Basic-Local anesthetics Flashcards
Where do local anesthetics bind? What makes crossing the lipid cell membrane faster? Charge of a local anesthetic depends on what?
Local anesthetics (at least the ones used clinically nowadays) bind to the alpha subunit of voltage gated sodium channels on the intracellular surface of the cell membrane (not extracellular surface). By blocking these channels, it prevents action potentials from being propagated. Crossing the lipid cell membrane occurs quicker when the local anesthetic (a base) is uncharged. The charge of the local anesthetic depends on its pKa (the pH where ½ of the molecules are ionized and ½ are uncharged) and the pH of the local environment. Therefore, a local anesthetic with a pKa of ~8 (bupivacaine, tetracaine, lidocaine) will have more than half the molecules in the charged form at a pH of 7. In other words, putting a base in a more acidic environment will lead to more than half the molecules picking up an additional H+ and having a positive (cation) charge. Therefore, the more uncharged molecules (the closer the pKa is to pH), the more molecules can quickly cross the membrane.
Why is this statement false?
Onset of action is directly proportional to its pKa in all commonly used agents
The reason that answer choice “Onset of action is directly proportional to its pKa in all commonly used agents” is not correct is that there are two major complicating situations where the pKa cannot, in itself, be used as perfect guide to determine onset alone (although IT IS a major determinant). First, more lipid soluble local anesthetics can more easily pass through connective tissue and the epineurium to reach the neuron. Secondly, chloroprocaine (for example) is clinically given in such high doses (number of molecules) that its onset is quicker than many other local anesthetics with pKa’s closer to physiological pH’s.
Sodium channels in the activated or inactivated (meaning it was just active) have greater affinity for local anesthetics than in the resting state (hasn’t been active for a “long” time).
T/F
True
Finally, the addition of epinephrine in commercially available solutions require the solution to have _____. Why?
A lower pH. It’s for stability. This
leads to fewer unprotonated (uncharged) local anesthetics available to cross the cell membrane.
Potency=
Duration of action=
Onset=
potency = lipid solubility; duration of action = protein binding; and onset = pKa
Rate of absorption
IV > tracheal > intercostal > caudal > paracervical > epidural > brachial plexus > sciatic > subQ
Adding 1:200,000 of epinephrine to 2% lidocaine just prior to placing supraclavicular block will:
A. Limit its toxic side effects B. Increase duration by 150% C. Increase vascular uptake D. Increase licocaine’s protein binding E. Lower the pH
A: Limit its toxic side effects
Adding epinephrine to short and intermediate duration local anesthetics have many potential benefits. First, induced vasoconstriction decreases the rate of washout (decreased vascular absorption) leading to a longer block and increasing its toxic dose. Duration increases are mild to moderate, and in the case of lidocaine, about a 50% increase in duration would be expected for a peripheral nerve block. Second, the density of the block can be increased with epinephrine by increasing neural uptake (by decreasing washout – i.e. more time the neuron is exposed to the local anesthetic). Prepared commercial epinephrine containing solutions require a lower pH for molecular stability (for a long shelf life), but adding epinephrine just prior to use does not affect the pH. Finally, epinephrine does not prolong or enhance bupivicaine and ropivicaine, as its duration of action is based on protein binding.
Most allergic reactions to local anesthetics are due to? How to tell difference between amides and esters? What metabolizes esters?
A: Procaine
Allergic reactions to local anesthetics are typically due to either preservatives, PABA as a byproduct of metabolism, or a reaction to epinephrine (incorrectly classified as an allergy). The esters procaine and benzocaine are metabolized by pseudocholinesterase to PABA. Abnormal pseudocholinesterase (remember me!) not only can decrease the rate of metabolism of succinylcholine and mivacurium, but also ester local anesthetics (with the exception of cocaine). An easy way to remember which local anesthetics are amides vs esters, is that amides have two ‘I’s” in the name (lIdocaIne = amide; procaine = ester). Amides are metabolized in the liver. Preparations of amides sometimes contain the preservative methylparaben, which is structurally similar to PABA and can also lead to allergic reactions.
With methaemoglobinemia, the iron goes to what? What does this do?
It’s oxidized to 3+
leading to a significant left shift in the oxygen- haemoglobin dissociation curve and decreased oxygen release to the tissues (tissue hypoxia).
Blockade with a local anesthetic mixed with epinephrine enhances the quality of the block by:
A. Decreasing absorption B. Changing the activation state of the sodium channel C. Direct adrenergic activation D. All of the above E. Two of the above
E: Two of the above
Epinephrine causes vasoconstriction and therefore limits the uptake of local anesthetics, which results in a denser and longer block. It can increase density (in some cases) because the local anesthetic is exposed to the neuron for a longer period of time (at a greater concentration as the uptake into surrounding tissues and blood are decreased). The block is lengthened in most cases because vasoconstriction limits how much of the local anesthetic is taken up by the systemic circulation. An exception to this is bupivacaine and ropivacaine because these two local anesthetics are highly protein bound (outlasting any beneficial effects of epinephrine).
Direct adrenergic activation of the alpha-2 receptor by epinephrine can produce analgesia independent of local anesthetic effects. Epinephrine does not change the activation state of the sodium channel.
Esters are metabolized by Pseudocholineaterase with the exception of one local anesthetic:
Cocaine
Does changing pH change the pKa of the drug?
Changing the pH, does not change the pKa of a drug, as pKa is an inherent property of the drug.
Which of the following is true regarding pKa:
A. The higher the pKa, the more rapid the onset
B. The higher the pKa, more of the local anesthetic will exist as a conjugate acid
C. pKa is defined by the pH that maximally speeds onset of action
D. Adding sodium bicarbonate to a local anesthetic solution will change the local anesthetic pKa
B: The higher the pKa, more of the local anesthetic will exist as a conjugate acid, because it will have to accept an H+ (#10)
You inform your resident that one should always use non-epinephrine containing local anesthetic and add the epinephrine in just prior to injection for a nerve block. The advantage of this as compared to using local anesthetic with premixed epinephrine (at the same concentration) is:
A. Degradation of the epinephrine in premixed bottles makes the actual concentration of epinephrine unpredictable
B. Block onset will be quicker when the epinephrine is mixed in just prior to use
C. Duration will be longer when the epinephrine is mixed in just prior to use
D. You can more effectively torture residents by having them mix their own solutions
B: Block onset will be quicker when the epinephrine is mixed in just prior to use
Epinephrine will degrade quicker in alkaline environments than acidic environments, therefore manufacturers will make their solutions more acidic (around pH 4-5) to ensure such degradation does not occur. Since local anesthetics are bases with high pKa’s, this will increase the proportion of the drug in the ionized (BH, conjugate acid) form that cannot cross the cell membrane (where the binding site of the voltage-gated sodium channel exists for local anesthetics). Therefore by adding in the epinephrine to solutions without epinephrine (pH 6-7), a greater proportion of the drug is in the non-ionized state allowing for transit across the cellular membrane and faster onset. Since the vasopressor activity of epinephrine will be essentially equivalent in premade solution or added just before use, the duration of the two blocks will be about the same.
Basic drugs bind to _____ vs acidic drugs bind to _____.
Protein bound drugs are mostly bound to albumin or alpha-1-acid glycoprotein (AAG). Albumin carries acidic drugs (like barbiturates) and AAG more often caries basic drugs like local anesthetics.
