Local anaesthetic Flashcards
Mechanism of Action (LA)
Stop axonal conduction by blocking sodium channels in the axonal membrane (loss of nociception) when applied locally in appropriate concentration in a reversible manner –> prevent sodium ion entry –> slow down or bring conduction to a halt.
Many LAs bind most strongly to the inactivated and activated states (interacting with residues of the S6 transmembrane helical domain)
Passage of train of action potentials causes the sodium channel to cycle through open and inactivated states
Many LAs bind most strongly to the _____________
Many LAs bind most strongly to the inactivated and activated states sodium channels
Use-Dependency of LA
Use-Dependency
Depth of LA nerve block increases with action potential frequency because LA molecules:
- gain access to the channel more readily when channel is open
- have higher affinity for the inactivated than for the resting (closed) channels
pH-Dependency of LA
• LA molecules are weak bases (pKa 8-9)
– Mainly but not completely ionized @ physiological pH
• LAs therefore are strongly pH-dependent
– Alkaline pH = INCREASE LA activity (proportion of nonionized molecules is high)
– Acidic pH - DECREASE LA activity (proportion of nonionized molecules is low)
• Plays critical role in LA penetrate nerve sheath and axon membrane –> to reach the inner end of the sodium channel (LA binding site)
The susceptibility of nerve fibres to LA blockade depends on
– unmyelinated small fibres can only passively propagate electrical impulses over a short distance; myelinated larger fibres, at least 2 or 3 nodes of ranvier need to be blocked to halt impulse propagation
– sensory (pain) fibres have higher firing rates (MORE ACTIVATED), motor fibres have a slower firing rate
– in large nerve trunks, fibres located circumferentially are the first to be exposed to LA injected into surrounding tissue (eg. proximal sensory fibres in neres to extremities)
in summary
Small, non-myelinated neurons are blocked more rapidly than large, myelinated neurons i.e. pain sensation is blocked more readily than other sensory modalities (touch etc)
Class of LA
Ester
amide
Compare between class of LA
Characteristic (ESTER VS AMIDE)
Chemistry
- Ester bond VS Amide bond
Representative Agents
- Procaine VS Lidocaine*
Incidence of Allergic Reactions
- Low VS Very low
Method of Metabolism
- Plasma/tissue non-specific esterases VS
Hepatic enzymes
PK of LA
LA are usually applied around nerves, onset of action is NOT determined by absorption or distribution but offset of action and systemic toxicity are
Onset:
LAs that penetrate the axon most rapidly have the fastest onset :
i.e. small molecules, high lipid solubility, low ionization (@ tissue pH) –> faster onset
Systemic Absorption depends on: dosage site of injection (highly vascularize areas) tissue binding local blood flow drug properties
Therefore use of vasoconstrictor (epinephrine) –> prevention
Metabolism:
Ester-type by esterases in blood (ie. very short plasma half live)
Amide-type by enzymes in liver by microsomal CYP P450 isoenzymes - Reduced metabolism in patients with LIVER DISEASE LIVER BLOOD FLOW MEDICATIONS INDUCE/INHIBIT P450
Excretion: metabolites by kidney
Caution:
- Unintended large dose of LA if accidently injected IV / intraarterial can give rise to systemic toxicity.
- Another way to give rise to systemic toxicity is excessive (over dose) LA injected locally & subsequently leads to high (& toxic) blood level following absorption – hence the onset of toxic symptoms & signs may appear late as compare to the direct IV scenario (immediate)
LA can combine with Epinephrine
- Prevent LA systemic distribution from the site of action
Toxicity
CNS
- Direct neurotoxicity (high [LA] in close proximity to spinal cord or nerve trunks)
1) sleepiness
2) visual and auditory
3) restlessness
4) nystamus
5) shivering
6) convulsion
7) stoppage of vital function
8) death
9) respiratory depression
CVS
- Cardiac/vascular smooth muscle
1) Decrease cardiac contraction
2) arteriorlar dilation
3) hypotension
4) Cardiovascular collapse- heart attack
- cardiac arrest
Allergy
Allergic Reactions (ester-type): allergic dermatitis to anaphylaxis can be triggered by ester-type LAs and their metabolites. If allergy happens, use amide-type LA (not known cross-hypersensitivity)
type of LA
• Topical
- eg. nasal mucosa
• Major nerve trunks (blocks)
- Brachial plexus
• Spinal
- Sympathetic ganglion
- Epidural (extradural) block
- Subarachnoid (spinal) block
• Intravenous
- Injected into distal vein of limb isolated by proximal tourniquet
• Trigger points
Trigger points are discrete, focal, hyperirritable spots that are painful on compression and can produce referred pain or tenderness as well as problems with muscle function. Trigger points are seen in myofascial pain syndrome, a common painful muscle disorder.
Topical LA uses
• Topical (surface)
– Skin
minor burns/inflamed/wounds
– Eye
remove foreign objects
– Dental
applied to gum due to entry of injection needle
– Otorhinolaryngology
insertion of endoscope for gastric ulcer scope
– Gynaecology episiotomy cuts (lidocaine)
Injected LA uses
– Epidural anaesthetics
• Regional nerve block (analgesia)
• Lidocaine, bupivacaine (may combine with opioid fentanyl to reduce LA dose)
– Dental anaesthesia
• Lidocaine (short time)
• Bupivacaine (long time)
(may combine with epinephrine –> vasoconstrictor –> control bleeding)
• Choice of LA and other concomitant medications
• Choice of LA and other concomitant medications
– Duration of effect required
• Short acting : procaine
• Medium acting: lidocaine
• Long acting: bupivacaine
– Anaesthetic effect can be prolonged by
• Increased dose
• Adding a vasoconstrictor (eg. ephinephrine)
– Onset of action can be accelerated by
• Adding sodium bicarbonate into solutions
• Choosing LA with rapid penentration of skin
