Neuro non drug table Flashcards
potency of anaesthetic agents in linearly correlated with
Lipid solubility
◦ Relates to their ability to cross and manipulate the activity of ion channels --> ligand gated channels are moe sensitive to the action fo general anaesthetics than voltage gated channels
Lipid solubility of local anaesthetics is determined by>
pKa which in turn determines potency
How are local anaesthetics formulated
Hydrochloride salt with sodium metabisulfite and fungiside preservatives; further preservative 1mg/mL methyl parahydroxybenzoate in multidose bottles
What concentration is adrenaline in when added to LA
1:200 000
5mcg/mL
pKa for LA
Acid or base
- pKa for most of them is ~8-9, and they are weak bases
Describe how pKa and MOA work for LA
◦ After injection, at body pH they become more lipid soluble –> solubility and lipophilicity are primary determinants of absorption into the neuron/potency but also affects local distirbution and likelihood of being washed away by local blood flow
◦ This allows them to penetrate the cell and bind to the intracellular part of the voltaged-gated sodium channel, which is their site of action
◦ Most local anaesthetics have a pKa of something like 8.0-9.0, and are presented in an aqueous solution.
◦ Aqueous solutions of local anaesthetics are buffered down to a pH of 5.0-6.0, which makes them ionised and therefore water-soluble.
◦ Once injected into the tissues, this acidic liquid dilutes into extracellular fluid and the local anaesthetic molecules become more lipid-soluble (now being bathed in a pH of 7.40).
◦ Now they can penetrate into the cells.
◦ Inside the cells, conditions are slightly more acidic (pH ~ 6.9)
◦ Thus, more of the agent will be present in its cationic form
◦ This is good because only the charged form can bind to the voltage-gated sodium channel.
LA binding domain? What characteristics of the channel are required for binding? What important characterstics of the LA are required to bind?
◦ Bind to INTRACELLULAR domain of voltage gated sodium channels in their OPEN state inside the channel pore then blocking the channel by stabilising its inactive state
‣ Also block other ion channels
‣ Needs to be in its ionised form (protonated) to do this –> the axoplasm is more acidic favouring this anyway
Is local anaesthetic action concentration dependent?
Yes, decrease in amplitude of action potential is concentration dependent, and if enough are blocked the membrane does not reach threshold
What state do the LA stabilise
Inactive
What states can a sodium channel be in?
Open
Inactive
Resting
What does phasic block refer to?
Property of LA
- They preferentially bind to the channel in its open state, stabilising it in the inactive state
◦ This gives rise to use-dependent block (PHASIC block), where repeated stimulation of the axon makes more open channels available, and increases the blockade effect.
What is the term for block that i use dependent in LA
- They preferentially bind to the channel in its open state, stabilising it in the inactive state
◦ This gives rise to use-dependent block (PHASIC block), where repeated stimulation of the axon makes more open channels available, and increases the blockade effect.
Differential block means what?
- Differential block
◦ They preferentially affect pain and temperature fibres (“Differential block”), possible because they are largely unmyelinated (C-fibres); but also autonomic neurotramission with motor block only at HIGH concentrations
What afferents do local anaesthetics primarily affect?
- Differential block
◦ They preferentially affect pain and temperature fibres (“Differential block”), possible because they are largely unmyelinated (C-fibres); but also autonomic neurotramission with motor block only at HIGH concentrations
Potency of local anaesthetics is related to?
◦ Correlated to lipid solubility - tissue distribution and vasodilator properties determine amount of clocal anaesthetic available
‣ e.g. vasodilation at low concentrations (prilocaine > lidocaine > bupivocaine > ropivocaine) - vaso constrcti at high concentrations.
◦ Ineffective in infected tissue as acidic environment reduced unionised fraction and increased vascularity removes drug from area
Duration of action of a local anaesthetic agent is related to?
Protein binding
Onset of action of a local anaesthetic is related to?
◦ Related to pKa - high pKa have more in the ionised form and cannot penetrate the nerve as quickly, and the inverse
What is the structure of a local anaesthetic 3
Lipophilic aromatic ring - essential to anaesthetic activity
Hydrophilic amine group - allows ionisation and water soluble. Alkalyl substitutions make for larger molecules adn more lipid solubility = higher potency
Intermediate chain linkage - ester or amide
Distirbution and protein binding for local anaestheteics
◦ Highly protein bound e.g. lignocaine bound to both albumin and alpha 1 acid glycoprotein (bupivocaine and ropivocaine also >95% bound)
‣ Free fraction reduced when lots of protein e.g. pregnancy, MI, renal failure, post op, infancy
‣ Note if foetus becomes acidotic then there will be increased local anaesthetic accumulation there (ion trapping); esters do not cross the placenta in significant amounts
◦ Vd 0.9L/kg for lignocaine and 2.7L/kg for prilocaine (the largest)
◦ Esters minimally bounds
◦ Amide protein binding: bupicacaine > ropivacaine > lidocaine > prilocaine
What are the two subclasses of local anaesthetics? 3 examples of each
Amides - lignocaine, ropivocaine, bupivocaine
Esters - cocaine, procaine, amethocaine
What structurally is differnent between esters and amides
- Esters have an ester intermediate chain
- e.g.
Amides have an amino intermediate chain
Metabolism and clearance for esters
◦ Plasma esterases rapidly degrade via hydrolysis e.g. prilocaine <10 minutes to para-aminobenzoate which has been associated with hypersensitivity reactions
◦ Cocaine the exception undergoing a hepatic metabolism by amidases
◦ Additionally also has a shorter shelf life as esters degrade more easily
Metabolism and clearance of amides
- Metabolism and clearance
◦ longer halflives
◦ cleared by the liver - lignocaine has active metabolites - reduced hepatic blood flow or hepatic dysfunction markedly reduces clearance
LA toxicity affects which 2 systems things primarily
CNS
CV
Methaemoglobinaemia in prilocaine
Which more commonly occurs in local anaesthetic toxicity - CNS or CV
CNS at lower doses
Usually 1:3 dose relationhip
Bupivocaine has a reduced ratio
Describe the phases of CNS toxicity for local anaesthetic agents
◦ At lower doses: (inhibitory interneurons blocked)
‣ Visual disturbances (resembling nystagmus) - objects oscillate
‣ Perioral numbness
‣ Lightheaded, tinnitus
◦ At increasing doses: all neurons blocked
‣ Slurred speech
‣ Incoherent conversation
‣ Confusion and decreased level of consciousness
◦ With very large doses:
‣ Seizures - as inhibitory neuronal activity is suppressed
‣ Coma with EEG features of non-convulsive status or burst suppression
Cardiovascular toxicity of local anaesthetics
◦ Lower dose effects are sympathomimetic:
‣ Hypertension
‣ Vasoconstriction
‣ Tachycardia
◦ With increasing doses cardiodepression occurs and vasoconstriction changes to vasodilation
◦ Higher dose effects:
‣ Hypotension (systemic vasodilation)
‣ Bradycardia and heart block - spontaneous pacemaker activity prolonged
‣ Decreased VMax (prolonged 0 phase), QRS prolongation, QT shortened, arrhythmias, cardiac arrest
What patient risk factors increase the risk of local anaesthetic toxicity 6
◦ Acidosis
‣ Only the charged version can bind to voltage gated sodium channels - in intracellular acidosis more of them in active ionised state
‣ Acidosis also reduced protein binding increasing free drug
‣ Acidosis increases the partition coefficient of local anaesthetic to the myocardium
◦ Old age: slower clearance due to reduced hepatic blood flow, more cardiofragile
◦ Young age: lower α1-acid glycoprotein level, higher free fraction
◦ Pregnant patients: lower α1-acid glycoprotein level, better perfusion of blocked tissue therefore faster systemic washout
◦ Concomitant use of another antiarrhythmic
◦ Hyperkalemia (decreased toxic dose of agent)
Pharmacologcial factors increaase the change of local anaesthetic toxicity 5
◦ Dose (obviously) - dose to ideal no actual body weight
◦ Choice of agent (some drugs, eg. bupivacaine, have a lower CC/CNS ratio)
‣ The difference in the dose required to cause cardiac complications vs CNS
◦ Site of administration (eg. closer to large vessels, hyperaemic site, epidural)
‣ Increased risk of direct intravascular injection:
* Interscalene block
* intercostal
* Epidural
* Brachial plexus block
* Stellate ganglion block
* Intercostal nerve block
‣ Increased risk of rapid absorption:
* Scalp
* Bronchial mucosa
* Interpleural cavity
* Epidural
◦ Coadministration of vasoconstrictor (slows systemic absorption)
◦ Slower dissociation from sodium channels (eg. bupivacaine)
◦ Drug interactions:
‣ displacement from protein binding (eg. by phenytoin)
‣ decreased metabolism (eg. by cimetidine of amides)
‣ Delayed absorption - adrenaline
Management of locala anesthetic toxicity comes down to 3 factors
◦ Supportive
‣ Seizures - Benzos to raise seizure threshold
‣ Decreased GCS - intubated
‣ Cardiovascular collapse - supportive +/- ECMO
◦ Alkalinise or hyperventilate as binding is pH dependent
‣ Increase protein binding when alkalosis
‣ Decrease charged fraction (active and capable of binding sodium channels)
◦ Increase the distribution into lipid:
what is the dose for intralipid
‣ Give intralipid emulsion to increase lipid-bound fraction and decrease free fraction
* 1.5mL/kg IV over 1 minute then continuous infusion 0.25mL/kg/minute
◦ Bolus can be repeated and infusion doubled if resistance
◦ Maximum dose over first 30 minutes 10mL/.kg
What is the MOA for intralipid (4)
- Lipid sink - highly lipid soluble LA moelcules absorbed into intralipid reducing free fraction
◦ Tissue extraction because free fraction drops decreased CNS and CVS
* Lipid shuttle - deliver anaesthetic to the liver enhancing rate of elimination
* Metabolic changes in mycoardium - increased fatty acid reverses LA reduced reduction in FFA metabolism in mitochondria, providing energy substrate
* May prevent Na channel inhibition
* Inoconstrictor - inhibits NO release
Give the 2 classes of classical antipsycotics and 2 examples of each
- Phenothiazines
◦ CHlorpramazine
◦ Prochlorperazine - Butyrophenones
◦ Haloperidol
◦ Droperidol
What is a phenothiazine
1st Gen classical antipsychotic
Chlorpromazine and prochloperazine
What is a butyrophenone?
- 1st Gen antipsyhotic
- Butyrophenones
◦ Haloperidol
◦ Droperidol
