Local Anaesthetic Agents Flashcards
Define Local Anaesthetic
A drug that causes reversible local anaesthesia and analgaesia. when these agents are applied to specific nerve pathways , they have a range of effects from analgaesia alone (sensory block) to a complete motor block with paralysis.
What are the three functional anatomical components of the nerve cell relevant to conduction and how is the action potential generated and propagated
- Axoplasm
- Phospholipid membrane
- Transmembranous spanning proteins
The action potential is generated and propagated by altered Na permeability across the membrane
How long does a nerve cell action potential last.
Compare this the an atrial pacemaker cell and a cardiomyocyte.
Nerve cell: 1 - 2 ms
Atrial PM cell: 200 ms
Myocyte: 300 ms
Describe the process of an action potential with reference to:
- Resting membrane potential
- Threshold potential
- Depolarization and repolarization
The membrane potential is the charge inside the cell minus the charge outside the cell. The resting membrane potential is negative due to a combination of two factors: 1. The 3Na/2K ATPase and 2. Increased membrane permeability to K+. The 3Na/2K ATPase pushes 3Na out and 1K in. A small amount of positively charges K leaks out leading to the inside of the cell being more negative than the outsid of the cell and creating the negative RMP of -70mV.
Chemical or electrical stimulation cause a slow rise (less negative) in the membrane toward the threshold potential of -50 mV. Once the membrane potential reaches this value and all or nothing response occurs with opening of sodium channels and mass movement of Na from the outside of the cell to the inside until these sodium channels close at +30mV. This is called depolarization. At the point that the Na channels close, the K channels open and mass movement of K move down the concentration gradient into the outside of the cell moving the membrane potential back down to its resting membrane potential of -70. This is called repolarization. The 3Na/2K ATPase then restores the resting membrane potential by moving NA out and K in ready for the next threshold breaching stimulus to arrive.
Classify nerve fibres
Aa M3 15 100 Motor
Ab M2 10 50 Touch, Pressure, Proprio
Ag M2 10 50 Tone (Muscle spindles)
Ad M1 5 25 Pain, Temp
B M1 2.5 10 Pre-ganglionic - ANS
C M0 1 1 Post ganglionic - ANS, Pain, Temp
How does nerve cell thickness and myelination affect ease of neural blockade –> rank ease of blockade of different nerve fibres from easiest to block with low concentration LA to hardest to block with high concentration LA
Thin nerves - easy to block
Thick nerves - harder to block
Myelination - easier to block just nodes of Ranvier
From easiest to block to hardest to block:
- Vasodilation and increased skin temperature (C & B)
- Pain & Temp (C and Ad)
- Proprioception (Ab)
- Touch, pressure (Ab)
- Motor (Aa)
Why do the legs go warm during spinal anaesthesia
Cold receptors fire tonically from the leg
Hot receptors do not
Neuraxial anaesthesia blocks all conduction so cold receptors is disproportionally affected and increased leg temperature is perceived by the patient
Describe the general chemical structure of local anaesthetics demonstrating how amides differ from esters.
AROMATIC RING (Lipophilic) connected to a TERTIARY AMINE (Hydrophilic) via an INTERMEDIATE CHAIN.
The intermediate chain is either an:
- ESTER LINKAGE (-COO-)
- AMIDE LINKAGE (-NCO-)
List the Esters
- Amethocaine
- Benzocaine
- Cocaine
- Tetracaine
- Procaine and chloroprocaine
List the Amides
- Lignocaine
- Bupivacaine
- Ropivacaine
- Levobupivacaine
- Prilocaine
Define pKa
pKa = -logKa
pKa is the negative log of the acid dissociation constant or Ka value. A lower pKa value indicates a stronger acid. That is, the lower value indicates the acid more fully dissociates in water.
Define pKa in terms of LA ionized/unionized forms and explain the effect of adding NaHCO3 to the LA mixture
The pKa is the physiological pH at which the drug is 50% ionized and 50% unionized.
As a rule:
Acids ionize at pH Above their pKa
Bases ionize at pH Below their pKa
LA are weak bases. Therefore LA ionize at pH below their pKa (in an acidic environment. An ionized LA can’t cross cell membranes and can’t bring about its effect. The unionized portion of the LA exerts the clinically effect. Therefore at higher pH, the LA weak base will be less ionized as bases ionize at pH below their pKa therefore the higher the pH is the more ionized LA drug is present. Hence, addition of NaHCO3- will increase of speed of onset of the clinical effect
Chemically –> when the tertiary amine moiety of the LA molecule becomes protonated (quaternary)
What is the mechanism of action of local anaesthetics?
- Voltage gated sodium channels permit initiation and propagation of action potentials along neurons
- Unionized LA can diffuse across the cell membrane
- Unionized LA becomes ionized (active form) at the lower intracellular pH (±7.1)
- The ionized agent blocks the inner portion of the voltage gated sodium channel preventing the propagation of action potentials
Describe the preparation of local anaesthetics
Must be water soluble and stable in solution
pH is acidified to enhance chemical stability and prolong shelf life (esp. preparations with epinephrine)
e.g.
- Bupivacaine hydrochloride
- Lignocaine hydrochloride
The drug in the ampoules will be hihgly ionized until injected into the body
Addition of NaHCO3 can increase the speed of onset of these preparations by increasing the unionized portion of the drug.
List the factors that influence local anaesthetic activity and explain what influence these factors have
- Lipid solubility - increased –> faster onset, increased potency and duration
- Intermediate chain - lengthening this decreases potency
- Protein binding - increased –> increased duration
- pKa - lower - (Bases ionize below) –> faster onset
- pH - reduces potency (e.g. infected tissue)
