Local anaesthetics. Antidysrhythmic drugs. Flashcards
When are local anaesthetics (LAs) used ?
What do they do ?
How do they work ?
- To produce reversible regional loss of sensation or pain without loss of consciousness
- LAs reversibly block the generation and conduction of the action potential
- They work by affecting voltage-gated Na+ channels
What was the first LA ?
How what is used ?
The first local anaesthetic was cocaine :
• isolated from coca leaves (1862)
• used as local anaesthetic during eye surgery (1884)
• first used in dental surgery (1884)
Why were cocaine analogs searched for ?
What were these analogs ?
The toxic and addictive properties led to search for analogs:
- procaine (1905) trade name Novocainefrom the Latin novus (new) and caine (as in ‘cocaine’)
- lidocaine (1943) trade name Xylocaine
What is the common general structure of a LA ?
Name LAs that have this structure.
- an aromatic group
- an intermediate chain (ester or amide bond)
- a tertiary or secondary amino group
Procaine, tetracaine, lidocaine, bupivocaine.
What is the ionic bases of the action potential ?
What are the channels involved ?
What are they responsible for ?
What is channel activation ?
Two channels underlie the action potential (AP) :
• Na+ channels allow Na+ influx - depolarisation
–> [Na+] is low inside and high outside
•K+ channels allow K+ efflux - repolarisation
–> [K+] is high inside and low outside
Both channel types are voltage-dependent
The membrane depolarisation causes channels to open
Transition from closed–open = activation
• Na+ channel activation is rapid, followed by inactivation
• K+ channel activation is delayed
Depolarisation past a critical threshold triggers AP.
What is this threshold ?
– when Na+ influx > resting K+ efflux, and
–when depolarisation due to Na+ influx is sufficient to activate neighbouring Na+ channels (a regenerative positive-feedback process)
What is the effect of increased Na+ conductance on the membrane potential ?
The selective increase in Na+ conductance causes a shift in membrane potential towards E(Na) (about +60 mV).
What triggers repolarization during the AP ?
Repolarisation begins when the Na+ channels rapidly inactivate and the K+ channels slowly activate.
Most LAs are weak bases.
Why is this crucial for their absorption from tissue fluid ?
- LAs are administered as water soluble hydrochlorides (B.HCl)
- after injection, the tertiary amine base (B) is liberated by the relatively alkaline pH of tissue fluids:
B.HCl + HCO3- ⇌ B + H2CO3 + Cl- - in tissue fluid the LA will be present in both an ionised (BH+) and non-ionised form (B) :
B + H+ ⇌ BH+ - the non-ionised base (B) diffuses through the nerve sheath, perineuronal tissues and the neuronal membrane, to reach the axoplasm where it partially ionises again
How do LA block Na+ channels ?
- when the Na+ channel opens, the ionised form BH+ enters the channel and combines with a specific channel subunit resulting in channel blockade
Where do LAs bind on the Na+ channel ?
- Local anaesthetics bind to sites located in the inner cavity of the pore of the sodium channel.
- Amino acid residues in the S6 segments from at least three of the four domains that contribute to the receptor site, with the IVS6 segment playing the dominant role.
What are the 2 pathways by which LAs can act ?
Which of these is use dependent ?
What is use-dependency ?
Why is one pathway use dependant and the other not ?
- 2 pathways = hydrophilic + hydrophobic pathway
- the hydrophilic pathway exhibits strong use-dependency –> block develops faster and is greater when the fibre is conducting PAs at high frequency (e.g. 10 Hz vs. 1 Hz)
- this is because the channels are open more often allowing the charged LA into the channel
- in the inactivated state the channel has a higher affinity for LA (charged and uncharged) than in the resting state
What are the properties that determine the potency, duration and onset of block of LAs ?
Potency
- Lipid solubility is the most significant property of LAs in determining anaesthetic potency. Those that are highly lipophilic, easily penetrate nerve cell membranes.
Duration of Conduction Block
- The duration of conduction block is +ely correlated with the capacity of a LAs to bind to plasma and tissue proteins.
Onset of Conduction Block
- pKa is pH at which 50% of the agent exists in the ionic and 50% non-ionic form.
- Lower pKa = greater fraction of the molecules exist in the uncharged form : pKa = pH + log([B]/[BH+])
- pKa affects onset of conduction blockade as this is related to the concentration of the LA present in the non-ionic form. (= more able to across nerve membranes = faster onset).
All nerve fibers can be blocked.
Which ones are blocked first depends of their characteristics.
What are these characteristics ?
- Thin fibres are more easily blocked than thick ones.
Small myelinated fibres are more readily blocked than non-myelinated ones. - Degree of block at a given concentration of LA depends upon the recent frequency of nerve activity –> use-dependence of block
- Small diameter C and Aδ pain fibres fire at a high frequency and are blocked earlier and sooner with low concentrations of LA than are the Aα fibres
Put the order in which the following elements are blocked :
- cold
- pressure
- warmth
- touch
- pain
- motor
pain > cold > warmth > touch > pressure > motor
LA exits either as amino ester or amino amides ?
How are these metabolized ?
Which is more stable and why ?
- Amino esters types (e.g. procaine, tetracaine) are relatively unstable in solution and are rapidly hydrolysed in the body by plasma cholinesterase (and other esterases).
- Amino amides (e.g. lidocaine, prilocaine) are stable in solution, are slowly metabolised by hepatic amidases.
What are possible toxic/side effects of LA use ?
Local tissue injury
• May occur with infiltration and spinal anaesthesia CNS effects
• Low concentrations –> tinnitus, numbness of the tongue, blurring of vision, drowsiness.
• Higher concentrations –> agitation with hyperactivity, occasionally convulsions, followed by profound CNS depression and respiratory depression.
CV effects
• Vasodilation, depression of myocardium and cardiac slowing, leading to hypotension. Cardiac block.
Allergic reactions
• One of the main breakdown products of ester types is
para-amino benzoate (PABA) which can be associated with allergic phenomena and hypersensitivity reactions.
What are the different methods of LA administration ?
- surface anaesthesia
- infiltration anaesthesia
- nerve block anaesthesia
- spinal anaesthesia
- epidural anaesthesia
- intravenous regional anaesthesia
What is surface anaesthesia ?
Which drugs are usually used for this ?
Topical application to mucosa (solution, spray, jelly, lozenge) e.g. cornea, mouth and larynx, bronchial tree,
urethra and bladder
Drugs of choice :
- lidocaine
- benzocaine - may be used as powder for prolonged anaesthesia of skin ulcers or burns
- lidocaine/prilocaine cream (EMLA - “eutectic mixture of local anaesthetics”)
What is infiltration anaesthesia ?
Drug injected directly into the tissue to anaesthetise nerve endings. e.g. wound stitching, minor surgery, episiotomy during childbirth, vasectomy Drugs of choice: - lidocaine - prilocaine Supplemented with vasoconstrictors to delay absorption --> prolongs duration of action and reduces risk of systemic toxicity : - AD or NA - vasopressin - felypressin
What is nerve block anaesthesia ?
Drug injection close to nerve trunk to anaesthetise area served by the nerve. e.g.
- mandibular nerve –> dentistry
- brachial plexus –> hand surgery
