BASIC NERVE CELL PHYSIOLOGY
What is the resting potential value of a nerve cell membrane?
All cells have a resting potential: an electrical charge across the plasma membrane with the interior of the cell negative with respect to the exterior. The size of the resting potential can vary, but in excitable cells it is about –70 millivolts (mV).
What determines the resting potential of a nerve cell?
The resting potential arises from two activities:
1. The sodium/potassium ATPase, which moves three sodium ions outside the cell for every two potassium ions inside the cell and produces a net loss of positive charges and results in a negative intracellular charge.
2. Facilitated diffusion of potassium outside the cell.
Describe the ionic relations in the cell for sodium, potassium, chloride, and calcium ions.
1. The sodium/potassium ATPase produces:
a. A concentration of Na+ outside the cell that is some 10 times greater than that inside the cell.
b. A concentration of K+ inside the cell some 20 times greater than that outside the cell
2. The concentrations of chloride ions (Cl–) and calcium ions (Ca2+) are maintained at greater levels outside the cell.
Describe the depolarization of a nerve cell membrane.
Before an action potential can be formed, the nerve cell membrane is depolarized by either a mechanical stimulus (sound, stretch, etc.) or a neurotransmitter (e.g., acetylcholine). This allows the facilitated diffusion of sodium into the cell, which reduces the resting potential at that area on the cell and creates an excitatory postsynaptic potential or EPSP.
If the initial depolarization stimulus reaches a threshold voltage of −50 mV, then an action potential will be generated from that area of the cell membrane. This opens hundreds of voltage-gated sodium channels and creates a massive influx of sodium. The sudden complete depolarization of the membrane opens up more of the voltage-gated sodium channels in adjacent portions of the membrane. In this way, a wave of depolarization sweeps along the cell. This is the action potential, or nerve impulse.
Why is the action potential an all-or-nothing event?
If the critical threshold of a −50 mV membrane depolarization is reached, then an action potential will be produced, if not, then no action potential will result. Strong stimuli produce no stronger action potentials than weak ones.
How is membrane repolarization reestablished?
1. Diffusion of potassium ions out of the cell.
2. Closure of sodium channels.
What is the refractory period?
A second stimulus applied to a neuron less than 0.001 second after the first will not trigger another impulse. The membrane is depolarized, and the neuron is in its refractory period. Not until the −70 mV polarity is reestablished will the neuron be ready to fire again.
How long does the refractory period last?
Varies in some human neurons the refractory period lasts only 0.001 to 0.002 seconds. This means that the neuron can transmit 500 to 1,000 impulses per second.
What is the node of Ranvier?
Myelinated neurons are encased in a fatty sheath called the myelin sheath, which is the expanded plasma membrane of an accessory cell called the Schwann cell. Where the sheath of one Schwann cell meets the next, the axon is unprotected. This area is called the node of Ranvier.
Why is conduction in myelinated neurons faster than in unmyelinated ones?
Voltage-gated sodium channels of myelinated neurons are confined to the nodes of Ranvier. The inflow of sodium ions at one node creates just enough depolarization to reach the threshold of the next. In this way, the action potential jumps from one node to the next. This results in much faster propagation of the nerve impulse than is possible in unmyelinated neurons.
ACTION OF LOCAL ANESTHETICS
What is a conduction block?
It is the reversible interruption of conduction within a neural structure by a local anesthetic.
It occurs when local anesthetic molecules occupy enough sodium channels within an axon to interrupt its activity.
How does conduction block by a local anesthetic occur?
Local anesthetics act by binding to open-gated sodium channels causing them to remain inactive, thus preventing subsequent depolarization.
Why do local anesthetics have a higher potency for nerves with a higher frequency of stimulation?
Nerves that have a higher frequency of stimulation have more activated open sodium channels that are more susceptible to the action of local anesthetics.
Why are myelinated nerves easier to block than unmyelinated ones?
In myelinated nerves, only the nodes of Ranvier need to be exposed to local anesthetic for conduction block to occur. In unmyelinated fibers, the full length and circumference of the nerve must be exposed to local anesthetic.
During local anesthesia, what is the sequence of blockade and which nerve fibers are affected?
1. Vasodilation (nerve type B, preganglionic autonomic, sympathetic, light myelin)
2. Loss of pain and temperature sensation (nerve types A-δ and C, moderate and no myelin, respectively)
3. Loss of pressure sensation (nerve type A-β, heavy myelin)
4. Loss of motor function (nerve type A-α, heavy myelin)
What three structures make up the anesthetic molecule?
1. Aromatic ring (hydrophobic)
2. Tertiary amine (hydrophilic)
3. Intermediate chain (contains either an amide or ester bond)
Local anesthetics are classified into which two groups?
1. Amino esters
2. Amino amides
What is the pH of local anesthetic solutions?
Local anesthetics are weak base with a pKa ranging from 7.7 to 9.1. Commercially prepared solutions are prepared as hydrochloride salts of the cation with a pH of 5.0 to 6.0 without epinephrine and a pH of 2.0 to 3.0 with epinephrine. This is why they burn so much.
How can pain from local anesthetic blocks be minimized?
The pain associated with use of local anesthetics can be decreased by adding sodium bicarbonate to the anesthetic. Alkalinization of the local anesthetic solution allows the anesthetic to enter the nerve more quickly thereby increasing the rapidity of onset and effectiveness. Normal dose for sodium bicarbonate is 1 mEq/10 mL lidocaine and 0.1 mEq/20 mL bupivacaine. It can decrease the pain of local anesthetic injection by adding 1-mL sodium bicarbonate for every 9-mL local anesthetic.
1. Lipid solubility
2. Protein binding
How does lipid solubility affect the action of local anesthetics?
Increased lipid solubility of a local anesthetic will increase its potency because nerve cell membranes are highly hydrophobic. Increased nerve block will occur because of facilitated entry across the nerve cell membrane.
How does protein binding affect the action of local anesthetics?
Local anesthetics with a higher-protein binding will have greater contact with the nerve membrane and thus a longer duration of action.
How does the pKa affect the action of local anesthetics?
The pKa of a local anesthetic determines the speed of onset of the nerve conduction block. Fifty percent of the anesthetic will exist in its basic and cationic form at a given pKa. The nonionized basic form has the highest lipid solubility and hence highest speed of onset. Because local anesthetics are prepared as hydrochloride salts with a pH of 5.0 to 6.0, some delay in onset will occur because of physiological buffering which is required to establish a significant base form concentration.
In what two ways can the onset of local anesthetics be accelerated?
1. Preparation of the local anesthetic solution as a hydrocarbonate salt instead of a hydrochloride salt.
2. Addition of sodium bicarbonate to the local anesthetic prior to injection.
List four ester local anesthetics.
List three amide local anesthetics.
Note that these all have an “i” before the “-aine.”
How are esters metabolized?
Esters are rapidly hydrolyzed by plasma pseudocholinesterase that creates a short plasma half-life. Products of metabolism include para-aminobenzoic acid (PABA), which can be associated with hypersensitivity reactions in certain patients.
Liver cells metabolize amides intracellularly. Because of this longer process, an accumulation of repeated doses can cause systemic toxicity. Patients with poor liver function and congestive heart failure will have a significantly prolonged amide half-life. Normal half-life is 2 to 3 hours and unlike esters, true allergies are rare.
TOXICITY OF LOCAL ANESTHETICS
What types of toxicities are related to local anesthetics?
1. Direct tissue toxicity (buffers, preservatives, potential for intraneural injection)
2. Systemic toxicity (CNS, cardiac, methemoglobinemia)
What factors determine the toxicity of a local anesthetic?
1. Potency or lipid solubility (increased CNS toxicity)
2. Total dose delivered
3. Rate of plasma uptake
4. Protein binding
5. Site of injection (highly vascularized tissues increase the rate of uptake)
How does the addition of epinephrine reduce a local anesthetic’s toxicity?
Produces vasoconstriction which:
1. Decreases vascular uptake
2. Lowers peak plasma levels
3. Slows time course to peak level (reduced CNS toxicity)
What toxic effects are associated with the addition of epinephrine?
3. Cardiac arrhythmia
4. Myocardial ischemia
Name three factors that decrease seizure threshold and increase the risk of CNS toxicity.
Name two agents that can be used to treat seizures following CNS toxicity.
1. Benzodiazepine (increases seizure threshold and can prevent seizure activity)
2. Sodium thiopental
1. CNS excitation (occurs first):
d. Circumoral numbness
e. Metallic taste in the mouth
f. Loss of consciousness
g. Muscular twitching
2. CNS depression (occurs later):
a. Respiratory depression
b. Cardiorespiratory arrest
What are the effects of local anesthetic toxicity on the cardiovascular system?
1. Increased sodium channel blockade within the cardiac conduction system causes:
a. Decreased Purkinje fiber firing and prolonged conduction time
b. Long PR interval
c. Widened QRS complex
d. Sinus bradycardia and asystole
e. Direct myocardial depressant
f. Ventricular arrhythmia (increased reentrant pathway activity)
What measures can be used to prevent or minimize systemic reactions to local anesthetics?
1. Avoid intravascular injections (frequent aspirations while injecting).
2. Always use smallest possible dose and concentration.
3. Add epinephrine (avoid in digits and in patients with ischemic heart disease).
4. Premedication with benzodiazepine (elevates convulsive threshold).
5. Use a small test dose.