Local Anesthetics

1. Local Anesthetics • Liming zhou (周黎明）Department of pharmacology • 2010,3

2. Introduction and history • Mechanisms of action • Pharmacokinetics • Pharmacological effects • Clinic use • Adverse effects • Common drugs

3. INTRODUCTION AND HISTORY Cocaine • is a naturally • occurring compound indigenous to the Andes Mountains, West Indies, and Java. • It was the first anesthetic to be discovered and is the only naturally occurring local anesthetic

4. INTRODUCTION AND HISTORY • many of cocaine's pharmacologic actions and adverse effects were elucidated in the latter half of the 1800s. • Koller introduced cocaine to the field of ophthalmology • Hall introduced it to dentistry. • Halsted was the first to report the use of cocaine for nerve blocks in the United States in 1885 and also became addicted to the drug.

5. INTRODUCTION AND HISTORY • Procaine, the first derivative of cocaine, was developed in 1898. • Lofgren developed lidocaine, the most widely used cocaine derivative, during World War II.

6. What is local anesthetics? • block transmission of impulses along nerves • short to medium duration of action (1-6 hrs) • useful for pain control • overdoses may cause convulsions

7. What is local anesthetics? • Applied in the vicinity of peripheral nerve ending or major nerve trunks • inhibits action potential generation and propagation • Prevent conduction of electrical impulses from the periphery to the CNS • Produce transient loss of sensory, motor, and autonomic function in a discrete portion of the body without producing unconsciousness

8. The structure of local anesthetics

9. The classification of local anesthetics Ester • Cocaine • Procaine • Tetracaine Amides • Lidocaine • Bupivicaine

10. All local anesthetics have an intermediate chain linking an amine on one end to an aromatic ring on the other • . • The amine end is hydrophilic, and the aromatic end is lipophilic. • Variation of the amine or aromatic ends changes the chemical activity of the drug.

11. Two basic classes of local anesthetics • The amino amides and the amino esters. • Amino amides have an amide link between the intermediate chain and the aromatic end • amino esters have an ester link between the intermediate chain and the aromatic end.

12. Amino esters and amino amides differ in several respects. • Amino esters are metabolized in the plasma via pseudocholinesterases, • Amino amides are metabolized in the liver. • Amino esters are unstable in solution, but amino amides are very stable in solution. • Amino esters are much more likely than amino amides to cause true allergic reactions

13. Pharmalogical effect 1 Local effect: • temporary loss of sensation in a confined region • reversible

14. adverse effects Systemic Toxicity(CNS Toxicity ) • Cause: excessively high plasma local anesthetic concentration • Manifestation: seizures • Treatment: diazepam

15. Effect of absorption • CNS system • exciting seizure Cardiovascular system • decrease the action of the heart

16. Mechanisms of action • Fig.

17. Mechanisms of action • Inhibiting excitation of nerve endings or blocking conduction in peripheral nerves. • Binding to and inactivating sodium channels.

18. Mechanisms of action • Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve. • when a nerve loses depolarization and capacity to propagate an impulse, the individual loses sensation in the area supplied by the nerve

19. block nerve fiber conduction by acting on nerve membranes • inhibit sodium ion activity • blocks depolarization--> blocks nerve conduction

20. Pharmacokinetics Absorption & Distribution: • Factors: Vascularity: • Highly vascular area (e.g. tracheal mucosa): promotes rapid absorption resulting in higher blood levels • Poorly vascular area (tendon) is associated with relatively poor absorption

21. Presence of vasoconstrictors (e.g. epinephrine) Reduced systemic absorption due to local vasoconstriction -- Increased neuronal uptake (higher local concentration) --Blood levels: reduced as much as 1/3

22. distribution factors • Rate of tissue distribution ·     Initial high uptake into lungs and redistribution to highly perfusion tissues (heart, kidney, brain) Following distribution to brain, kidney, heart-- redistribution to other tissues (less perfused)-- e.g. muscle, fat

23. The PH of local site    • Local anesthetics is weak bases (pKa8-9)  • the fluid pH is higher, rapid onset of action • the fluid pH is lower, decrease onset of action • (question is why?)

24. Clinical Uses Clinical Uses: • --Most frequent use: regional anesthesia • --Less common use:  Prevention & treatment of cardiac arrhythmias

25. Clinical Uses • Surface/topical anesthesia • Local infiltration • Peripheral nerve block •  Epidural anesthesia • Spinal anesthesia (subarachnoid)

27. Epidural anesthesia

28. Spinal anesthesia

29. Surface/topical anesthesia application to mucous membranes Location: •  Nose •  Mouth •  Esophagus •  Tracheobronchial tree •  Genitourinary tract Commonly used drugs: • Cocaine (4%-10%)

30. Local infiltration • Definition:Extravascular placement of the local anesthetic in the region to be anesthetized •  Most common: lidocaine

31. Peripheral Nerve Block Procedure:local anesthetic injection into tissues around individual nerves or nerve plexuses (e.g. brachial plexus) Most common drug: 0.5% bupivacaine

32. Epidural Anesthesia Definition Anesthesia caused by local anesthetic solutions injected into epidural Mechanisms  Direct action on nerve roots and spinal cord following local anesthetic diffusion across the dura

33. Spinal Anesthesia Definition • Anesthesia following local anesthetic injection into lumbar subarachnoid space Site of action: • Primary: preganglionic fibers leading the spinal cord in the anterior rami •  Secondary: superficial spinal cord layers

34. adverse effects Systemic Toxicity(CNS Toxicity ) • Cause: excessively high plasma local anesthetic concentration Manifestation: seizures Treatment: diazepam

35. adverse effects Allergic Reactions: • Rare occurrence -- < 1% of local anesthetic adverse reactions due to allergic mechanism Higher-risk: ester-type local anesthetics (those which are metabolized to p-aminobenzoic acid-related compounds)

36. Cross Sensitivity • May be due to common metabolite profile (p-aminobenzoic acid) • No cross sensitivity between ester vs. amide local anesthetic classes