What is the purpose of local anesthetics?
- Reversibly block nerve conduction of sensory impulses from the periphery to the CNS
- Abolish sensation in a limited area of the body without producing LOC
- Small unmyelinated nerve fibers that conduct impulses for pain, temp and autonomic activity are more sensitive to actions of local anesthetics.
Most local anesthetics consist of what kind of chemistry?
Lipophilic group connected by an intermediate chain (ester or amide) to an ionizable group (tertiary amine)
—note ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action
Local anesthetics are weak bases. They are marketed as water soluble salts, usually hydrochlorides. Their hydrochloride salts are mildly acidic. This property increases what?
Increases the stability of the local anesthetics esters
–and any accompanying vasoconstrictor substance.
Since the pK of most local anesthetics is in the range of 8.0-9.0, what does this mean?
The larger fraction in the body fluids at physiologic pH will be the cationic form.
–cationic form is thought to be most active form at the receptor site, but the uncharged form is important for rapid penetration of the biologic membranes: the local anesthetic receptor is not accessible from the external side of the cell membrane.
Therefore why are local anesthetics much less effective in infected tissues?
These tissues have a low extracellular pH, so that a very low fraction of nonionized local anesthetics is available for diffusion into the cell
The duration of action of a local anesthetic is proportional to what?
The time during which it is in contact with the nerve
Therefore in clinical practice preparations of local anesthetics often contain a vasoconstrictor, usually epinephrine. What does epinephrine do?
Reduce systemic absorption of local anesthetics from the depot site by decreasing blood flow to these areas
–as a consequence neuronal uptake of the drug is enhanced due to the higher local drug concentration and the system toxic effects are reduced.
When epinephrine is used in spinal anesthesia, it acts directly in the cord to both enhance and prolong local anesthetic induced spinal anesthesia by how?
Acting on the alpha 2 receptors
- -these inhibit release of substance P and reduce sensory neuron firing
- -recognition of this fact has lead to the used of the alpha 2 agonist clonidine and dexmedetomidine to augment local anesthetic effect in the subarachnoid space and on peripheral nerves.
What is the metabolism and excretion of ester linked local anesthetics?
- -metabolized by tissues and plasma esterases
- -excreted by the kidney
What is the metabolism and excretion of amide linked local anesthetics?
Degraded by liver cytochrome P450 enzymes and metabolites are excreted by the kidney
–therefore metabolism is slowed in patients with liver disease
What is the MOA for local anesthetics?
Blockade of voltage gated sodium channels
–bind to receptors near the intracellular end of the channel and block the channel
When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber what happens?
- The threshold for excitation increases
- Impulse conduction slows
- The rate of rise of the action potential declines
- The action potential amplitude decreases
- Finally the ability to generate an action potential is abolished
- -these effects are due to binding of the local anesthetic to more and more Na channels
The blockade of sodium channels by most local anesthetics is voltage and time dependent, what does this mean?
Channels in the rested state, which predominate at more negative membrane potentials, have a lower affinity for local anesthetics than activated and inactivated channels, which predominate at more positive membrane potentials
–therefore the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers
The physiochemical properties of these agents influence their potency and duration of action, what does this mean?
Liposolubility correlates with both potency and duration of action
–but more toxicity
pKa correlates with the speed of onset of action of most local anesthetics
–closer the pKa to the body pH, the faster the onset
What are some ester and amide local anesthetics potency and duration of action?
Esters: Cocaine: 2 (P) ; Medium (DOA) Procaine: 1 (P) ; Short (DOA) Tetracaine: 16 (P) ; Long (DOA) Benzocaine: surface use only Amides: Lidocaine: 4 (P) ; Medium (DOA) Bupivacaine: 16 (P) ; Long (DOA) Prilocaine: 3 (P); Medium (DOA) Ropivacaine: 16 (P); Long (DOA)
Which nerves are blocked first?
Pain fibers (small myelinated alpha fibers)
- -other sensations disappear next (small unmyelinated C fibers)
- -and motor function is blocked last
CVS effects of local anesthetics result partly from direct effects on cardiac and smooth muscle membranes and from indirect effects upon the autonomic nerves. Local anesthetics block sodium channels and thus what happens?
Depress cardiac pacemaker activity, excitability and condition
- -at very high concentrations, they may also block Ca2+ channels
- -with the exception of cocaine they also depress the strength of cardiac contraction and cause arteriolar dilation, leading to hypotension
How is cocaine different from other local anesthetics in regards to its CVS effects?
Blockade of NE uptake results in vasocosntriction and hypertension
–can lead to ischemia and in chronic abusers to ulceration of the mucous membranes and even damage to the nasal septum.
Which local anesthetic is the most cardiotoxic?
The administration of large doses of prilocaine during regional anesthesia may lead to what?
Accumulation of the metabolite o-toluidine, an oxidizing agent capable of converting hemoglobin to methemoglobin
–reducing agents such as methylene blue may be given IV to convert methemoglobin to hemoglobin
What is responsible for allergic reactions to local anesthetics?
Ester type local anesthetics are metabolized by paraaminobenzoic acid (PABA) derivatives
–amides are not metabolized by PABA so now allergic reactions
Which local anesthetic should not be administered to patients taking sulfonamide drugs?
Procaine is hydrolyzed in vivo to produce paraaminobenzoic acid, which inhibits the action of sulfonamides