5. Local Anaesthetics Flashcards
Amides include
lidocaine, prilocaine, bupivacaine and ropivacaine Mepivicaine
More common in practice
esters
amethocaine procaine Cocaine Chloroprocaine Tetracaine, and Articaine.
Lipid solubility influences
Lipid solubility influences the time it takes the local anaesthetic to penetrate the neuronal membrane and is one of the most important determinants of potency, particularly in vitro
dissociation constant, pKa
affects the speed of onset of action and it determines the proportion of drug in the un-ionised (that is, lipid soluble) form.
When the pH equals the pKa of the drug, the ionised and un-ionised forms are present in equal proportions (that is, 50:50).
At phys pH
Buipvicaine / ropicane - unionised %
pKa
Lido + prilo unionised %
pkA
At physiological pH (pH 7.4)
17% unionised form for bupivacaine (pKa 8.1)
/ropivacaine
33% in unionised form for lidocaine (70% prot bound) and prilocaine (pKa 7.7)
Procaine pka 8.9
Bupivicaine Type Dose Mix + affects Pka
Affect on heart
Amide
Dose 2mg/kg Racemic S- less cardiotox block voltage Na affect ph 0 of potential S- also affect RyR2 - Ca rel from SR pka 8.1 long duration lido
Produce dilatation @ clin dose
Subclin intradermal - vascon biphasic peripheral CV
Expressed as- %
what is 1%
Local anaesthetic agents and glucose-containing solutions are expressed as a percentage.
A 1% solution is 1 g per 100 ml solution or 1000 mg per 100 ml solution.
10 ml of a 1% solution contains 100 mg of solute.
Ambulatory surgery
The ideal local anaesthetic for a spinal anaesthetic for day case surgery are chloroprocaine (duration of surgery up to 40 minutes) and prilocaine (duration of surgery up to 90 minutes). Accurate estimation of duration of surgery is key to the choice of drug.
TNS w/ lidocaine & mepivicane - unsuit
failure rate w/ bupivicaine / may need fentanyl or top up
Lidocaine
Type
Chirality
Group?
Broken down by what
pKa
uv:m vs bupivicaine
Lidocaine is an achiral amide local anaesthetic and contains a lipophilic aromatic group, an intermediate amide (-NH.CO-) chain and a hydrophilic group.
Amide local anaesthetics are broken down by amidases in the liver, whereas ester local anaesthetics are rapidly hydrolysed by plasma cholinesterase.
The pKa of lidocaine is 7.8-7.9
In general, highly protein-bound drugs have a low umbilical vein to maternal blood ratio (uv:m). The uv:m ratio for bupivacaine is approximately 0.2; and for lidocaine and prilocaine it is 0.5. Therefore, lidocaine transfers across the placenta more than bupivacaine.
ivra
ntravenous regional anaesthesia is prilocaine. It has the largest therapeutic index of all the amide local anaesthetics. Prilocaine has become the agent of choice for Bier’s block, since 1983 when the product licence of bupivacaine was withdrawn for this purpose owing to fatal or serious complications.
Lidocaine is a suitable alternative but the volume and dose is likely to be inadequate for this procedure.
Lipid solubility
Protein binding -
pka
A) to act they need to penetrate the lipid cell membrane to enter the cell. The higher the lipid solubility the more penetration there is through the cell membrane.
Protein binding reflects on the ability of the drug to be bound to membrane proteins so the greater the binding the longer the duration of action.
All local anaesthetics are weak bases and it is the unionised form that diffuses more readily across the nerve membrane than its protonated form. So, a drug with a higher pKa will have more ionised drug than a LA with a lower pKa at a given pH, and so a slower onset of action.
LAST likelihood depends
The likelihood of local anaesthetic toxicity is dependent on a number of factors. These include:
Site of injection, i.e. vascularity and presence of fat
Drug dose and concentration
Use of vasoconstrictors, and
Changes in protein binding in relation to intracellular pH.
The most vascular areas into which local anaesthesia is more prone to systemic absorption (in order) are:
Intercostal and paracervical block Caudal block Lumbar and thoracic epidural block Brachial plexus block Sciatic/femoral nerve block Subcutaneous infiltration.
Levobupivicaine
Enantiopure
D isomer of bupivacaine had a higher potential for toxicity
Blockade of the sodium channels is stereoselective
D isomer - potenter - includes cardiac
pKa of levobupivacaine is 8.1
Protein binding of levobupivacaine >97% (vs 95 for bupiv)
3% is free - toxic effects
In nephrotic + other hypoprotinaemic patients - higher potential tox - less prot for bind)
LAST
Why light head
Side effect - bupiv v levo
VF easy to rx
Light-headedness is usually due to the direct effect of local anaesthetic toxicity on the central nervous system.
Fentanyl is not a local anaesthetic and therefore cannot cause local anaesthetic toxicity.
L-bupivacaine and ropivacaine have better side effect profiles than bupivacaine and are considered safer in the event of toxicity. Intermittent boluses of 0.1% bupivacaine are not usually associated with cardiac side effects in healthy patients.
Ventricular fibrillation due to bupivacaine is resistant to treatment (refractory) and resuscitative efforts are usually prolonged.
Adjuvant drugs for LA
work by
Adjuvant drugs interact with neurotransmitters at the dorsal horn systems and block nociceptive transmission in the spinal cord.
The most widely used include:
Alpha 2 adrenergic drugs (clonidine) Anticholinesterases (neostigmine) NMDA receptor antagonists (ketamine) N-specific calcium-channel antagonists (ziconotide) Opioids Adrenaline.
EMLA
mix of what & what percent
Phsyical prop
Speed onset
Forms what by what
Where can it be used
is the Eutectic Mixture of Local Anaesthetics. Eutectic mixture is formed by two compounds mixing to produce a substance of a single set of physical characteristics. EMLA contains 2.5% lidocaine and 2.5% prilocaine in oil:water emulsion. The melting point is lowered to produce an oil at room temperature.
Unlike amethocaine (22-25 minutes), it has a slower speed of onset of 60 minutes.
EMLA may cause the formation of methaemoglobin due to the o-toluidine produced when prilocaine is metabolised. Therefore, it should be avoided in patients with methaemoglobinaemia.
It should not be used on mucous membrane due to excessive systemic absorption.
Which LA are chrial
Anaesthetic activity of LA
- vs Bupivicaine
S - or R +
activity
Potency
Vasoconstriction
Toxicity
Chirocaine is…
Prilocaine and bupivacaine are chiral compounds.
(prilo safe dose 6mg kg)
Most ester local anaesthetics, as well as lidocaine are achiral.
Individual enantiomers have approximately equal local anaesthetic activity, although R (+) bupivacine may be more potent than the S (-) enantiomer.
The S (-) enantiomers produce enhanced vasoconstriction and have prolonged local anaesthetic activity; they may also be less cardiotoxic.
The S (-) enantiomers (nor R) may have reduced potential for toxicity when compared with the racemic mixture of the drug.
Chirocaine is the S (-) enantiomer of bupivacaine and is commercially available for clinical use.
Local anaes are weak -
Produce what
How do they act
Esters metabolised by -
effect pregnancy
effect lvier disease
Amides metabolised by
Depends on
Infected tissues?
Local anaesthetics are poorly water soluble weak bases
Produce a reversible block of conduction along nerves.
They enter the nerve in lipid soluble form and once in the nerve the ionised form binds to and blocks the sodium channels from within. Thus sodium entry during depolarisation is prevented, which results in failure to reach the threshold potential and failure of propagation of the action potential (membrane stabilising effect).
Esters are metabolised by plasma and liver cholinersterases and the level of these enzymes is low in pregnancy and liver disease.
Amides are metabolised by liver microsomal enzymes, which are dependent on liver function and blood flow (not independent).
The pH in infected tissues is lower than normal, so the effects of local anaesthetics is reduced (not increased).
Prilocaine
type of anaesthetic
Amide
- liver
- can undergo renal and pulmonary biotransformation.
Amide hydrolysis
- O-toluidine
development of methaemoglobinaemia.
N-propylamine.
All LA membrane stabilisers
-Block sodium channels in excitable tissue.
44-50% protein bound
- alpha-1-acid glycoprotein
Prilocaine spray can produce topical anaesthesia when used as a spray but gets rapidly absorbed.
It is more effective when combined with lidocaine (as a eutectic mixture) or phenylephrine.
Local anaesthetics are
Drugs compounds that produce temporary blockade of neuronal transmission when apply to a nerve fibre
Both consist liphilic aromatic ring, link hydrophil amine
Difference between esters and amides
draw the basic structure
Structural & functional differences
Structural
Link between aromatic ring & amine,
ester have -O-CO-
Amides have -Nh-CO-
Draw - page 203
Functional difference - stability sooln
Ester - unstable
Amide remain stable 2 year
PL prop
ester minimally protein bound
Amid more extense bound
Metabolism diffce
Ester rapidly hydrolysed plsama cholinesterase - > inactive
Amide meatbolised - slower in liver - amidases
Acummulate in dysfnx
Ester - higher incidence allergy - paraminobenozate
