Pharmacology I: Lecture 4b - LAs Flashcards
(42 cards)
Who first described the clinical use of cocaine as a local anesthetic?
Its first clinical use was described by Freud described in Uber Coca in 1884
Carl Koeller used cocaine as a topical anesthetic for cataract surgery
Freud described its use in his work ‘Uber Coca’.
What is a significant property of cocaine aside from its local anesthetic effects?
Blocks the reuptake of neurotransmitters: dopamine, serotonin, norepinephrine
Second most common abused illicit substance with 1.5 million adults in the US reporting recent use
Cocaine Overview
Local anesthetic and intense Vasoconstrictor (Cerebral and Cardiac)
Dopamine reuptake inhibitor and Na+ channel blocker
Euphoric high and increased energy
Modern Local Anesthetics
Reversibly blocks voltage gated sodium channels
Reversible interruption of nerve impulse propagation
Inhibition of cardiac ion channels, class 1B antiarrhythmic agent
Procaine (Novocaine) synthesized in 1905 (ester)
Long onset time, short duration and low potency
Breakthrough in 1940 with introduction of Lidocaine (Xylocaine)
amide
What was the breakthrough in local anesthetics introduced in 1940?
Lidocaine (Xylocaine)
What is the main mechanism of action of local anesthetics?
Reversibly block conduction along nerve fibers to prevent membrane depolarization
Local anesthetics are classified into which two main categories?
- Amino amides
- Amino esters
Structure of Local Anesthetics
Local Anesthetics classified as amino AMIDES or amnio ESTERS
Amides
Extremely stable
Enzymatic degradation in liver
Minimal allergy concern
Chiral centers consisting of racemic mixtures of stereoisomers
Bupivacaine cardiotoxic in R(+) leading to development of Ropivacaine
Esters
Unstable
Hydrolyzed in plasma by esterases
Allergy potential from metabolite p-aminobenzoic acid (PABA)
Amide vs Esters
Amides
Lidocaine
Bupivacaine
Mepivacaine
Ropivacaine
***Amides: “i” before “caine”
Esters
Cocaine
Procaine
Benzocaine
Tetracaine
Local Anesthetics DOA
Action of Local Anesthetics
Local Anesthetics are not effective in Acidic Environments (INFECTIONS????)
Mechanism of Action
Reversibly block conduction along nerve fibers to prevent membrane depolarization
This prevents impulse transmission along nerve by preventing the opening of the Na+ channels, thus never reach threshold
Rate of depolarization is slowed to the point where action potential cannot be reached
LA must penetrate through the lipid-rich nerve sheath and cell membrane to reach Na+ channels (More Lipid Soluble = More Potent)
Potency is related to lipid solubility and pH
A LA can cross the membrane faster in if it is neutral and lipophilic form rather then changed
Once inside the cell, the lower pH shifts the equilibrium toward the positively charged protonated form, which antagonizes the Na+ channels more potently then the neutral form
What is the key difference in the stability of amides and esters?
Amides are extremely stable, while esters are unstable
What is a common allergic reaction associated with ester local anesthetics?
Allergy potential from metabolite p-aminobenzoic acid (PABA)
Fill in the blank: Procaine is an example of an _______ local anesthetic.
ester
What determines the duration of action of local anesthetics?
Primary determined by protein binding
Local Anesthetics Properties (Weak Base)
Local anesthetics are weak bases
pKa > physiologic pH (lower the pKa the stronger the acid… lower the lipid solubility, lower the potency???? RESEARCH THIS MORE - THINK I HEARD THIS WRONG)
High % are ionized at pH of 7.4
< 50% of local anesthetic exists in lipid-soluble, non-ionized form at pH 7.4
Acidosis (i.e. infection) further increases the % in the ionized form
Local Anesthetics Properties (Onset and Potency)
Lipid Solubility
The aromatic ring (and alkyl substitutions) determines lipophilic nature
Correlates with the ability to penetrate through a lipid bilayer
It is the primary determinant of LA potency and decreased time on Onset
Lower the pka the greater the potency and lower the time of onset
Local Anesthetic Properties (Duration of Action)
Primary determined protein binding
Greater the protein binding the longer the duration of action
Which local anesthetic has the highest protein binding?
Bupivacaine (96%)
Properties of Local Anesthetics
Pharmacokinetics - Absorption
Depends on the following:
Dosage
Pharmacologic characteristics of LA
Addition of Epinephrine
Site of administration: quickest to slowest
IV
Intercostal
Spinal (SAB)
Caudal
Epidural
Brachial plexus
Sciatic/femoral
SQ
Pharmacokinetics - Distribution
Rapidly distributed
Lipid solubility and protein binding dictates redistribution to tissue sites
After systemic absorption, amides are more widely distributed than esters
Pharmacokinetics - Metabolism
Amides
Hepatic CYP 450 via hydroxylation and N-dealkylation
Prilo > lido,mepiva > etido, bupiva, ropivacaine (slow)
More complex & slower = sustained plasma [ ]
Toxicity is more likely
Ester
Hydrolysis by plasma cholinesterase
Chloroprocaine > procaine > tetracaine (slow)
Exception is cocaine by liver
Toxicity is inversely related to rate of hydrolysis
Slowed by liver disease
