Local Anesthetics Flashcards
Describe the general structure of local anesthetics, and key chemical properties of the structures.
Structure: tripartite structure with
1) . Lipophilic aromatic portion: allows the local anesthetic to travel through the plasma membrane.
2) . Intermediate alkyl chain ==> ester or amide moiety (determines side effects & metabolism)
3) . Hydrophilic amine portion: area that can become a cation and therefore bind to the Na channel.
Describe the structural and chemical differences between amide and ester local anesthetics.
Amide anesthetics are significantly bound by the plasma protein α1-acid glycoprotein
•these have a LONGER duration of action than do ester local anesthetics.
•Amides can only be metabolized by the liver- Do not use these kind in liver-failure pts.! Also, can be more toxic because lots of things are broken down by the liver
Esters are primarily hydrolyzed by an esterase (cholinesterase).
Describe the role of pH in determining the effectiveness of local anesthetics.
Local anesthetics are weak bases with pKa values of 7.7 to 9.0 that are partially ionized at pH 7.4:
•Rapid protonation/deprotonation reaction at the N of the amino group so that local anesthetic molecules rapidly interconvert between positively charged and neutral.
•At pH 7.4: more drug molecules are in the charged form than neutral one
Charged form = binds to the local anesthetic binding site
Neutral form = can cross the plasma membrane to reach its site of action
•Tissue acidity decreases the amount of neutral local anesthetic present and requires applied dose to be increased.
Describe the molecular target and structure-based mechanism of action of local anesthetics.
Binding Site for local anesthetic: in a wide region of the water-filled pore of the Na+ channel.
- Ion conduction pathway of the channel is too narrow for the drug to reach its binding site via the extracellular entrance to the channel.
- Main route: when the channel is open and Na ions are rushing in (fast).
- Alternative route: partition into the plasma membrane and cross over to the intracellular compartment due to membrane solubility (slow).
Form that binds: the cationic form
Describe physicochemical properties of local anesthetics that determine potency, onset and of drug action.
- Low potency: procaine
- Medium potency: lidocaine
- High potency: bupivacaine, etidocaine
Potency determined by lipid solubility. Larger the percentage of anesthetic bound to protein, the longer the duration of action. Lower pKa = more rapid onset time
Describe methods of local anesthetic application.
Topical Infiltration (injection) Nerve block Intravenous regional (Bier's block) Spinal anesthesia Epidural
Describe the rationale for use of a vasoconstrictor with a local anesthetic
Co-utilization of a vasoconstrictor: the vasoconstrictor prolongs the duration of conduction blockade by reducing blood flow in the vicinity of the injection to retard systemic absorption of the anesthetic.
- Epinephrine is usually used.
- Prevents plasma anesthetic levels from rising to potentially toxic levels.
- Cocaine is the only anesthetic that you do not need a vasoconstrictor with.
Describe side effects of local anesthetics (overdose)
- Convulsions via action on inhibitory interneurons of the CNS (they cross blood-brain barrier).
- Interfere with autonomic nervous system function (why use epinephrine).
- Act on the heart in a pro-arrhythmic method – especially bupivacaine.
- Vascular smooth muscle actions – significant arteriolar dilation
- Fetal damage
- Inhibit neuromuscular transmission – block nicotinic Ach receptors.
- Allergy
Describe how local anesthetics differ in action from tetrodotoxin and saxitoxin.
Two most potents toxins known: tetrodoxin + saxitoxin
- Both act to bind and block the extracellular entrance of voltage-gated Na+ channels.
- Na channels in nerve and muscle have nanomolar affinity for these 2 toxins
- people die from paralyzed respiratory muscles, not heart.
- Cardiac Na channels exhibit micromolar affinity