Lecture nites

COMMON LOCAL ANESTHETICS CLASS ESTERS: Benzoic acid esters

EXAMPLES COCAINE

INDICATION M.O.A Rarely used now, occasionally for ENT surgeries controlled drug, can cause addiction, and toxicity, 1884 Rapid penetration of mucous membrane, effective surface anesthetic, and never given by injection **Current status - drug of abuse ‘crack’

ESTERS: PABA esters

*Except tetracaine, esters are of lesser potency and shorter duration of action than amides.

AMIDES

PROCAINE Low potency (short DOA)

BENZOCAINE

LIGNOCAINE LIDOCAINE Intermediate potency

BUPIVACAINE High potency

ROPIVACAINE

Miscellaneous LA

OXYBUPROCAINE PROPARACAINE ETIDOCAINE

MEPIVACAINE Intermediate potency

PABA – ester type, not absorbed through mucous membrane (no topical use) Short duration (hydrolyzed by plasma Cholinesterase), slow onset, low potency Tends to depress respiration than CVS Interfere with antibacterial action of sulfonamides Ester type, hydrolyzed into PABA, low potency, nonirritant surface LA Compound benzocaine lozenges (100mg) used for: (1) taking dental impression (2) passing bronchoscope and laryngoscope in conscious patient (3) relieving pain of oral aphthous ulcer, acute pharyngitis, laceration, oral cancer Direct application as dusting powder, insufflations, oily solution Most widely used LA, 1948 LA & membrane stability→ Class 1B antiarrhythmic. Used in Ventricular arrhythmias. Rapid onset & Intermediate duration Vasoconstrictor may be added to enhance duration of action( Adrenaline 1:200,000) Absorbed through intact skin when mixed with Prilocaine (EMLA cream) Widely used amide type LA, takes 30 min for full effect, 1963, LEVOBUPIVACAINE, 2000 Potent prolonged LA, up to 8 hours, more sensory than motor block Suitable for continuous epidural analgesia during labor and for post-op pain Used for spinal anesthesia, infiltration, nerve & plexus blocks. Similar to bupivacaine, but less cardio-toxic and less potent; suitable for both epidural and regional LA. Now preferred for long term usage. for eye long acting amino-amide, fast onset, long duration like bupivacaine, more motor blockade useful for intense muscle skeletal muscle relaxation Intermediate acting, toxic to neonate (ion trapping in lower pH of fetal blood), not effective as topical agent.

SIDE EFFECTS Intense vasoconstriction (S.E. = corneal sloughing) CNS stimulation, convulsion, death Increases heart rate, body temperature Allergy is common; otherwise, safe and least toxic

Cardio toxic (VA, myocardial depression)- very difficult to treat

DEFINATION

• •

A local anesthetic is a drug that can reversibly interrupt the initiation and propagation of electrical impulses in nerve conduction. There is analgesia(sensory loss), muscle relaxation(motor loss), loss of Autonomic function ( sympathetic Vasoconstrictor fibers)

SITE OF ACTION

*Pain Awareness (nociception)  Nerve ending receptors  Primary afferent fibers  Secondary afferent fibers  Brain

MODE OF ACTION

*LA effectively and reversibly block impulse conduction along nerve axons and other excitable membranes that use sodium channels as the primary means of action potential generation, eg, cardiac muscle. *LA Bind reversibly to a specific receptor site within the pore of the Na+ channels (in the cytoplasmic inner part of the receptors) in nerves and block ion movement through this pore.

CHARACTERS

• • •

Local anesthetics are weak bases. In the body, they exist either as the uncharged base or as charged cation. The relative proportions of these two forms are governed by their pKa and the pH of the body fluids.

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By definition, the pKa of a molecule represents the pH at which 50% of the molecules exist in the uncharged and 50% in the charged form. The pKa of all local anesthetics is >7.4 Uncharged form penetrates the nerve sheath. Charged form is the active components which blocks the Na+ channels

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• •

ORDER OF NERVE FIBRE BLOCK

LA uses

• • I. II. III. IV. V. VI. • • • • • •

In an ACID ENVIRONMENT (infection, shock) more of ionized (charged) form is available, making LA ineffective and difficult to penetrate the nerve sheath. In an ALKALINE ENVIRONMENT, more LA is unionized (uncharged), makes the drug more effective. pH of LA -3.3-6.8 Adding NaHCO3 →↑tissue pH- shortens onset of action This sodium channel blockade first affects the smaller nerve fibers reduction in pain and temperature sensation Followed by loss of touch, deep pressure sensation. Motor function (largest nerve fibers) are last to go. The A delta (sharp pain) fibers are blocked before the C fibers (dull pain). Fiber position- proximal fibers outside, thus blocked first Anesthesia–Dentistry, Eye &ENT, Shoulder & arm, Heart &Lung ( with GA),Obstetric & Gynae, Bone & joint, Abdominal Painless procedures- venipuncture, ascites drainage, amniocentesis,cystoscopy, bronchoscopy Acute pain relief - Labor pain Antiarrhythmic To reduce ICP, reduce tracheal and laryngeal reflexes for ET intubation To treat Chronic pain

RATE OF ABSORPTION

determined by: 1. Presence or absence of vasoconstrictor: enhances duration and maximum safe dose – Add. Epinephrine/ felypressin 2. Site of administration: speed of absorption: intercostal > caudal canal > epidural > brachial plexus 3. Chemical properties of the drug 4. Vascularity of the area

DISTRIBUTION High protein binding (55-90%) mainly to α1 acid glycoprotein, widely distributed, readily cross the BBB METABOLISM

TERMINATION OF ACTION

Metabolism (prilo> lido> mepi> ropi> bupi> levobupi) • Ester type LAs are hydrolyzed by plasma cholinesterase (no enzyme in CSF), except cocaine • Amide type LAs are metabolized by liver amidases, by N-dealkylation and hydrolysis • Metabolites of Prilocaine (o-toluidine derivatives), which accumulate after large doses of drug (> 10 mg/kg), convert hemoglobin to meth haemoglobin. • •

LA EFFECTS

LA TOXICITY

METHODS OF ADMIN

Treatment of systemic local anesthetic toxicity (LAST)

Local anesthetic action terminates by absorption into circulation, and metabolism in plasma or liver. Water soluble metabolites excreted in urine.

CNS EFFECTS: Readily cross BBB; effects related to plasma concentration Low conc: Sedation, depress brain excitability (anticonvulsant), lightheadedness, dizziness, tinnitus, drowsiness, altered taste Mod. conc: Slurred speech, shivering, muscular twitching High conc: Muscular twitching, convulsions, loss of consciousness, respiratory arrest, death SMOOTH MUSCLE , NMJ & GANGLION: Smooth Muscle – depress contraction in GIT, bronchi, blood vessels NMJ & Ganglion – reduce transmission CVE EFFECTS: *Dilate arterioles  reduce BP in high doses. (cocaine has opposite effect by blocking uptake of catecholamines) *↓ electrical excitability of myocardium (antiarrhythmic effect) *↓ force and rate of cardiac contraction *Sympathetic nerve blockade during spinal or epidural  ↓ venous tone  ↓ CO  ↓ BP ALLERGIC REACTIONS: • Ester-type LA are converted to PABA derivatives  allergic reactions • Rare with amide group • Hypersensitivity reactions ( procaine, benzocaine are metabolized to PABA) and meth hemoglobinemia • Systemic toxicity DUE TO OVERDOSAGE. • Systemic toxicity DUE TO ABNORMAL PSEUDOCHOLINESTERASE. • LA cross the placenta – cardiac depression in fetus • Topical anesthesia / Surface analgesia • Direct application of aqueous solution (amethocaine, lignocaine, cocaine) • Eutectic mixture (EMLA) of Lidocaine 2.5% and prilocaine 2.5% • Topical Lignocaine is used for post herpetic neuralgia. • Inhaled Lignocaine can act as an anti-tussive • GET HELP • Initial focus: seizure control (benzodiazepines) + Airway (ventilate with 100% O2. • ACLS: Manage Arrhythmias • LIPID EMULSION (20%) THERAPY

Drug

Ester/ Amide

Onset of action

Duration of action

Procaine

E

Slow

Short

Prilocaine

A

Fast

Mepivacaine

A

Bupivacaine

Clinical Use

Properties

Limited Diagnostic procedures

Vasodilation Allergenic

Moderate

IV Infiltration Peripheral Nn. blocks

Least toxic in amides MaethHb. at↑ doses

Fast

Moderate

Infiltration, Peripheral Nv. blocks

Versatile Mod. V. D

A

Moderate

Long

Infiltration Peripheral blocks Spinal & Epidural

Separation of sensory & motor blocks

Lignocaine

A

Fast

Moderate

All above + IVRA

Most versatile moderate V. D

Ropivacaine

A

Moderate

Long

Same as Bupivacaine

Less cardiac toxicity than Bupivacaine