Mod 3: Local Anaesthetic Pharmacological Principles Flashcards
The Plasma membrane separates the interior of all cells to the extracellular space, this membrane is full of channels which?
Control the flow of IONs and other compounds from outside the cell and vice versa.
ION channels conrtol, what?
The Voltage gradient across a plasma membrane
What does VGSC mean? and what do they do?
Voltage Gated Sodium Channel, function ad gated conduits for Sodium IONS
What is RMP?
Resting Membrane Potential. Inside cell membrane is -ve as opposed +ve outside membrane approx -70mv
What 2 activities cause RMP?
- Na/K pump pushes only 2 K+ ions into the cell for every 3 Na+ ions pushed out = net loss of charge.
- Leaky K+ channels allowing slow diffusion of K+ from high conc. to low conc.
Stimulation of the cell results in a reduction in RMP, if this reduction reaches the threshold voltage, what is generated?
An Action Potential at -50mv
Action potentials involve rapid changes in membrane potentials from -ve to +ve causing what?
The opening of VGSC which causes rapid influx of Na+ depolarizing the cell to +ve on the inside.
RMP is reestablished when?
Na+ channels are closed and K+ channels are opened allowing K+ to efflux from the cell.
LA’s block?
VGSC
Blocking Na+ influx prevents?
Depolarization required for action potential propagation and impulse conduction.
LA’s are a class off drug that?
Reversibly block the generation and conduction of action potentials in all excitable cells
Self regenerating action potential occurs when?
Cells become depolarized and VGSC are opened allowing Na+to influx into the cell leading to more VGSC to open.
Sustained depolarization causes?
- Inactivation of VGSC which shuts off influx of Na+
- concurrent opening of voltage-gated K+ channels.
- Resultant K+ efflux the K+ channels return membrane to resting potential
LA”S act by?
Selectively binding to VGSC blocking the pathway for Na+ (block channels) thus preventing depolarization necessary for action potential propagation and impulse conduction.
Once LA is stopped it…
Dissociates from the VGSC rapidly, diffusing away to be absorbed by the local circulation, impulse activity is then restored.
What are the ideal characteristics of LA’s?
- Complete reversibilty
- Low local and systemic toxicity.
- Action confined mainly to nerve tissue
- Short onset
- Duration sufficient for required procedure.
- Will not increase recovery.
- solubility in saline and lipids
- Sterilizability and storability without deterioration
- Vasoconstrictor compatible
- Non irritability to tissues.
In what order are nerves affected by LA”S
All nerves are affected by LA, however not all are affected equally, non-myelinated neurones (C fibres) are affected first, with heavily myelinated neurones (A fibres) last 1st Sympathetic function (C fibres) 2nd Pinprick and Temperature 3rd Motor function (A fibres) Nerves recover in reverse order.
Describe Activity Dependent Blockade.
- Increased nerve activity leads to increased susceptibility to LA’s
- LA’s have a greater affinity to to depolarized Na+ channels than polarized.
- therefore the more active a nerve fiber the more effective the blockade.
List the 2 types of LA’s.
- Esters
2. Amides
Describe LA’s chemical base.
Weak bases, consisting of an amide (hydrophilic) component which is connected via either an ESTER OR AMIDE link to an aromatic (hydrophobic/lipophilic) portion
Amide LA’s are chemically stable and metabolized where?
Liver
Ester LA’s are hydrolized where?
Plasma Cholinesterase
The Hydrophilic component is water soluble enabling….
The drug to diffuse through tissues to the nerve
The Hydrphobic component is fat soluble enabling…
The drug to diffuse through lipid membranes to its binding site at the VGSC’s
LA’s must pass through 3 sheaths to reach VGSC’s. These are?
- Epineurium
- Perineurium
- Endoneurium
Optimum pKa of LA’s is?
the optimum pH level where 50%of the drug is dissociated is between 8-9
Inflammation causes increased local acidosis which reduces pH causing what?
An increase in ionization of LA’s making cell diffusion difficult and less effective.
Bicarbonate can be added to increase the pH of LA’s making them less painful to inject, but what ratio?
Lidocaine & Mepivicaine=1cc/10cc of drug
Bupivicaine=0.1cc/100cc of drug
Rate of onset factors are?
- Potency: correlates to lipophilicity, more lipophilic the higher the potency.
- Dose: increase dose (volume/conc); accelerates onset.
- Un-ionized fraction: adding bicarbonate accelerates onset
- Epinephrine: reduces rate at which LA is washed away.
- Elimination Pharmacokinetics: rapidly eliminated drugs generally have rapid onset due to higher doses.
Duration of action factors are?
- Rate of absorption: tissue vascularity, use of epinephrine.
- Rate of elimination: particularly esters which are metabolized locally.
- Potency
Short duration LA’s are?
Procaine, Chloroprocaine (esters)
Intermediate duration LA’s are?
Lidocaine, Mepivacaine, Prilocaine (amides)
Long duration LA’s are?
Tetracaine (ester)
bupivacaine, ropivacaine, etidocaine, levobupivacaine (amides)
Esters are hydrolized by?
Local plasma chlorinesterase
What half life doe esters have?
Short
PABA is what?
Para AminoBenzoic Acid and is what esters are hydrolized to.
Procaine (Novocaine)
Rarely used due to high sensitivity
May be considered with Lidocaine
Rapid onset 10-15 mins
Short acting - 1 hour
Tetracaine
10x more toxic than Procaine!
Not recommended for Peripheral Anaesthesia
Chloroprocaine (Nesacaine)
Rapid onset 10-15 mins
Intermediate acting: 3-4 hours
Low toxicity due to rapid metabolism
MSD 100mg
Benzocaine
Topical Anaesthesia
Amides are degraded by?
Hepatic Endoplasmic Retinaculum, adequate hepatic function is essential for normal elimination of LA
What may be present in an Amide LA of pt develops an immune response?
PABA used as a preservative
Lidocaine (Lignocaine, Xylocaine)
Most commonly used LA MSD 300-500mg (3-5mg/kg) plain MSD 500mg (5-7mg/kg) with epinephrine Rapid onset: 5-10mins Intermediate acting: 1-3 hours
Bupivacaine (Marcaine, Sensorcaine)
More toxic than Lidocaine MSD 175mg plain (2.5mg/kg) MSD 225mg epin (3.5mg/kg) Slow onset: 10-30 mins Long duration: 3-12 hours
EMLA (Lidocaine+Prilocaine)
Topical Anaesthetic
Lidocaine MSD?
3-5mg/kg not exceeding 350mg plain,
7mg/kg not exceeding 500mg with epi
Marcaine MSD
- 5mg/kg not exceeding 175mg plain
3. 5mg/kg not exceeding 225mg with epi
LA adjustment for Paediatric pt’s over 1 yr old: Clark’s rule is?
weight of child (lbs)/150 x adult dose=adjusted dose.
LA adjustment for Paediatric pt’s over 1 yr old: Cowlig’s rule is?
Childs age/24 x adult dose = adjusted dose
LA adjustment for Paediatric pt’s under 1 yr old: Freids rule is?
Child age in months/15 x adult dose = adjusted dose
Sample question: What is MSD of Lidocaine Plain for 90kg healthy adult male?
MSD for Lidocaine Plain = 3-5mg/kg not exceeding 350mg. so (3-5mg x 90) = 270-450mg. recall MSD for Lidocaine so MSD would be 270mg-350mg
Sample question: Max single Volume of 0.75% Marcaine plain in 60kg adult female?
MSD for Marcaine Plain = 2.5mg/kg not exceeding 175mg, therefore (2.5 x 60) = 150mg.
0.75% = 7.5mg/ml so
150/7.5 = 20ml so max safe vol = 20ml
Epinephrine is the most common of Vasoconstrictors/Adrenergic agonists used with LA’s, what are the characteristics of Vasoconstrictors in LA?
Red Top on vials Creates Homeostasis Decreases Rate of Onset Increases Duration of Action Decreases toxicity Decreases dosage of LA required May contribute to ischaemic changes in Nerve
