Newer local anaesthetics

(Ropivacaine, Levobupivacaine,Proparacaine)

Presenter-Dr Surabhi Gupta

Moderator- Dr Bharti Taneja
 History of LA
Cocaine isolated 1856
1884 cocaine used in occular surgery
1880’s Regional anesthesia plexus
1898 cocaine used in spinal anesthesia
1905 1st synthetic LA (procaine) introduced
1943 lidocaine synthesized
Mepivacaine (1957), Bupiv (’63), Ropiv (’96)
 Why the need for newer LA:
shortcomings in the
conventionally used LA
Slower onset
Lesser safety index
CNS and CVS Toxicity
Need for differential block in certain situations
Special situations; cardiac patient
 Newer LA
Ropivacaine
Levo bupivacaine
Proparacaine
EMLA (lignocaine and prilocaine)
 Let us compare…..
Between older drug – Bupivacaine and the newer drugs

 Ropivacaine and Levobupivacaine

 STRUCTURE
 Family of N-alkylsubstituted pipecoloxylidide
 BUPIVACAINE has a butyl grp at amino terminal
more lipophillic and more potent..Same is the case with levo-
bupivacaine
 ROPIVACAINE has a propyl grp less lipophillic and less
potent
highly lipid soluble, chiral centre – piperidine grp
Lipophilicity accounts for potency of the drugs..
 contd…..
Potency – ropivacaine< bupivacaine and levobupivacaine….
 Physiochemical & Pharmacokinetic

Activity of local anesthetics is a function of their

• Lipid solubility,
• Diffusibility,
• Affinity for protein binding,
• Percent ionization at physiologic pH
• Vasodilating properties
Physiochemical & Pharmacokinetic
Bupivacaine Levobupivacaine Ropivacaine

Molecular wt 288 274 288

Pka 8.1 8.1 8.1

Protein binding 95% >97% 94%

Lipid Solubility 30 30 2.8

Vol of Distribution (lt) 73 55 59

Clearance (lt/min) 0.58 0.32 0.72

Elimination T1/2 (min) 210 156 108

All have slow onset with duration of 4-8 hours

 pH & pKa
pH of the tissue determines the ratio of ionized to non-ionized drug.
This ratio depends on the pKa of the drug.
Ionization determines onset, duration and pharmacodynamics of LA
Henderson Hasselbalch equation:   pKa - pH= log_ionized
 non-ionized

pKa equals the pH where the ionized and non-ionized forms are at
equilibrium. In other words, 50% of each form is present.
Local anesthetics are weak bases
At physiological pH, more in ionized form
Explains the action of bicarbonisation for increasing the onset of
action
Contd…
• pH acidic in conditions of infection or inflammation.
• Results in a greater proportion of the ionized (charged) form of the
anaesthetic,
• Delayed onset or inadequate action.
• For example, if lidocaine (pKa 7.9) is administered into an area of
infection (pH 4.9) emanating from a dental abscess, then:
7.9 - 4.9 = log [ionized/non-ionized]
103 = ionized/non-ionized           
The resulting ratio of 1,000:1 ionized to non-ionized indicates a poorer
penetration into the nerve tissue and therefore a less effective nerve
block
 Lipid solubility
Lipid solubility is an important characteristic. Potency is related
to lipid solubility, because 90% of the nerve cell membrane is
composed of lipid. This improve transit into the cell membrane
Consequent to a low lipid solubility (2.8), Ropivacaine has a slow
onset of action
 Protein binding
Protein binding implies the duration of action of the drug. The
site of action (the Na channel) is primarily protein in a lipid
environment. Binding affinity will thus affect duration of action.
Higher protein binding less free fraction thus reduced
metabolism and longer duration of action
Protein binding also plays a part in the availability of the drug as
LA binds to lipoproteins in the blood stream
More free fraction greater toxicity
 levobupivacaine (>97%) has the longest duration of action of
the three drugs
 Contd………
Highly plasma protein bound drug will stay in plasma and less
will go to tissues thereby less volume of distribution – hence
larger dose will be required to attain the adequate plasma
concentration- as in the case with levobupivacaine among the
three drugs.
Plasma protein binding will then decrease the toxicity of drug as
less will go to the tissues..
Higher clearance and lower elimination T 1/2 implies to earlier
removal of the drug from the circulation as seen with
ropivacaine….hence less of the systemic toxicity..
 Metabolism
 Amino amide – microsomal degradation (Liver)
 More complex & slower than amino ester group
- ↑ systemic toxicity & cumulative effect

BUPIVACAINE Ropivacaine

• > 40 % excreted via kidney only 1 % excreted unchanged in urine

• N- desbutylbupivacaine 2,6 propylcoloxylidide & 3 hydroxy ropivacaine

 HENCE clearance is higher and elimination half life

shorter for ropivacaine as compared to bupivacaine,
therefore it has lesser systemic toxicity.
 So, what do these tables mean?
Ropivacaine is less potent of the three
Bupivacaine requires lesser dose for the adequate effect
Levobupivacaine has longest duration of action
Ropivacaine has the least systemic toxicity
CLINICAL APPLICATION
 Surgical anaesthesia
 Epidural blocks for surgery,including caesarian section
 Intrathecal(spinal)block
 Major nerve blocks
 Field blocks
 Acute pain management
 Labor analgesia
 Caudal analgesia
 Topical
 Local infiltration
 Clinical Application
(comparison)
Infiltration Anesthesia

Bupivacaine Levobupivacaine Ropivacaine

Concentration (%) 0.25 – 0.5 0.25 0.2 - 0.5
Max dose (mg)
175/200 150/200 200/250
(plain/with adr)
Duration (hr)
2-4/3-4 2-4/3-4 2-4/3-4
(plain/with adr)

Doses- bupivacaine 3 mg /kg

levobupivacaine 3 mg/kg
ropivacaine 4 mg/kg
Contd..
Minor Block
Bupivacaine Levobupivacaine Ropivacaine

Concentration (%) 0.25 – 0.5 0.25 – 0.5 0.2 – 0.5

Volume (ml) 5-20 5-20 5-20
Dosage (mg) 12.5 – 100 10 – 100 12.5 – 100
Duration
3-6/4-7 3-6/4-7 3-6/4-7
(plain/with adr)

Major Nerve Blocks

 Similar Volume – 30 -50 ml
 Similar Onset – 20-30 mins
 Similar Duration – 6-9 hrs
 except fpr max dose which is ropivacaine (250mg) & other (225 mg)
 Contd..
Epidural Anesthesia
Similar Volume (15-30 ml)
Similar Onset (15-20 mins)
Similar Duration (3-6 hours)
Similar total dose (40-225 mg)

Spinal Anesthesia
 Similar Volume (0.5 % 3-4ml) & (0.75% 2-3ml)
 Similar Dose (15-20 mg)
 Similar Duration (90-200 min)
 Special considerations
Ropivacaine is 2-3 times less lipid soluble and has a smaller
volume of distribution, greater clearance, and shorter
elimination half-life than bupivacaine in humans. The two drugs
have a similar pKa and plasma protein binding
Epinephrine does not prolong the duration of ropivacaine block.
The addition of epinephrine does not prolong the duration of
ropivacaine in subclavian brachial plexus or epidural block. Low
concentrations of ropivaciane may produce clinically significant
vasoconstriction, which is not increased further by the addition of
epinephrine
 Contd…
Ropivacaine is slightly less potent than bupivacaine.
When used for spinal anesthesia, 0.75% ropivacaine
produces less intense sensory and motor block than 0.5%
bupivacaine. However, multiple clinical trials comparing the
two local anesthetics in epidural and axillary block
demonstrate similar potency of bupivacaine and ropivacaine
with respect to the intensity of sensory anesthesia
 CONTRAINDICATION
Not recommended for emergency situations where a fast onset
of surgical anesthesia is necessary
IVRA
Avoid injections in inflamed areas
Hypovolemia,hypotension
Intravenous use
SYSTEMIC TOXICITY
 Central Nervous System
 Sign & Symptoms
 Light Headedness
 Dizziness
 Visual & auditory disturbance (difficulity focusing & tinitus)
 Shivering
 Muscular twitching & tremors → GTCS
 Respiratory depression ( terminated by small doses of i.v
benzodiazepines or small dose of i.v thiopentone)
Bupivacaine > Levobupivacaine & Ropivacaine
(racemic mixture) ( left isomers)
 Contd..
 CARDIOVASCULAR TOXICITY
 Depress myocardium but stimulate sympathetic system – often can
be overlooked
 ↑ PR interval & QRS duration & QTc Prolongation
 Negative ionotropic effect
 ↓ Myocardial Contractility proptional to lipid solubility & nerve
blocking potency of LA
Bupivacaine > Levobupivacaine > Ropivacaine
 MYOTOXICITY
The long term myotoxic effects of bupivacaine and
ropivacaine after continuous peripheral nerve blocks

IMPLICATIONS: In a period of 4 wk after peripheral nerve block, both

long-acting local anesthetics, bupivacaine and ropivacaine, produced
calcific myonecrosis suggestive of irreversible skeletal muscle damage.
In comparison with ropivacaine, however, the extent of bupivacaine-
induced muscle lesions was significantly larger.

 Anesth Analg. 2005 Aug;101(2):548-54

 Treatment of toxicity
Identify the problem
signs and symptoms
temporal relationship
IV injection
40-60 min post for peak plasmalevels

CNS
treatment with benzodiazepines
 Contd…
With CVS toxicity
The agent is an important consideration
bretyllium and
lipid rescue- intralipids , lipid infusion may create plasma lipid droplets capable of
segregating uncharged bupivacaine molecules from plasma, which makes them unavailable
for interaction at their target sites.
 act on nitric oxide pathways and reverse bupivacaine’s inhibitory
effects.
Rapid bolus of 20% intra lipid
Dose 1.5 ml/kg or 100 ml in adults
f/b infusion of 0.25 ml/kg/min for the next 10 min.
 Contd….
When there is CVS collapse
A B C’s
defibrillation
Epinephrine
Vasopressin
Lidocaine
Bretylium
Amiodarone
Intra lipids
 New and not-so new Developments in
Local Anesthetics
Liposomal encapsulated local anesthetics
Ionotophoresis
 Tumescent Anesthesia
TAC patch
EMLA
Proparacaine
 TAC ( topical L.A. )
Tetracaine, Adrenaline (Epinephrine), and Cocaine
Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent
tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent
cocaine
first topical anesthetic mixture found to be effective for nonmucosal
skin lacerations to the face and scalp.
 From 2 to 5 mL of solution is applied directly to the wound using a
cotton-tipped applicator with firm pressure that is maintained for 20
to 40 minutes.
However, the use of TAC is no longer supported by the literature
because of general concern about toxicity and expense, and federal
regulatory issues involving medications containing cocaine.
 COMMERCIALLY available as
TAC
constitute of-tetracaine 0.5% epi 1 in 2000
cocaine 10%
Application into wound
Max Dose for kids 0.05ml/Kg
Toxicity due to cocaine
 Technique of iontophoresis
charged ions of drug are driven across the epidermis by
applying a direct electric current
When an electrical potential difference is established, ions of
the drug migrate across the skin, and the dose delivered is
therefore a product of the magnitude and duration of
current
allows us to deliver drugs to the skin without the trauma
associated with intradermal injection
Therapeutic iontophoresis devices typically use a current of
2±4 mA
 Mechanism of action
Repulsive electromotive force cause transdermal migration of
medication using a small electrical charge
An iontophoretic chamber contains a similarly charged active
agent and its vehicle.
One or two chambers are filled with a solution containing an
active ingredient and its solvent, also called the vehicle.
The anode will repel a positively charged chemical, whereas the
cathode will repel a negatively charged chemical into the skin.
 LA IONTOPHORESIS
Lidocaine-soaked sponges are applied to intact skin, and electrodes
are placed on top of the anesthetic.
 A DC current is then applied to the skin.The anesthetic effect occurs
within 10 minutes and lasts approximately 15 minutes.
 The depth of anesthesia can reach up to 1 to 2 cm.
 Iontophoresis vs EMLA
Although the effectiveness of iontophoresis has been compared
favorably to that of EMLA, it remains underused.
Some patients find the mild electrical sensation uncomfortable.
The apparatus is expensive and bulky, and cannot be used over large
surface areas of the body.
Other applications using iontophoresis are still being developed
 LIPOSOMAL DRUGS
Liposomes are comprised of lipid layers surrounded by aqueous
layers. They are able to penetrate the stratum corneum because
they resemble the lipid bilayers of the cell membrane.
vary in size from 0.3-10microns
Drug can be incorporated either in the aqueous or lipid layer
Often act as barrier to drug diffusion
Act as a slow release preparation with prolonged action
MECHANISM - gradual erosion or reorganization of the lipid membranes
 Contd .....
The liposome-encapsulated formulation protects the
anaesthetic from being metabolized too quickly
Thus, prolonged action
Increased lipophilicity
Thus, It has short onset of action
Minimal vasoactive properties that minimize any potential
interference with cannulation success
Not associated with methemoglobinemia.
 ELA-MAX
4 percent lidocaine cream in a liposomal matrix
 FDA-approved for the temporary relief of pain resulting from minor
cuts and abrasions.
ELA-Max is applied to intact skin for 15 to 40 minutes without
occlusion.
ELA-Max has also proved effective in providing dermal analgesia
before chemical peeling.
The safety of its application to mucous membranes has not been
evaluated.
 Liposomal Bupivacaine
A Novel Formulation to Produce Ultralong-Acting Analgesia –( a
favorable drug-to-phospholipid ratio and prolonged the duration of
bupivacaine analgesia in a dose-dependent manner. )
The median duration of analgesia with 0.5% standard bupivacaine
was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0%
liposomal bupivacaine were 19, 38, and 48 h, respectively.
 EMLA
Eutectic mixture of 2.5%lignocaine and 2.5%prilocaine along
with carboxy polymethylene (thickening agent)and sodium
hydroxide ( to adjust pH )
(Most pure anesthetic agents exist as solids. Eutectic mixtures are
liquids and melt at lower temperatures than any of their
components, permitting higher concentrations of anesthetics. )
Mechanism of action-when applied to intact skin under
occlusive dressing it provides dermal analgesia by acting on
dermal pain receptors and nerve endings thereby inhibiting
the ionic fluxes required for initiation and conduction of
impulse
 Pharmacokinetics
 Volume of distribution more woth lignocaine
 Plasma protien binding more with lignocaine
 Crosses blood brain barrier and placental barrier
 Metabolized in liver and kidney
 Elimination half life-1.5 hrs(adult) 2.5hrs(elderly)
 Absorption – 1 to 3 hrs through intact skin
5 to 10 min. through mucosa
 dose – 2.5 gm over 20 to 25 sq.cm.
to 2 gm per 10 sq cm.
 CLINICAL APPLICATION
 Prior to i.v. cannulation
 Prior to skin graft harvesting
 In laser treatment of facial port wine stain in children
 Genital mucosa membranes for minor superficial
surgical procedure
 LIMITING FACTORS IN CLINICAL USE
Ineffective in presence of pus; thus, cannot be used for I & D.
Vasoconstriction: can make cannulation difficult.
Not suitable for use in infants less than 6 months.
 INTERACTION
 Local reaction
 Allergic phenomenon
 Carcinogenicity
 Meth-hemoglobinemia: specially in G6PD deficiency
antimalarials,sulfonamide.
 PROPARACAINE
Topical anaesthetic
Available as proparacaine hydrochloride
Sterile aqueous ophthalmic solution
Each ml = proparacaine hydrochloride 0.5%
benzalkonium chloride 0.01%
Stored at 2 -8 degree celsius
To be discarded if darker than pale yellow
 MECHANISM OF ACTION
Acts on nerve cell membrane
Interferes with transient increase in membrane permeability to
sodium ions
Hence prevents fundamental change necessary for generation
of action potential
Onset -30 sec.
Duration of action- few minutes
 INDICATIONS
 Tonometry
 Removal of foreign bodies in cornea
 Removal of corneal sutures
 Gonioscopy
 Conjunctival scraping for diagnosis
 Cataract extraction
 SIDE EFFECTS
 Pupillary dilatation
 Hyperallergic corneal reaction
 Iritis
 Epithelial keratitis
 Allergic contact dermatitis
 Erosion of corneal epithelium
 Conjunctival congestion and heamorrhage
 Tumescent anesthesia
Jeffery Klein, 1987
anesthesia in liposuction
use of dilute solutions of lidocaine (0.05-0.1%) in large volumes to
provide superior anesthesia.
Epinephrine (1:1,000,000) is added for hemostasis, and the solution is
buffered with sodium bicarbonate to decrease injection discomfort.
Concentrations as high as 55 mg/kg have been used safely with the
tumescent technique.
Subcutaneous injection of large volumes of dilute L.A.
Total dose- 35 – 55 mg/kg
May peak more than 8 to 12 hrs after infusion
Contd…
• high total doses of anesthetic without systemic
toxicity ???
The absorption kinetics of lidocaine change with
high-volume, low-concentration solutions.
Decreased concentrations of lidocaine result in
slower plasma absorption with decreased peak
plasma levels.
The development of this anesthetic delivery
system has revolutionized the surgical
technique of liposuction.
THANK
YOU