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27 Cards in this Set
- Front
- Back
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What does alkalinisation do to LAs and why?
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Alkalinization gives faster rate of onset, enhances depth of sensory and motor blockade, increases spread of epidural blockade.
LAs are weak bases with pKA=8. Only about 3% exists in lipid soluble form --> alkalinisation increases lipid soluble form that can diffuse across lipid cell barriers. Adding NaHCO3 will speed the onset of peripheral nerve and epidural blocks by 3-5 min |
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How are LAs classified?
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Ester LAs and amide LAs.
Esters have a -CO- bond linking hydrocarbon chain to the lipophilic aromatic ring, whereas amide LAs have a -NHC- bond joining them |
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Which LAs are chiral?
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The pipecoloxylidide LAs: mepivacaine, bupivacaine, ropivacaine, levobupivacaine
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Which LAs are commercially available as racemic mixtures?
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Bupivacaine and mepivacaine
(note: the S enantiomers of these drugs are less toxic than the racemic mixtures!) |
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Which LAs are available as pure stereoisomers?
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Ropivacaine and levobupivacaine have been developed as pure S enantiomers
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What is the mechanism of action of LAs?
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Prevent transmission of nerve impulses (conduction blockade) by inhibiting passage of Na+ ions through ion-selective Na channels in nerve membranes
Also, open sodium channels can be occluded by LA molecules (contributes little to overall inhibition) Failure of Na ion channel permeability to increase slows rate of depolarisation such that threshold potential is not reached and AP is not propagated. LAs do not alter RMP. |
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Tell me more about how LAs affect sodium channels
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Sodium channels exist in activated-open, inactivated-closed, and rested-closed states during various phases of the action potential.
LAs selectively bind to Na+ channels in inactivated-closed states, stabilising these channels in this configuration (not permeable to Na) and preventing their change to rested-closed and activated-open states in response to nerve impulses. |
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What happens when you substitute the amine group on the benzene ring of procaine for a butyl group?
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Changes procaine to tetracaine - more lipid soluble, 10x more potent, longer duration of action due to 4-5x decrease in rate of metabolism
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What happens when you halogenate procaine?
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Halogenated procaine is chloroprocaine. 3-4x increase in the hydrolysis rate of chloroprocaine by plasma cholinesterase, thus decreaseing duration of action and systemic toxicity.
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What happens when you substitute a propyl group for the ethyl group at the amine end of lignocaine, and add an ethyl group on the alpha carbon of the connecting hydrocarbon chain?
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Changes lignocaine to etidocaine - 50x increase in lipid solubility and 2-3 fold increase in duration of action
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What happens when you add a butyl group to the piperidine nitrogen of mepivacaine?
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Results in bupivacaine, which is 35 times more lipid soluble and has potency and duration of action 3-4 times that of mepivacaine
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What is Cm for LAs?
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Analogous to the MAC for inhaled anaesthetics, it is the minimum concentration of LA necessary to provide conduction blockade of nerve impulses
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What factors affect Cm?
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Nerve fibre diameter: larger nerve fibres require higher conc of LA (higher Cm)
Type of nerve: Cm of motor fibres is approx 2x that of sensor fibres, hence sensory anaesthesia is not always accompanied by motor paralysis |
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Why is less LA needed for subarachnoid anaesthesia than epidural anaesthesia?
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The Cm for both are actually the same, but subarachnoid route gives better access of LAs to unprotected nerves in the subarachnoid space
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How many nodes of Ranvier must be bocked for conduction blockade?
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A minimal length of myelinated nerve fiber must be exposed to an adequate concentration of LA for conduction blockade to occur.
If only 1 node of Ranvier is blocked, the nerve impulse can skip across this node. For conduction blockade to occur in an A (myelinated) fibre, it is necessary to expose at least 2-3 successive nodes of Ranvier (approx 1 cm) to adequate conc of LA |
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What nerve fibres are myelinated?
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A and B fibres
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What nerve fibre type is more readily blocked by LAs than any other fibre?
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Preganglionic B fibres (myelinated)
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What is differential conduction blockade?
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Differential conduction blockade is illustrated by selective blockade of preganglionic sympathetic nervous system B fibres using low concentrations of LAs. Slightly higher onc intterupts conduction in small C fires and small and medium sized A fibres with loss of pain and temperature sensation
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What percentage of LA exists in nonionised form at physiological pH?
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LAs are weak bases with pKa (7.6 to 8.9) above physiological pH, thus <50% of LA exists as nonionised in the body. LAs with pKa nearest to physiologic pH have the most rapid onset of action.
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What happens when LA is injected into an infected area?
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Infected sites are acidic. Acidification of the environment where LAs are injected in makes the proportion of nonionised LA lower, thus decreasing the duration of action and potency of the LA.
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Tell me about lignocaine
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Amide LA
Rapid onset Medium (60-120 min) duration of action Toxic plasma conc: 5 mcg/ml pKa: 7.9 Nonionised: 17% |
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How is lignocaine metabolised?
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Oxidative dealkylation in the liver to mono-ethyl-glycine-xylidide, followed by hydrolysis to xylidide.
MEGX has approx 80% of lignocaine's anti-dysrrhythmic activity. Xylidide has 10% |
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What can impair lignocaine metabolism?
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Liver disease or decreased hepatic blood flow (i.e. during anaesthesia with volatiles). Elimination t1/2 is increased x 5 with liver dysfunction.
Maternal clearance is prolonged in pregnancy induced hypertension |
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What are the potential side effects of LAs?
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Allergy
Systemic toxicity Neurotoxicity CVS toxicity Methemoglobinemia Altered ventilatory response Hepatotoxicity Dysphoria |
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Tell me about allergic responses to LAs
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Rare. More likely with LAs that metabolise to paraaminobenzoic acid (procaine, chloroprocaine)
Cross sensitivity reflects the common metabolite paraaminobenzoic acid. So if a person is allergic to ester, can still receive amide LA |
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Tell me about systemic toxicity with LAs
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Due to excess plasma concentration, depends on:
1. dose administered into tissues. 2. vascularity of injection site. 3. presence if adrenaline in solution. 4. physicochemical properties of drug. With increasing plasma conc: numbness of tongue and circumoral tissues --> restlessness, vertigo, tinnitus, difficulty focussing --> slurred speech, skeletal musle twitching --> drowsiness, tonic-clonic seizures |
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Tell me about the development of seizures in LA toxicity
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Skeletal muscle twitching is often first evident in face and extremities, signals imminence of tonic-clonic seizures
Amides may cause drowsiness before seizure. Seizures are followed by CNS depression, and may also have hypotension and apnoea. Mechanism: selective depression of inhibitory cortical neurons by LAs, leaving excitatory pathways unopposed. Or, LA inhibition of neurotransmitters such as GABA. Site of seizures appears to be temporal lobe or amygdala |
