Novel Long Local anesthetics updated(2015)

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Novel Long Acting Anesthetic:

Novel Long Acting Anesthetic Done by: Dr. Ahmed Bakhet Anesthesia and Intensive care Department Fujairah hospital , MOH .UAE.

Objectives :

Objectives History Classify local anesthtics General scope on pharmacokinetics and toxic effects of local anesthetics. Isomers and Enantomers. Novel Long acting LA. Ultra –long Acting LA. Liposomal Bupivacaine

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Local anesthetics (LAs):

Local anesthetics (LAs) LAs are drugs that: used to prevent or relieve pain in specific regions of the body without loss of consciousness Reversibly block pain sensation by blocking nerve conduction of sensory impulse from the periphery to the CNS 4

General Information about LA Chemistry of LAs:

General Information about LA Chemistry of LAs The LAs consists of three parts. A lipophilic ‘hydrophobic’ aromatic group. An intermediate chain (ester or amide). A hydrophilic an ionizable group (usually a tertiary amine group). Esters usually have a shorter duration of action because ester links are more prone to hydrolysis than amide links 5

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N Lipophilic Head (Benzene Ring) Hydrophilic Tail (Quaternary Amide) Intermediate Chain (Hydrocarbon) Ester (-CO-) Amide (-NHC-) R R H+ Adopted from: Barash PG, Cullen BF, & Stoelting RK. (eds) Clinical Anesthesia 1997. J.B. Lippincott

Classes: The rule of “i”:

Classes: The rule of “i” Am i des Lidocaine Bupivacaine Levobupivacaine Ropivacaine Mepivacaine Etidocaine Prilocaine Esters Procaine Chloroprocaine Tetracaine Benzocaine Cocaine 7

Clinical pharmacology of LAs:

Clinical pharmacology of LAs Short : Procaine chlorprocaine Intermediate: Lidocaine, mepivacaine prilocaine Long acting : tetracaine, Bupivacaine, etidocaine Ropivacaine . The choice of LA for a specific procedure is usually based on the duration of procedure required 8

Local anesthetics:

Local anesthetics Local anesthetics are weak bases. The pKa for most local anesthetics is in the range of 8-9 (Except benzocaine). As the larger percentage in body fluids at physiologic pH LA will be the charged, cationic form. The ratio between the cationic and uncharged forms of these drugs is determined by the Henderson-Hasselbalch equation: Log cation ( charged )/ uncharged = pKa - pH 9

Effectiveness of Local anesthetics are affected by pH of the application site :

Effectiveness of Local anesthetics are affected by pH of the application site 10 Effect of pH : Charged (cationic) form binds to receptor site uncharged form penetrates membrane ,efficacy of drug can be changed by altering extracellular or intracellular pH

Variables Affecting Ionization:

Local Anesthetic Molecule pH of site pH of solution Intrinsic structure pKa Variables Affecting Ionization Adjuncts H+ Non- H+

Local Anesthetics and Ionization: Both ionized and non-ionized forms are needed for function:

Local Anesthetics and Ionization: Both ionized and non-ionized forms are needed for function In infected tissue, the LA is completely ionized and won’t work- hence the need for sedation or GA

Membrane Potential and neurotransmission :

Membrane Potential and neurotransmission As a result of depolarization: the Na + channels close (inactivate) & K + channels open → outward flow of K + repolarizes the membrane toward the K + equilibrium potential about -95mv As a result of repolarization the Na + channels returns to the rested state. 14

LAs mechanism of action:

LAs mechanism of action Local anesthetics reversibly bind to the voltage-gated Na + channel, block Na + influx, and thus block action potential and nerve conduction. LA . gain access to the inner axonal membrane by passage directly through the plasma membrane traversing sodium channels while they are more often in an open configuration 15

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Potency = lipid solubility Higher solubility = can use a lower concentration and reduce potential for toxicity. Duration = Protein Binding . Bupivacaine >>> 95% Lignocaine>>>> 65 %. Anesthetic Potency and Duration of Action of LA

LA : Esters vs. Amides:

LA : Esters vs. Amides Clearance : >>> metabolic pathway Esters Ester hydrolysis by plasma cholinesterase Amides N-dealkylation and hydroxylation in the liver via hepatic enzyme “ Cytochrome P50” This patient has pre-existing liver disease- we would worry about accumulation of the drug

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18 Relative size and susceptibility to block of types of nerve fibers 1. pain, 2. cold, 3. warmth, 4. touch, 5. deep pressure & 6. motor Recovery in reverse order

Which nerve fibers transfers Acute Pain ? :

Which nerve fibers transfers Acute Pain ?

Sequence of clinical anesthesia :

Sympathetic block (vasodilatation) Loss of pain and temperature sensation Loss of proprioception Loss of touch and pressure sensation Loss of motor function Sequence of clinical anesthesia

Systemic absorption:

Systemic absorption LA are removed from depot site mainly by absorption into blood. Systemic absorption is determined by several factors, including: Dosage Site of injection ; Local blood flow: highly or poorly perfused Use vasoconstrictors (e.g., epinephrine) Drug tissue binding Physicochemical properties of the drug itself 21

Toxic Dose Ranges- Amides:

Toxic Dose Ranges- Amides Amide LA Max Dose Plain Max Dose + Epi Bupivacaine 2.5 3 Lidocaine 4.5 7 Ropivacaine 3 N/A Doses are in mg/kg, dose ranges change depending on site of injection

Acute Toxicity:

Acute Toxicity Main concern is CNS and Cardiac toxicity CNS Tinnitus, dizziness, lightheadedness are early signs Anxiety  disorientation  loss of consciousness  seizures  respiratory arrest Cardiac Hypotension All local anesthetics are negative inotropes PVC  wide QRS  Multiform VT VF, or Pattern with bupivacaine Bradycardia  asystole Pattern with bupivacaine + lignocaine

Toxicity and side effects :

Toxicity and side effects Symptoms and signs A. CNS: At low dose: sleepiness, light headedness, visual and auditory disturbances, restlessness, circumoral & tongue numbness. At high dose (stimulatory effects) : nystagmus, muscular twitching, finally tonic-clonic convulsions, followed by CNS depression→ death may occur. Convulsion because of cortical inhibitory pathways → unopposed activity of excitatory components. 24

Acute Toxicity:

Acute Toxicity With most drugs like Lignocaine, CNS toxicity precedes cardiac toxicity, providing a warning of impending disaster. With Bupivacaine, acute toxicity rapidly progresses to cardiovascular collapse. Pregnancy enhances the risk of cardiac toxicity.

Site of Injection: Likelihood of Toxicity:

Site of Injection: Likelihood of Toxicity IV Tracheal Intercostal Caudal Paracervical Epidural Brachial plexus Sciatic/Femoral Subcutaneous Most Most Least Least Vascularity Toxicity Liklihood Schematic is illustrative in nature and not intended to reflect absolute correlation

Neurotoxicity:

Neurotoxicity Lignocaine Initially seen with formulation in 10% dextrose Now seen with all formulations No longer recommended for spinal anesthesia Bupivacaine appears free of neurotoxicity as it goes directly to Cardiovascular toxicity.

Treatment of overdose:

Treatment of overdose Airway: Call for senior help.. fellow ABCD protocol 100% oxygen Intubate if necessary to ventilate CNS: Break seizure with propofol, thiopental, or midazolam Cardiovascular Amiodarone has demonstrated efficacy. Use 300 mg. IV Resuscitation difficult with Bupivacaine , more frequently successful in animal studies following Ropivacaine and Levo-Bupivacaine overdose. Intra-lipid 20 % for Bupivacaine Toxicity

ILE in the treatment of acute poisoning: a mini-review of human and animal studies.:

ILE in the treatment of acute poisoning: a mini-review of human and animal studies . Moshiri M. Etamad L. Fadaei H. 2010

Local anesthesia still awaits the development of the Ideal LA.:

Local anesthesia still awaits the development of the Ideal LA. Modern LAs are sufficiently effective and safe for the majority of clinical practice, but the search for Ideal LA ; - Has longer durations of action, - Has better nerve fiber selectivity , - Has lesser degrees of motor blockade , - And has lower incidences of systemic toxicity. ***researches continuing>>>> 30

Prolongation of action :

Prolongation of action Add vasoconstrictor – adrenaline ( Not to – fingers, toes, nose, penis ) Can use a larger dose\ higher concentration To use other , medication with especial physiochemical property make it longer

Long Acting LA amides.:

Long Acting LA amides. Amide Bupivacaine Levo-Bupivacaine Ropivacaine > Liposomal Bupivacaine

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What is Isomers ?:

What is Isomers ?   organic compounds which have: * same molecular formula but with different chemical properties as they have different structural formula

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Stereo-isomers These compounds have the same constitution and sequence of carbon bonds but differ in their relative positions of atoms or groups in 3-D or space . Subdivided to A. Geometrical isomerism >> Have the same chemical constitutes, same arrangement of double bonds ,but differs in spatial arrangement of atom, Ex . Mivacurim >>> Contain 3- Geomertrical Cis-cis and trans- cis , Trans-trans stereo-isomers. Atricurium >> Contain10 Geo. stereo-isomers ,one of them is Cis-atracurium . .

B. Optical Stereo-isomerism “Enantiomers” . :

B. Optical Stereo-isomerism “ Enantiomers ” . They are non- superimposable mirror image of each others. It called as Enantiomers . Enantiomers are used to represent by R and S These isomers was previously named according to reaction plane polarized light. (physical Name) either Dextro-rotatory > >D- Or Levo-rotatory .>> L.to the light colours out of prism. The names now replaced by according Chiral centre atome with inforamtion of atome wieght of each atome R>>Rectus >>Descent of the atomic numbers in Clokwise manner. S>> Sinster >> Descent of atomic numbers of the atoms in rotating groups in anticlockwise manner. Optical S. Isomers has the same pharmaco -chemical property, color , density ,and boiling point , but differs reactivity when binding to receptors.

Bupivacaine :

Bupivacaine No topical effect Slower onset and one of longer duration agents Unique property of sensory and motor dissociation can provide sensory analgesia with minimal motor block has been popular drug for analgesia during labor More cardio toxic than other LA

Bupivacaine (Marcain):

Bupivacaine ( Marcain ) N N O N N O S Bupivacaine R Bupivacaine * * Enantiomer : levo-bupivacaine , Chirocaine Equipotent, but less cardiotoxic than bupivacaine

Levo- Bupiovacaine:

Levo- Bupiovacaine S - enantiomer  of  bupivacaine . [ S - enantiomer  of  bupivacaine . [

Levo- Bupiovacaine:

Levo- Bupiovacaine Compared to bupivacaine , levobupivacaine is associated with less vasodilation , and has a longer duration of action. It is approximately 13 percent less potent (by molarity ) than racemic bupivacaine and has a longer   motor block   onset time & Dose : same like Bupivacaine . Bioavailability n/a Metabolism : Hepatic Half-life : 2–2.6 hours Excretion : Renal  70%,  faecal  24% Main Adv.: Less Cardiotoxicity .

What is Ropivacaine? :

What is Ropivacaine? Ropivacaine is a long-acting, local anesthetic with both anesthetic and analgesic effects. At high doses it produces surgical anesthesia and at lower doses it produces analgesia (sensory block) with limited motor block. 0.75% is indicated for surgical anesthesia 0.2% is indicated for postoperative pain relief .

ROPIVACAINE :

ROPIVACAINE No topical effectiveness Enantiomer of propivacaine ( S- stereoisomer ) Structurally very similar to Bupivacaine Clinically ~ equivalent to Bupivacaine as bupivacaine with significantly less CV toxicity.

PHARMACOLOGY OF ROPIVACAINE :

PHARMACOLOGY OF ROPIVACAINE Ropivacaine is less lipid soluble Less penetration in nerve fibers Less motor block Early mobilization Early recovery

PHARMACOLOGY OF ROPIVACAINE :

PHARMACOLOGY OF ROPIVACAINE Cardio toxicity Less toxic effects to CVS Does not cause arrhythmias Does not cause ECG Changes Neurotoxicity Less toxic effects to CNS Ropivacaine will not cause seizures, convulsions Visual and hearing disturbances, paraesthesia rarely

Ropivacaine (Narobin)®:

N N O * Ropivacaine (Narobin) ® N N O * Only available as pure S isomer Causes vasoconstriction Less motor block than Bupivacaine Otherwise, Equipotent Anesthesia. But, less cardiotoxic S bupivacaine

Liposomes Delivery system :

Liposomes Delivery system Developed to prolong duration of LA . Administration of a durable LA without need of adjuvant drugs, nerve sheath catheter, or infusion pumps. Liposomes are microscopic lipid vesicles ranging from 0.02 to 40 um. Created from amphipathic lipid molecule, with polar , hydrophilic head , and a hydrophopic , hydrocarbone tail . When they are in aqueous media .. Vesicle formed , with a central aqueous component surrounded with a Bifat layer 47

EXPAREL ( How Supplied ) http://www.exparel.com/how-to-use/dosing.shtml :

EXPAREL ( How Supplied ) http://www.exparel.com/how-to-use/dosing.shtml EXPAREL (bupivacaine liposome injectable suspension) is available in single-use vials for local administration 20 mL vial, 1.3% (13.3 mg/mL) packaged in cartons of 10 (NDC 65250-266-20) Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of bupivacaine to EXPAREL. 1

Liposomal Bupivacaine :

Liposomal Bupivacaine Bupisomes , Large Multivesicular Vesicles remote loaded with LA Bupivacaine by ammonium sulfate gradient , achieving high level of drug encapsulation , and having high drug /lipid mole ratio ( > 1.5 ) . Bupisomes encapsulated in hydrogel breaded of alginate form >>> Bupigel . Bupisomes and bupigel formulation tested in vivo can be defined as ULAL , showing prologed analgesia when compared with free Bupivacaine . Bupigel not affect nerve conductivity , no residual nerve injury ( on animal study ) . 51

What is Achieved so far , Liposomal Bupivacaine :

What is Achieved so far , Liposomal Bupivacaine ULAL acting for at least two or three consecutive days. Blood levels below threshold for toxicity. Stable product with highest depot of LA drug substance. High drug (LA) payload combined with slow and prolonged release profile greater than 2% encapsulated drug . Neural block efficacy. Lack of irreversible toxicity. Common approved pharmaceutical ingredients. Cost of Ampoule less than 50 USD /Unit. Final sterilization to support aseptic production in process. 53

What the real future of liposomal Bupivacaine?:

What the real future of liposomal Bupivacaine? Prof. Dr. Professor Henrik Kehlet. Father of the perioperative medicine. and Enhanced Recovery after surgery in 1 st Pan Arab ERAS , and Professor Dr. Nick Scott .HOD Anesthesia Hamad Medical Institute in Qatar.

Prof. Dr. Henrik Kehlet.:

Prof. Dr. Henrik Kehlet. It is very Expensive medicine around 280 $\Ampoule.( about Exparel ). There is no enough independent ( truthable ) studies till us it is safe –non toxic – in humans. Yes , it approved in USA .but not yet in Europe ,and I do not think so. May be successful in limited areas in bile surgery for ex. ,but not in knee surgery nor abdominal.

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