing motor strength needed in labor labor or ambulation.

 

 Absorption, Distribution, Distribution, and Metabolism Metabolism  Absorption Systemic absorption following local injection or application depends on blood flow and is determined by the following factors: 1) Site of injection-The injection-The rate of absorption absorption is related to the vascula vascularity rity at the injection injection site. intravenous > trachea intravenous tracheall > intercostal intercostal > caudal caudal > paracervical paracervical > epidural epidural > brachial brachial plexus plexus > sciatic > subcutaneous 2) Presence of vasoconstrictor --The The addition of epinephrine, and occasionally phenylephrine, decreases vascular absorption leading to increased neuronal uptake. This enhances the quality of analgesia, increases duration of action, and limits toxic side effects. effects. The effect is is more pronounce pronounced d with shorter-a shorter-acting cting LAs LAs like lidocaine. lidocaine. Epinephrine Epinephrine also also prolongs prolongs and augments analgesia through activation of α2-adrenergic receptors. 3) Local Anesthetic Agent-LAs Agent-LAs that bind avidly avidly to local tissues tissues are more slowly absorbed absorbed.. They also differ in intrinsic vasodilator properties. Distribution Organ uptake depends on the degree of tissue profusion, the tissue/blood partition coefficient, and organ mass. -Highly perfused -Highly perfused organs such as brain, brain, lungs, lungs, liver, liver, kidney, kidney, and heart heart have more more rapid uptake than than less-highly less-highly perfused perfused organs like like muscle and fat. -Strong plasma protein binding -Strong binding retains LAs in the blood whereas high lipid solubility solubility facilitates tissue uptake. -Massive organs like muscle provide a large reservoir of drug.

 

Metabolism  An ester or amide-linkage between the lipophilic and hydrophilic ends of the LA molecule determines metabolism. Esters:: Ester LAs are metabolized predominantly by plasma pseudocholinesterase. Hydrolysis is Esters rapid and the water-soluble metabolites are excreted in the urine. The rate of hydrolysis depends on the type and location of the substitutions present on the aromatic ring. Clinical Pearls: Procaine Procain e and benzocaine benzocaine are metabolize metabolized d to p-aminobenz p-aminobenzoic oic acid (PABA) (PABA) which which has been been associated with allergic reactions. Patients with genetically abnormal pseudocholinesterase are at increased risk for toxic side effects as metabolism is slower.  Amides:: These LAs are transported in the circulation from the neural site of injection to the liver  Amides prior to metabolism by dealkalization or hydroxylation. Therefore, clearance is determined by hepatic blood flow and hepatic function. Drugs such as general anesthetics, norepinephrine, cimetidine, and propranolol, among others, decrease hepatic blood flow and increase the half-life of these LAs. Decreased hepatic function can be caused by hypothermia, immature hepatic enzyme system, or liver damage.

 

Section 2C: Side Effects of LAs LAs block voltage-gated Na+ channels channels affecting propagation propagation of action potentials potentials throughout the body, not just in nerve cells. Toxicity is often directly proportional proportional to potency and mixtures should be considered to have additive effects. (link (link to next slide with chart of drugs). drugs). Systemic toxicity primarily involves the central nervous system (CNS) and cardiovascular system. to LAs. CNS symptoms are usually seen before cardiovascular due to higher susceptibility Central Nervous System Early symptoms: circumoral numbness, tongue paresthesia, dizziness, dizziness, tinnitus, blurred visi vision on Excitatory symptoms: restlessness, agitation, nervousness, paranoia, muscle twitches Depressive symptoms: slurred speech, drowsiness, loss of consciousness, respiratory depression Seizures: Ultimately, generalized generalized tonic-clonic seizures will result result Clinical Pearl: Seizures produce hypoventilation resulting in combined metabolic and respiratory respirator y acidosis enhancing CNS toxicity. Respirator Respiratory y or metabolic acidosis and elevated PaCO2 enhances cerebral bloodflow delivering more LA to the brain. It also also increases increases the 2 in neurons thus raising intracellular pH trapping cations within the cell. amount of CO cell. By decreasing cerebral blood flow and drug exposure, benzodiazepines and hyperventilation raise the threshold for LA-induced LA-induced seizures. seizures. Thiopental quickly and reliably reliably ends seizures but adequate ventilation and oxygenation must be maintained.

 

Cardiovascular: Local anesthetics affect the heart heart and peripheral peripheral blood vesse vessels ls directly and indirectly via inhibition of Na+ channels and the autonomic nervous system. Direct Cardiac Effects Cardiac muscle Na+ channel blockade and autonomic nervous system inhibition-->depressed myocardial myocar dial automaticity automaticity and reduced refractory refractory period duration duration  At higher concentrations contractility and conduction velocity are also reduced.

Direct Peripheral Vascular Effects LAs have a biphasic effect on vascular smooth muscle producing vasoconstriction at lower doses and vasodilation vasodi lation at higher doses doses leading leading to hypotension. hypotension. **Cocaine is the only local anesthetic that consistently causes vasoconstriction at all concentrations because becaus e of its ability ability to inhibit the the uptake of of norepinephrine norepinephrine by premotor premotor neurons neurons and thus potentiate potentiate neurogenic neurog enic vasoco vasoconstric nstriction. tion. More potent drugs such as bupivac bupivacaine aine and etidocaine etidocaine produce produce profound profound cardiovascula cardiovascularr (CV) depression in the following manner: ·The ratio of the dosage causing irreversible CV collapse and that producing CNS toxicity is lower  ·Ventricular arrhythmias and fatal ventricular fibrillation may occur more often ·Pregnant ·Pregn ant patients patients may be more sensitive to cardiotoxic cardiotoxic effects effects ·Resuscitation is more difficult after bupivacaine-induced CV collapse (the R-isomer avidly blocks Na+ channels, dissociates slowly, and has a high degree of protein binding) ·Acidosis ·Acido sis and hypoxia hypoxia potentia potentiate te cardiotoxici cardiotoxicity ty of bupivacaine bupivacaine

 

 Agent

Uses

Available Concentration

Max dose (mg/kg)

Duration (min)

Max dose wi with th epi epi (mg) (mg)

Duration with ep epii (min (min))

Benzocaine

Topical

20%

Chloroprocaine

Epidural, iin nfiltration, PNB

1%, 2%, 3%

12

30-60

1000

30

Cocaine

Topical

4%, 10%

3

30-60

Procaine

Spinal, infiltration, PNB

1%, 2%, 10%

12

20-60

600

30

Tetracaine

Spinal, topical

0.2%, 0.3%, 0.5%, 1%, 2%

3

90-400

Bupivacaine

Epidural, spinal, infiltration, PNB

0.25, 0.5, 0.75%

3

90-240

225

180

Etidocaine

PNB

0.5, 1.0%

4.5

120-180

400

180

Lidocaine

Epidural, spinal, PNB,

0.5, 1, 1.5, 2, 4, 5%

4.5

30-120

500

120

Esters 30-60

 Amides

IV regional, topical Mepivacaine

Epidural, infiltration, PNB

1, 1.5, 2, 3%

4.5

45-90

500

120

Prilocaine

PNB

4%

8

30-90

600

120

Ropivacaine

Epidural, spinal, infiltration, PNB

0.2, 0.5, 0.75, 1%

3

90-500

PNB PN B=P Periph eriph eral nerve bloc k

 

A dap ted fr o m Mo rg an Mik ael an and d Mur ray ’ s Cl i ni cal A nes th esi a and Mil Mi l l er’ s A n est hes i a

Respiratory: Lidocain Lido caine e depresses depresses hypoxic hypoxic drive. drive.  Apnea can result from phrenic and intercostal nerve paralysis or depression depression of the medullary respiratory center due to direct exposure to LA agents. Local anesthetics relax bronchial bronchial smooth but but can cause bronchospasm in patients with with reactive airway disease. Hypersensitivity Reactions: These reactions are uncommon but are more likely to be caused by esters as they are derivatives of PABA. Many commercial preparations contain contain the preservative preservative methylparaben which has a structure similar to PABA and may cause the rare reactions to amide agents.. Musculoskeletal: Direct muscle injection injection of LAs (bupivacaine>lidocaine>pro (bupivacaine>lidocaine>procaine) caine) causes myofibril myofibril hypercontraction, then lytic lytic degenerati degeneration, on, edema, edema, and necrosis. necrosis. Hematological: Methemoglobul Methemogl obulinemi inemia a - This can result result after large doses of prilo prilocaine caine and benzocain benzocaine. e. The metabolism of prilocaine prilocaine in the liver results results in the formation of O-toluidi O-toluidine, ne, which is resp responsible onsible for the oxidation of hemoglobin to methemoglobin. It is reversible with methylene blue. It has also been demonstrated demonstrated that lidocaine lidocaine decreases coagulation coagulation and enha enhances nces fibrinolysis.

 

Dermatomes and peripheral nerves-anterior view

http://www.regionalabc.org/images/med-illustartion/ant-dermatome.jpg

 

Dermatomes and peripheral nerves-posterior view

http://www.regionalabc.org/images/med-illustartion/post-dermatome.jpg