General & Local Anaesthetics

1. General & Local Anaesthetics Aleena Hossain

2. Learning Objectives

3. General Anaesthetics Focus on: delivery, mechanisms, comparison

4. What are the 5 Clinically Desirable Objectives of GA?

5. 5 Clinically Desirable Objectives of GA • Loss of consciousness • Suppression of reflex responses • Analgesia • Muscle relaxation • Amnesia } all cause this at LOW conc ONLY 2 elements shared by all anaesthetics } at HIGH conc Increasing importance With increasing conc

6. O F Br N CH3-CH2-O-C F H C C N F Cl CH3-C-H N N O F F F CH2 (CH3) H O H C C C OH Cl F F CH(CH3) 2 2 types of GA Delivery *LESS SELECTIVE *SELECTIVE *Mediated by GABA predominantly + on receptor subtypes/subunit *Hit GABA/TREK/AChR Gaseous/Inhalation IV Nitrous Oxide Diethyl Ether Halothane Enflurane V simple Propofol Etomidate NO SIMILARITIES – unclear what the target is CH3-CH2-O-CH2-CH3 V complex

7. Comparison IH IV Injected  blood  brain BUT: once injected: excreted via liver + kidney} difficult to control rate of excretion Fast induction Less coughing/excitatory phenomena Airway irritation can  cough reflex • Gas  lungs, gas  blood, but large amount excreted back  lungs } v good control • If remove drug from lungs – conc grad shifts v quickly so that drug = excreted by airways • Rapidly eliminated • Rapid control of depth What is BGPC? BLOOD GAS PARTICION COEFFICIENT HIGH Dissolves WELL in blood doesn’t transfers  brain effectively LONGER to clear from system How gas will partition itself between the 2 phases after equilibrium is reached Dissolves POORLY, large % remains in gaseous form transfers  brain effectively V QUICK + EASY to CLEAR from brain} GOOD CONTROL LOW

8. Uses of IH + IV in Anaesthesia? Propofol to INDUCE Enflurane to MAINTAIN

9. Mechanism Of Action – Theory Meyer Overton correlation • Lipid solubility (oil/water coefficient) ∝ anaesthetic potency } • So lipid bilayer disruption anaesthetic potency of drugs PROBLEMS? BUT minute changes in anaestheticconc in bilayer BUT impact of changes on membrane protein ? Bc ion movement through these proteins  drove processes

10. Mechanisms Of Actions - Real ↓ Neuronal excitability Δ Altered synaptic function

11. Propofol IV – Altered synaptic function Understood the best! Etomidate • Powerful euphoriants! • Before LOC, get euphoric high! • So OD = lethal • More selective for GABAA receptors – potentiates it • alter synaptic function 5 subunits Different subunits in different parts of brain 3 – Suppresses reflex responses 5 – amnesia Where would you expect to find 5 subunits? in hippocampus – but not in many other places

12. IH – Altered synaptic function • Hit multiple targets} more complicated, less powerful • Affect multiple receptors • GABA • Glycinereceptors– especially important in spinal cord + lower brainstem • Have inhibitory role – particularly in lower brainstem + SC • Blocks Neuronal nicotinic ACh receptors • For analgesic effects – not LOC/hypnotic effects • IV anaesthetics can act on this but only if above the conc needed for anaesthesia • Blocks NMDA-type glutamate receptors • These = excitatory receptors • Competes with co-agonist glycine 1 – suppresses reflex responses halogenated agents Nitrous oxide

13. IH - reduced neuronal excitability • Activate TREK (background leak) K+ channels • First targets that influence neuronal excitability • Hyperpolarise neurons + reduce excitability •  LOC

14. Molecular targets IV = More selective – for GABA + glycine IH = Less selective, more targets potentiation inhibition

15. 5 Clinically Desirable Objectives • Loss of consciousness • Suppression of reflex responses • Analgesia • Muscle relaxation • Amnesia } all cause this at LOW conc ONLY 2 elements shared by all anaesthetics } at HIGH conc Increasing importance With increasing conc

16. Interacts with sleep/wake cycle Interferes with relay between cortex, thalamus, RAS 1. Loss of Consciousness Via GABAAR + TREK Decreases excitability of thalamocortical neurons less info  RAS activates it promotes sleep RAS comes from brainstem + projects  cerebral cortex via thalamus ACh = released from cholinergic nerve terminals from RAS  thalamus + cortex in highest conc in association with cortical activation that occurs natural in wakefulness Anaesthetics can directly hyperpolarize thalamocortical neurons by activating TREK channels +/or potentiating GABAaR Consciousness determined by the amount of cortical activity Influences reticular activating neurons

17. 2. Suppression of reflex responses IV + IH potentiate GABAaR + glycine R HIGH density of GABAaR in dorsal horn of spinal cord potentiation of GABAaR get suppression of info relay within spinal cord suppress reflex responses

18. QUICKEST RESPONSE SEEN! 5. Amnesia Occurs at conc well below those that cause sedation/analgesia Via GABAaR GABAaR + a5 subunits in hippocampus potentiation of GABAaR decreased synaptic transmission in hippocampus/amygdala Amnesia

19. Use these drugs for the additional effects • 3. Analgesia – opioid e.g. IV fentanyl • 4. Muscle relaxation – neuromuscular blocking drugs e.g. suxamethonium • 5. Amnesia – benzodiazepines e.g. IV midazolam

20. Question • How do general anaesthetics cause loss of consciousness?

21. Answer • Depresses excitability of thalamocortical neurons  due to hyperpolarisation (increased background leak of K+ channels) and enhanced GABA function, which means there is a disconnect between the periphery and the brain • Also depression of the reticular activating neurons

22. Local Anaesthetics MOA, pharmacokinetic profiles + adverse effects

23. Generation of a sensory neuronal action potential Fig. 1: Generation of a neuronal action potential Na+ channels close (inactivation) K+ channels open, K+ leaves cell V rapid ii Slower than VGSC Carries +ve charge with it 0 mV Na+ channels restored to resting state but K+ channels still open therefore cell refractory iii Resting Na+ channels open Na+ enters cells Down the grad i -70 mV (m secs) Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus (10-15 ms) iv Depolarization e.g. painful stimulus

24. Structures of LAs • Name 3 common properties between structures of LAs?

25. COOCH3 O CH2 C O NCH3 CH2 O CH2CH3 CH3 NH C CH2N CH3 CH2CH3 Structures of LAs Ester cocaine (drug of abuse) 3 properties in common: • Aromatic region • Basic amine side chain (3˚) 3. Connected by bridge – bond: Amide lidocaine (LA) 1 – AROMATIC REGION 2 – BASIC AMINE SIDE CHAIN Cocaine EXCEPTION: benzococaine – does NOT have amine side chain∴ so it’s weak ESTER Lidocaine (lignocaine) AMIDE

26. Mechanism of Action – interaction with sodium channels Very confusing diagram – so let’s orientate ourselves!

27. MOA – interaction with sodium channels The nerve bundle tends to contain many nerve axons, this diagram only shows the cross-section of one membrane in a single nerve axon Outside Inside Connective tissue sheath on outside of sensory neuron Outer membrane of single sensory neuron

28. MOA – interaction with sodium channels Lipid soluble – can only work INSIDE axon Fig. 3: Interaction of local anaesthetics with sodium channels BH+ LA Eqbm reestablished 😊 Inject it close to sensory neuron B B B B Free base Eqbm once again once B is in axon Only UNionised form can pass through lipid sheath Binds here – targets inside VGSC ∴ blocks Na + influx ALL = WEAK BASE BH+ CHANNEL OPEN Must be open for BH+ to bind to VGSC BH+ BH+ Na+ 😭 Charged form has LA property Hydrophobic pathway MOST important: LA  neurons + block inside of open VGSC For more lipid soluble LA Hydrophilic pathway (use-dependent) (VGSC) Goes to membrane So don’t need channels to be open - can drop into closed channel e.g. benzococaine Na+ BH+ More the neuron = used, more effective LA is (bc more channels will be open bc more firing) ∴ gives selectivity to LA to nociceptive neurons BH+ CHANNEL CLOSED B B Outside Inside If give too close to motor neuron, will have blockade of it too so weakness Connective tissue sheath Membrane

29. 4 Effects of LAs?

30. 4 major effects of LA Prevent generation + conduction of AP by blocking the VSSC RMP is unaffected as there is no interaction with the Na+/K+ ATPase pump Can influence channel gating + surface tension Selective block of small diameter + non-myelinated fibres (i.e. nociceptor neurones) *LAs are also weak bases (pKa 8-9) What is the significance of these effects? What is the pKa? pH at which 50% ionized/unionised • Small diameter = good bc: pain fibres = A delta + C fibres = v narrow • Non-myelinated = good bc pain fibres e.g. C fibres ≠ myelinated What is the effect on infected tissue? • Infected tissue =more difficult to anaesthesisebc more acidic (bc increased metabolites/toxins) so larger proportion of LA would be ionised

31. Name the 6 routes of administration?

32. 6 Routes of Administration

33. 1. Surface Anaesthesia • Mucosal surface • Mouth, bronchial tree • Spray/powder *needs high concentrations but  systemic toxicity* ☹️

34. 2. Infiltration Anaesthesia • Directly into tissues  sensory nerve terminals • Minor surgery • Suturing, draining abscesses • Adrenaline co-injection (NOT extremities) • At low dose, it’s vasoconstrictive at side of admin ∴ 2 effects • ↑ DOA of LA • ↓ % systemic SE/toxicity + ↓ bleeding from wound • E.g. subcutaneous injection WHY? Can lead to ischaemic damage

35. 3. Intravenous Regional Anaesthesia • Only time LA  venous blood • IV distal to pressure cuff • Limb surgery • Systemic toxicity of premature cuff release Why have a pressure cuff? To cut off the blood supply Why? Bc LA goes  heart/CNS ∴ keep cuff on for 20 mins – time required for LA to diffuse into tissue

36. 4. Nerve Block Anaesthesia • Close to nerve trunks e.g. dental nerves • Widely used • Use low doses ∴ slow onset • Vasoconstrictor co-injection e.g. adrenaline, terlepressin Why use low doses? Bc it’s so close to the nerve trunk

37. 5. Spinal Anaesthesia • Subarachnoid space – spinal roots • Which layers does it go through? tough outer dural membrane  arachnoid membrane  space below subarachnoid membrane (CSF) • Uses in: Abdominal, pelvic, lower limb surgery, hip replacement • Effects: very sharp ↓BP, prolonged headache • Add glucose to LA L3/L4 – to minimise damage to Spinal cord Bc LA mixes with CSF ∴ some access  brain Why? Why? Mix this into LA + move/tilt patient – it increases the specific gravity so the LA stays in the same place as injected instead of diffusing freely in CSF Preganglionic SNS neurons are smaller in diameter ∴ sensitive to LAs ∴ vasodilation ∴ ↓BP

38. 6. Epidural Anaesthesia • Into fatty tissue of epidural space – acts on spinal roots • ∴ not penetrating dura or arachnoid membrane – sits outside it • Uses? • same as spinal anaesthesia + painless childbirth • Slower onset – higher doses needed ∴ ↑% systemic side effects ☹️ • More restricted action ∴ less effect on BP ∴ advantage 😊

39.  CSF

40. Pharmacokinetic properties of lidocaine + cocaine ∴ used as surface anaesthetic Consequence? ∴ high drug interactions ∴ More resistant to metabolism

41. Unwanted effects See this at first, bc GABA = more sensitive than others so inhibition of GABA R in cerebral cortex  restlessness Unwanted when using it as an LA CNS Stimulation Euphoria Excitation !!!! Restlessnessconfusion ? Paradoxical CVS Tremor COCAINE Get these effects in OD LIDOCAINE Sympathetic actions Myocardial depression ↑CO Na+ channel blockade in myocardial tissue/SM vasculature Vasodilatation Vasoconstriction ↓BP ↑BP

42. Past SAQ • 2009 +2012 resit • A) Site of action of LAs (1) • B) Describe the 2 pathways (2) • C) Why do you use the term “use-dependent” (1) • D) 4 routes of administrating LAs (2) • E) Explain how changes in local pH may influence potency of LA (2) • F) CVS effects on i) lidocaine ii) cocaine (2)

43. Answers • A) Open voltage-sensitive sodium channels in small, unmyelinated neurones on the inside (cytoplasm facing) part of the nociceptive neurone • B) • Hydrophilic (main mode of action) • Non-ionised local anaesthetics must gain access to the inside of the cell neurone to become effective. Inside the neurone the anaesthetic becomes ionised BH+ and binds to the inside of the open voltage-gated Na+ channels preventing Na+ from entering and thus AP. • Hydrophobic (secondary mode of action) • When the local anaesthetic passes through the membrane, some enters the closed Na+ channel from the outside. This only accounts for around 10% of local anaesthetics as they are normally weak bases (and so ionise quickly). • C) The more active the neuron, the more Na+ channels are open open Na+ channels are the binding sites for LAs so therefore more local anaesthetic binds more receptor-drug complexes greater effect • E) LAs are weak bases pKA=8/9. Ionised in acidic environment i.e infection. pH affects the level of ionisation of local anaesthetics, thereby affecting their potency in blocking Na+ channels. Ionised local anaesthetics would be unable to cross the neuronal cell membrane reduced effect

44. Thank you! • ah2716@ic.ac.uk • Feedback link: bit.ly/muslimmedics