Pharmacology 6 Flashcards
Briefly, what are local anaesthetic agents, and what are they used for?
LAs are membrane stabilisers that block the propagation of action potentials along neuronal axons. They are used extensively throughout anaesthesia for analgesia, regional anaesthesia and as adjuncts to general anaesthesia. They may also be used for their antiarrhythmic properties.
What are the components of an neuronal axon?
- Phospholipid bilayer
- Membrane receptor proteins
- Transmembrane proteins forming pores, channels or transport mechanisms.
Describe the phases of transmission of a neuronal action potential
Phase 1: Resting transmembrane potential (TMP) of -80mV is maintained by Na/K/ATPase. 3xNa out, 2xK in for 1xATP.
Phase 2: An AP is initiated at the synapse, causing a stimulus which opens voltage-gated Na channels, allowing influx and increasing TMP to +30mV. (Depolarisation)
Phase 3: Voltage-gated K channels open allowing efflux of K+ ions. Na/K/ATPase continues its activity, restoring resting TMP. (Repolarisation)
Describe the mechanism of action of local anaesthetic agents
- Block axonal voltage-gated Na channels.
- Prevent depolarisation + propagation of AP.
- Exert effects INTRACELLULARLY, thus must cross membrane.
- Crossing membrane depends on amount of UNCHARGED drug.
- Intracellular effect exerted by IONISED drug.
- Degree of action possibly related to number of ‘open’ Na channels, thus LAs have less affinity for resting-state neurones.
- Clinical effects mediated through increase in threshold for depolarisation, slowing of conduction and decrease in slope and amplitude of AP
How do the physical properties of a nerve affect speed of onset of LA action?
- Small-diameter neurones affected prior to large
- Myelinated fibres are blocked prior to unmyelinated
How are LAs categorised?
Structurally - Esters and Amides
Esters: Ring-COOR1-N-R2/R3
Amides: Ring-NHCOR1-N-R2/R3
Why is pKa relevant to local anaesthetic agents?
- Determines relative ionisation state of LA molecule in a given solution
- LAs are weak bases, thus will be ionised more below pKa
- Crossing membrane to exert LA effect requires UNIONISED drug
- At physiological pH, a lower pKa will result in more unionised drug to cross membranes.
- Thus pKa determines speed of onset. (Lower pKa = faster onset)
Outline the physical properties of local anaesthetic agents
- Produced as hydrochloric salts as need to be water-soluble
- Single-use ampoules are preservative-free, though ‘heavy’ preparations contain glucose
- Multi-use ampoules may contain preservatives eg. Na metabisulphite or methyl parahydroxybenzoate and fungicide
- Many concentrations are available for different applications eg. topical vs IV vs subarachnoid
Outline the pharmacokinetics of local anaesthetic agents
A:
- Dependent on route/site of administration (vascularity)
- Affected by vasoactive properties of particular LA. eg. Cocaine vasoconstriction / amethocaine (tetracaine) vasodilatation + erythema
- Affected by co-administration of adrenaline
D:
- Dependent upon plasma protein binding
- More highly-bound = longer duration of effect
M:
- Dependent upon type of LA
- Esters are hydrolysed by plasma esterases (mainly pseudocholinesterase) -> short half-life
- Ester hydrolysis produces para-aminobenzoic acid (PABA) -> potential for anaphylaxis
- Amides are metabolised in the liver and may have active metabolites.
E:
-Amides are excreted renally, mainly following metabolism. 5% unchanged.
List the commonly used local anaesthetic agents
- Lidocaine
- Bupivacaine
- Ropivacaine
- Prilocaine
- Cocaine
- Topical agents (EMLA, Ametop)
What are the preparations and uses of lidocaine?
1% + 2% for surgical anaesthesia
5% for topical patches (use limited)
10% for topical airway anaesthesia
Uses:
- Local anaesthesia (onset <2mins, duration 20-40mins)
- Adjunctive analgesic for general anaesthesia as IVI
- Class Ib antiarrhythmic for Rx of ventricular tachyarrhythmias
What is levobupivacaine and why is it widely used?
- Pure S-enantiomer of bupivacaine
- Less cardiotoxic
- Higher hepatic metabolism
What are the features of ropivacaine?
-Long-lasting LA (though
What are the features of prilocaine?
- Amide similar to lidocaine, though more intermediate duration of action.
- Less vasodilatation and less protein bound than lidocaine -> increased VD -> less CNS/cardiotoxicity
- Used in Biers block (IVRA) as a 2% hyperbaric solution.
- Causes methaemoglobinaemia due to aromatic ring metabolism to o-toluidine. This oxidises the Ferrous haem ion to its Ferric (Fe3+) form which binds O2 more avidly, causing tissue hypoxia.
What are the features of cocaine?
- Ester of benzoic acid
- Mainly used for nasopharyngeal mucosal anaesthesia for anaesthetic and vasoconstrictor effect (local NA reuptake inhibitor)
- Readily crosses BBB
- Vasoconstrictive properties affect coronary circulation -> may cause dysrhythmias and death
- Hydrolysed in the liver (in contrast to other ester LAs)
What are the types and features of topical local anaesthetics in use?
EMLA:
- Eutectic mixture of local anaesthetic
- 2.5% lidocaine + 2.5% prilocaine = 5%
- Used prior to cannulation esp. in paeds
Ametop(TM):
- 4% tetracaine (amethocaine)
- Avoids prilocaine in kids
- Causes local vasodilatation
State the maximum safe doses of commonly used LAs (+/- adrenaline)
Lidocaine - 3mg/kg (7mg/kg) Bupivacaine - 2mg/kg (2.5mg/kg) Levobupivacaine - 2.5mg/kg Ropivacaine 4mg/kg Prilocaine - 6mg/kg (9mg/kg)
Which drugs may be co-administered with local anaesthetics and why?
Adrenaline:
- Prolongs duration of effect due to slower absorption
- Unsafe for use in blocks involving end-arteries (eg. penile/digital blocks)
Opioids:
- mu receptor activation potentiates block in spinal, epidural and caudal anaesthetics
- Effect not equivalent with peripheral nerve blocks
Clonidine:
- Centrally acting α2 blocker
- Potentiates neuraxial blockade
- Sedative and hypotensive effect must be taken into account
Glucose:
-Increases density of injectate enables manipulation of block height and laterality
List the side effects of LAs
- Antiarrhythmic (Ib)
- Foetal ion trapping, especially during foetal distress (due to acidosis)
- Methaemoglobinaemia (prilocaine, benzocaine, lidocaine[rare])
- Allergy (usually PABA mediated)
- Toxicity
What are the features of LA toxicity?
Neurological:
- Early excitatory - Altered taste, perioral tingling, tinnitus
- Progresses to twitching + seizures
- Finally coma/death
Cardio:
- Dose-dependent cardiac depression
- Arrhythmia
- CV collapse/death
What is the mechanism of action of paracetamol?
- COX-3 inhibition
- Found predominantly in the brain
- Inhibition of prostaglandins produces antipyretic and analgesic effects
- Thought to have relatively weak anti-inflammatory action
What is the mechanism of action of aspirin?
- COX-1/-2 inhibition
- Irreversible
- COX-2 inhibition prevents platelets from producing TXA2 (a promoter of platelet aggregation)
- Vascular endothelium continues to produce PGI2 (prostacyclin), which inhibits aggregation -> antiplatelet effect
Outline the pharmacokinetics of aspirin
A:
- Upper GIT
- 70% bioavailability
M:
- By esterases in gut wall/liver
- First order kinetics
E:
-Renal
