Pharmacology of local anestnetics.txt

• Local anesthetics are drugs that reversibly block nerve conduction when applied locally to nerve tissue
• In the clinical situation, local control of function progresses without loss of consciousness, and central control of vital function is not impaired

first pain and temperature - +++ sensitivity to block

Second pain and temperature ++++ sensitivity to block

• plays a role in onset and duration of anesthesia
• less myelination - faster onset and shorter-lasting

• Esters
• Amides
• hydrophobicity and pH sensitivity - affect action

will have a wider distribution - so shorter onset

• Local anesthetics act at the cell membrane to prevent generation and conduction of nerve impulses
• They do this by decreasing or preventing the large transient increase in permeability of excitable membranes to Na+ that normally is produced by slight depolarization of the membrane

• they work in cationic form
• wok on the lumenal side of the membrane
• for action local anesthetic has to penetrate through membrane (unprotonated form)
• be protonated, and then acts on Na+ channels
• therefore, need to have some hydrophobicity

• Resting conformation
• open conformation
• Inactivated conformation
• LA: has a preference for closed, open, and inactivated conformations, but NOT for resting conformation

• small diameter fibers are more sensitive to local anesthetic than large diameter fibers
• Smaller fibers are characterized by smaller internal distances
• Sensory susceptibilité: pain < cold < warmth < touch < pressure
• the radius of fiber reflects the # of nodes of rangier and # of spaces between the nodes (Na+ channels exist there)

• Local anesthetic action is terminated by systemic absorption followed by metabolism
• Ester-type: hydrolysis in plasma and liver
• Amide-type: metabolized in liver (hepatic microsomal enzymes)
• Action is prolonged by addition of epinephrine: its vasoconsrictive properties localize the local anesthetic at the site of injection
• Localization prolongs duration at site, diminishes systemic absorption and thereby diminishes toxicity
• Contraindicated for surgery of extremities - tissue necrosis!

• CNS: dose-dependent response; initial stimulation, leading to restlessness, tremors, and eventually convulsions; toxicity parallels anesthetic potency
• Cardiovascular system: Myocardium (decreased electrical excitability, contractile force, conduction rate) arteriolar dilatation - reduction in b.p. and can get a reflex increase in blood pressure

• sprays and ointments
• Skin: OTC sprays/ointments for sunburn (Benzocaine)
• Mucous membranes: nose, mouth, throat, tracheobronchial tree, genitourinary tract
• 1. Duration: 30-45 mins
• 2. Superficial anesthesia
• 3. Rapid absorption into circulation presents most serious risk of systemic toxicity. Toxicity parallels potency
• 4. Cocaine, tetracaine, lidocaine, but not procaine

• intradermal injection in immediate are oaf terminal nerve endings (no attempt to locate specific nerves)
• Localized surgical procedure: biopsies, orthopedic surgery
• Lidocaine; procaine: duration 45-60 minutes
• Epinephrine serves to diminish systemic absorption
• But, avoid use of epinephrine in digits

• Injection into region of peripheral nerve or nerve nexus for surgical procedures distal to site of deposition
• Sensory and motor functions are affected
• Onset depends on pKa and drug diffusion
• Duration: depends on lipid solubility and tissue binding
• Of use in dentistry and orthopedic surgery

• the anesthetic agent is deposited from a syringe and needle as close to the target nerve as possible
• Several injections are often made if the landmarks for the location of the nerve are not outstanding

Injection into lumbar subarachnoid space with intent to block somatic sensory and somatic motor fibers

concomitant block of preganglionic sympathetic fibers results in sympathetic denervation

• depends on volume injected, specific gravity of the solution, and patient posture
• sacral > lumbar > thoracic

• venous drainage (there is no esterase activity in CSF)
• Vasoconstrictors increase duration

• Autonomic - blocked first
• Sensations
• Somatic motor functions

• Sympathetic blockade results in diminished cardiac output and diminished blood pressure: decreased sympathetic tone -> decreased CO and decreased BP
• Minor: dilatation of arteries and arterioles leads to diminished peripheral vascular resistance and blood pressure
• Major: diminished venous tone leads to diminished cardiac output and diminished blood pressure -> decreased venous return --> decreased CO and BP; CO falls and may require intervention
• Maintenance of adequate venous return is essential: compression (stockings in lower extremities); addition of phenylephrine
• Local anesthetics exert only minimal effects on respiratory function; hepatic function is normal

• Headache - incidence is related to loss of CSF and the resulting fall in CSF pressure: a postural phenomenon
• Procaine, lidocaine, and tetracaine: are NOT neurotoxic!

• Greatest value: surgical procedures of lower abdomen and extremities
• Advantages: shorter post-operative period; muscle relaxation can be achieved
• Contraindicated: in patients with progressive disease of spinal cord; long procedures

• injection of local anesthetics into epidural space; produces regional nerve block that is more limited than with spinal anesthesia
• Two sites of action: the drug diffuses into 1. subarachnoid space - acts on nerve roots and spinal cord. 2. paravertebral areas.

• slower in onset; longer duration
• requires greater amounts of anesthetic - so systemic toxicity is higher, but neurological effects less, b/c don't have it spreading in the subarachnoid tissue
• systemic complications arise from absorption of high drug concentrations into circulation
• less neurological complications

• enantiomeric agents
• liposomes
• microspheres
• specific blockers of Na+ channel subtypes