=== Unfinished ===

Need to read [SH4:p194-203]

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Clinical uses of local anaesthetics

Includes:

• Topical anaesthesia
• Local infiltration
• Peripheral nerve block
• IV regional anaesthesia (Bier block)
• Epidural anaesthesia
• Spinal anaesthesia

Topical anaesthesia

• Dyclonine, hexylcaine, piperocaine are effective for producing topical anaesthesia of the mucous membranes

 

Topical application include:

• Skin
• Conjunctivae
• Tympanic membrane
• Mucous membrane of mouth, nose, airway, oesophagus, anal margin, lower genitourinary tract

Eutectic mixtures of local anaesthetics (EMLA)

See [Eutectic mixture of local anaesthetics (EMLA)]

• EMLA is not recommended for use on mucous membranes because lidocaine and prilocaine is absorbed faster through mucous membranes

Local infiltration

• Lidocaine is the drug most often selected for this purpose
• Epinephrine must not be injected intracutaneously or into tissues supplied by end-arteries
  --> Vasoconstriction may cause ischaemia or even gangrene

Peripheral nerve block anaesthesia

• Involves deposition of LA into tissues surrounding individual peripheral nerve or nerve plexuses

Onset of peripheral anaesthesia

• Nerve fibres located in the mantle (outer surface) of the mixed nerve are anaesthetised first
  * These fibres usually distributed to more proximal anatomical structures
  --> Anaesthesia develops proximally and spreads distally
• Onset also depends on
  * pK of the drug
  * pH of the tissue

Recovery of peripheral anaesthesia

• Nerve fibres in the mantle are exposed to extraneural fluids
  * First to lose anaesthesia
  --> Recovery occurs proximally and spreads distally
• Duration is prolonged by addition of epinephrine

IV regional anaesthesia (Bier block)

• Involves IV injection of LA into an extremity isolated from the rest of systemic circulation by a tourniquet
• Produces:
  * Rapid onset of anaesthesia
  * Skeletal muscle relaxation
• Duration of anaesthesia is:
  * Independent of the choice of LA agent
  * Determined by the duration of tourniquet application
• On release of tourniquet
  --> Concentration of LA is diluted
  --> Sensation and skeletal muscle tone return normal quickly
• Bupivacaine is not recommended for IV regional anaesthesia, due to greater risk of cardiotoxicity
• ??? What's the ideal agent

Epidural anaesthesia

• Involves LA being placed in the epidural or sacral caudal space
  * Drugs diffuse across the dura to act on nerve roots
  * Also goes to paravertebral area through intervertebral foramina
  --> Multiple paravertebral nerve blocks
• Levobupvacaine and ropivacaine are increasingly used instead of bupivacaine
  * Less risk for cardiac and CNS toxicity
  * Less likely to result in unwanted post-operative motor blockade

Nerve blockade with epidural

• Often there is no zone of differential sympathetic nervous system
  * Unlike spinal anaesthesia
• Zone of differential motor blockade may average up to 4 segments below the sensory level
  * With spinal, average up to 2 segments below sensory level
• Larger dose is required to produce epidural anaethesia
  * Compared with spinal
  * Substantial systemic absorption potentially

Adding epinephrine to epidural

• Addition of 1:200,000 epinephrine decreases systemic absorption by 1/3
• Systemic absorption
  --> beta-adrenergic stimulation
  --> Peripheral vasodilation and drop in BP

Adding opioid to epidural/spinal

• Synergistic analgesia
• In contrast, adding opioid to LA in peripheral nerve block
  --> No change in results

Spinal anaesthesia

• Involves injection of LA into subarachnoid space

Mechanism of action

• Principle mechanism is by action on preganglionic fibres branching from the spinal cord in the anterior rami
• LA also acts on superficial layers of the spinal cord

Sympathetic blockade

• Preganglionic sympathetic nervous systems are more sensitive to LA than sensory or motor fibres
• Thus, during spinal anaesthesia,
  --> Level of sympathetic nervous system block is approximately 2 levels higher than sensory block

Dosage requirement

Dosage required for spinal anaesthesia depends on

• Height
• Segmental level of anaesthesia required
• Duration of anaesthesia

NB:

• Total dose administered is more important than concentration or volume of the LA injected
• Specific gravity of LA solution is important in determining the spread of the drug
  * Hyperbaric solution is made by adding glucose
  * Hypobaric solution is made by adding distilled water

Physiological effect of spinal anaesthesia

• Mostly determined by effect of sympathetic blockade
• Plasma concentration of LA is too low to have effects

Cardiac arrest

• Cardiac arrest may accompany the hypotension and bradycardia associated with spinal anaesthesia

Hypotension

Hypotension produced by sympathetic blockade:

• Worse in hypovolaemia
• Associated with defective vasoconstriction response to stress
  --> May be refractory to treatment

Apnoea

• Severe hypotension
  --> Decrease in cerebral blood flow
  --> Ischaemic paralysis of the medullary ventilatory centre
  * The most likely cause of apnoea
• Rarely, the apnoea can also be caused by phrenic nerve paralysis
• Concentration of LA in CSF is too low to have direct effect on ventilatory centres

Anti-inflammatory effect

LA may modulate inflammatory responses, by

• Inhibiting inflammatory mediator signaling
• Inhibiting accumulation of neutrophil at sites of inflammation and thus impairing free radical and mediator release

Other uses of LA

Analgesia

Use of IV LA in production of analgesia is limited by the small margin of safety between IV analgesic doses and those that produce systemic toxicity

Suppression of ventricular cardiac dysrhythmia

IV administration of lidocaine can

• Suppress ventricular cardiac dysrhythmias
• Increase defibrillation threshold

Suppression of generalised tonic-clonic seizures

Generalised tonic-clonic seizures have been suppressed with low doses of IV lidocaine or mepivacaine

Bronchodilation

Inhaled lidocaine and ropivacaine cause:

• Attenuation of histamine-induced bronchospasm
• Airway anaesthesia (topical effect)

Tumescent liposuction

• Large volumes (5L) of highly diluted lidocaine (0.05-0.10%), with epinephrine (1:100,000)
• May have increased risk of lidocaine toxicity

 

 

=== from Peter Kam lecture ===

Cocaine - vasoconstriction due to blockage of reuptake of NE at NMJ

Potency increases with increasing alkyl group length on aromatic and tertiary amine group

Potency also increases with increasing hydrophobicity (or lipophilicity) of the total compound

Isomers: structural, geometric (cis, trans), optical isomers

Optical isomers: same formula, same connectivity, groups connected the same way, has chiral centre, non-superimposible mirror images

Frequency dependent blockade - LA can access receptors when channel is in activated-open state. Resting nerves are less sensitive to blockade than active ones.

Order of nerve blockade

Preganglionic sympathetic

Then pain and temperature

Then touch and pressure

Then motor

NB: Large mixed nerves may not follow this pattern.

LA are weak-bases with pKa of 8-9 (similar to opioids)

Renal failure

Clearance of LAs not altered as inactivation in liver (amides) or plasma (esteres)

Levobupivacaine

S(-) isomer

S isomer of ketamine

More sympathetic stimulation, greater clearance, 3x more potent analgesia

Tramadol

+ enantiomer - more effective as mu receptor and 5-HT receptor inhibitors

- enantiomer - inhibitor of NA reuptake and promotes NA release

The isomers of tramadol are synergystic --> Racemic mixture is superior

Thalidomide

R enantiomer - an effective sedative

S enantiomer - teratogenic

Administration of R isomer still produced teratogenic effects

Was being racemised back to S and R isomers following administration

Clinical trials

Phase 1 - new drug is tested in a small group (n=20-100) to evaluate safety, dosage, and side effects

Phase 2 - given to a larger group to check efficacy and incidence of side effects. Months to years.

Phase 3 - larger group confirm effectiveness and compare to current treatments. Several thousands patients. Trials are randomised and blinded. This stage lasts years

Phase 4 - post-marketing surveillence. Long term effectiveness. Specific groups (e.g. elderly)

Penothal
Thiopentone sodium
Active ingredient

Sodium carbonate

Nitrogen

Diprivan
Propofol --> Active ingredient
Water and lipid --> To form an emulsion (a stable mixture of oil and water)
Lecithin --> To stabilise the emulsion
Sodium hydroxide --> To adjust pH
Glycerol --> To adjust tonicity
Antimicrobial agents --> To reduce bacterial growth

Nomenclature
Chemical
N-diethylaminoacetyl-2,6-xylidine hydrochloride

Approved
Lignocaine
Lidocaine

Trade name – xylocaine

 

Diprivan = propofl = 2,6 Di-isopropyl phenol

Meperidine = pethidine

Adrenaline = epinephrine

====

 

Ropivacaine vs bupivacaine

Motor block by ropivacaine is less intense and of shorter duration [James] [???]

60% the potency of bupivacaine [???]