Pharmacology of LA - Dr Wai Ling Kok (2023-24) (1).pdf

Pharmacology of Local Anaesthesia Dr Wai Ling Kok Year 1 BDS & DTH 2024 Acknowledgement: Dr Zoë Brookes Learning Objectives: At the end of this session, students should be able to: Analyse the importance of pain management in dental practice Interpret action potential and pain pathways Investigate c...

Pharmacology of Local Anaesthesia Dr Wai Ling Kok Year 1 BDS & DTH 2024 Acknowledgement: Dr Zoë Brookes Learning Objectives: At the end of this session, students should be able to: Analyse the importance of pain management in dental practice Interpret action potential and pain pathways Investigate chemical composition, classification and mechanisms of action of local anaesthetics Summarise the importance of additives in local anaesthetics Formulate clinical parameters important for LA: potency, onset, metabolism, duration Pain Unpleasant sensory and emotional experience associated with actual or potential tissue damage A barrier to effective dental care Effective control of orofacial pain facilitates the delivery of care and reduces anxiety about dentistry Local anaesthetics - Introduction Local anaesthetics are drugs which reversibly prevent the transmission of nerve impulses in the region to which it is applied, without affecting consciousness They prevent or relieve pain and interrupt nerve conduction by inhibiting the influx of sodium (Na +) ions through voltage gated Na+ channels within nerve membranes Their effectiveness depends on lipid solubility and local pH https://www.nysora.com/topics/pharmacology/clinical-pharmacology-local-anesthetics/ Local anaesthetics - Introduction Local anaesthetics are injected locally or applied topically to avoid unwanted systemic effects The first local anaesthetic to be used was cocaine, but addictive with psychogenic effects Procaine (novocaine) not really used any more, others more effective Surface anaesthesia (topical application) to external or mucosal surfaces e.g. benzocaine, lidocaine (xylocaine) Infiltration anaesthesia Subcutaneous injection to act on nerve endings, usually combined with a vasoconstrictor such as adrenaline, e.g. lidocaine, articaine, bupivacaine, mepivacaine They all end in ‘caine’ You will cover techniques of local anaesthesia relevant to dental practice, as well as local and systemic complications in later years. Local anaesthetics - Introduction Used either via local injection or topical application, not ingested or used systemically: Dental procedures Oral ulcers Minor skin surgeries, e.g. mole, wart removal Epidurals Wound sites after minor surgeries Skin abrasions Skin patches to help with viral neuralgias Sunburn Insect bites Catheter insertion Skin grafts To understand the mechanisms of action of LA, need to understand first pain pathways, action potentials and the biochemical structure of local anaesthetics….. Local anaesthetics - structure Separated into two types: amino esters and amino amides Amino esters Short half-life, broken down by cholinesterase enzymes in the extracellular fluid Amino amides Longer half-life, broken down by enzymes in the liver ester amide BJA Education, 20(2): 34e41 (2020) Structure: Ester-linked LAs COCAINE- occurs naturally in the coca leaves. The only LA that causes vasoconstriction by inhibiting noradrenaline re-uptake PROCAINE - first synthetic LA. Low potency, slow onset, short duration TETRACAINE - long-acting but slow onset LA. More toxic Metabolised in plasma by pseudocholinesterase enzyme -Hydrolysis leads to the formation of para-aminobenzoic acid (PABA) - PABA and its derivatives carry a small risk potential for allergic reaction Structure: Amide-linked LAs LIDOCAINE - widely used LA, with or without vasoconstrictor. Intermediate duration. Causes vasodilation PRILOCAINE- similar to lidocaine but causes less vasodilation. Aromatic ring metabolised to o-toluidine; can cause methaemoglobinemia (haemoglobin cannot release oxygen). ARTICAINE- one of the most recent LAs. Shows greater lipid solubility and diffusion through nerves. Adverse effect of paraesthesia BUPIVACAINE - long-acting agent producing profound anaesthesia. Substantially more cardiotoxic - Metabolised in the liver by dealkalisation (amidase) - Renal clearance of unchanged LAs only 3-5% Nociceptors Sensory receptors responsible for the detection of noxious stimuli, transforming the stimuli into electrical signals, which then conducted to the CNS They are the free nerve endings of primary afferent Aδ and C fibres Distributed throughout the body (skin, muscles, joints) They can be stimulated by mechanical, thermal or chemical stimuli 1.13 An introduction to pain Pathways of Pain Action potential 1.04 The action potential Voltage gated Na+ channel Exterior BJA Education, 20(2): 34e41 (2020) Cytosol LA action Water soluble (4 bonds) Lipid soluble (3 bonds) Reed KL and Becker DE. Anesth Prog. 2012 59:90–102 Mechanism of action The lipid-soluble base (B) form is essential for penetration of both the tissue and nerve membrane. Once inside the nerve axon, the high concentrations of H+ force B in the direction of BH+ making the LA ionic. This ionic form BH+ form binds to the inactivation site of the Na+ channel, keeping the channel closed When Na+ cannot enter the nerve axon, it cannot conduct a nerve action potential, including transmission of pain The equilibrium between (BH+) and (B) is determined by the pH of the tissues and the pKa of the anaesthetic (pH/pKa) Mechanism of action pH effects solubility: An acidic pH is caused by increased number of H+ ions The more H+ ions in the tissue, the less B and the more BH+ ionised drug there will be BH+ cannot pass through the nerve membrane, and thus LA potency is reduced in a more acidic pH Thus, when tissue hypoxic/inflamed/acidotic, drugs do not absorb as well LA are less effective in inflamed tissue, and this relates to pH Mechanism of action The pKa value is a term often used in pharmacology and also has relevance to the potency of anaesthetics pKa is the pH at which 50% of the drug is ionised and 50% is present as a base pKa for all local anaesthetics is >7.4 (physiological pH), thus most of LAs exist in the quaternary (BH+) water-soluble form, that when injected is not soluble through the tissue The higher the pKa the less LA is in the (B) lipid soluble form For example, the lower pKa of mepivacaine (pKa 7.6) is more desirable for absorbing than the higher pKa of bupivacaine (pKa 8.1) Lower pKa values have lower ionisation (BH+) for given pH and thus have a more rapid onset of action A higher pKa makes onset slower, but drug may be more active because BH+ within the nerves blocks the Na+ Mechanism of action Lipid solubility Greater lipid solubility increases both the potency and duration of LAs This is due to a greater affinity of the drug to lipid membranes and therefore greater proximity to its sites of action (more rapid diffusion through lipid membranes) The longer the drug remains in the vicinity of the membrane, rather than being replaced by the blood, the more likely the drug will be to effect its action on the Na+ channel in the membrane Unfortunately, greater lipid solubility also increases toxicity, decreasing the therapeutic index for more hydrophobic drugs. Mechanism of action Duration of action: Depends on the physical characteristics of the LA, lipid solubility, and the presence or absence of vasoconstrictors LAs can be divided into three categories: - short acting (e.g. 2-chloroprocaine, 45-90 minutes) - intermediate acting (e.g. lidocaine; articaine, 90-180 minutes) - long acting (e.g. bupivacaine; ropivacaine, 4-18 hours) Vasoconstrictors in Local Anaesthetics Adrenaline (epinephrine) Acts locally at the injection or application site, with the vasoconstriction leading to less blood flow Less LA entering the systemic blood steam, less likely to affect the heart LA removed from the site at a slower rate → longer local half-life (t ½) Vasoconstrictors in Local Anaesthetics Results in: - Faster onset of anaesthesia - More profound effects - Longer duration - Reduction in operative and post operative haemorrhage DISADVANTAGES: alterations in cardiovascular response (tachycardia if enters systemic circulation), adverse drug interactions Concentrations used as - 1:80000 (12.5μg/ml), 1:100000 (10μg/ml) and 1:200000 (5μg/ml) FELYPRESSIN (OCTAPRESSIN) - also a vasoconstrictor, is related to vasopressin (0.03IU/ml; 0.54 μg/ml) Mechanism of action Differential effects on nerve fibres When a LA is deposited in proximity to a peripheral nerve, it diffuses from the outer surface toward the core along a concentration gradient. Consequently, nerve fibres located in the outer mantle of the nerve are blocked first. Smaller neuronal alpha-delta (A-δ) fibres that transmit pain are most effected by LAs. Larger neurons have more myelin or those that are positioned deeper within the tissue may take more time to be affected (may still feel pressure) Differential Sensitivity of Nerve Fibres The sensation of pain is usually the first modality to disappear; it is followed by the loss of sensations of cold, warmth, touch and deep pressure at the end Adverse reactions - systemic toxicity In addition to interrupting peripheral nerve conduction, LAs have important effects on the central nervous system (CNS), the autonomic ganglia, the neuromuscular junction, and musculature The following factors determine the plasma concentration of LAs: The dose of the drug administered The rate of absorption of the drug Site injected, vasoactivity of the drug, use of vasoconstrictors Biotransformation and elimination of the drug from the circulation Adverse reactions - systemic toxicity If lignocaine gets into the blood stream, the liver metabolises virtually all of it with an elimination half-life of 2 hours (first pass metabolism) Rapidly passes through the blood brain barrier Class Ib antiarrhythmic drug (Na+ Channels in the heart) Thus with poisoning it causes cardiovascular and CNS toxicity Complications Mild neurologic symptoms can occur at therapeutic plasma concentrations (tachycardia's from adrenaline) Early signs of CNS toxicity include light-headedness, agitation, confusion, hallucinations and dysarthria Toxic doses can cause cardiovascular collapse, convulsions and coma Progression of LA Toxicity Maximum doses Jim Carey Maximum doses Jim Carey Allergies to local anaesthesia True allergy to an amide local anaesthetics are very rare, especially lidocaine Genuine Type IV or Type I IgE-mediated immunological reaction represent only 1% of adverse reactions reported with LA Ester type (not really used in dentistry) are more likely to produce allergic reactions as they are metabolised to para-aminobenzoic acid (PABA), which is an allergenic compound Symptoms may include the following and can lead to death (medical emergency) - Lips and periorbital areas swell - Agitation - Generalised urticaria and pruritus, particularly of hands and feet - Abdominal cramps, nausea and diarrhoea - Tightness of the chest, with wheezing and difficulty in breathing fall in blood pressure and a rapid thready pulse - Flushing of the skin or rash Allergies to local anaesthesia Local anaesthetics also contain pyrogen-free distilled water, NaCl, citric acid, sodium metabisulphate, methylparaben Metabisulphite or parabens may be more likely to elicit allergic or adverse reactions Patients undergoing dental procedures may often exhibit some degree of autonomic response to an injection, such as sweating, tachycardia or even syncope - due to anxiety or adrenaline injection, not an allergy Choice of LA for dentistry Note: avoid octapressin in pregnancy, may induce labour What do we use most commonly in dentistry? Lidocaine (Xylocaine) 2% with 1:80,000 adrenaline (LignospanTM) Articaine 4% with 1:100,000 or 1:200,000 adrenaline (SeptonestTM) Avoiding adrenaline: Mepivacaine 3% plain (ScandonestTM) Prilocaine 3% with 0.03 IU/ml felypressin (CitanestTM) Lidocaine/lignocaine Dental formulation: - 2% lidocaine with 1:80,000 adrenaline (LignospanTM) - 2.2 ml cartridges (44mg per cartridge) - Maximum and toxic doses best calculated per body weight, (see next slide toxicity) - Safe dose = 500mg (10 X 2.2ml cartridge) Onset: fast onset Duration of action: short/medium (1.5h altered sensation; 3 h to wear off without adrenaline the duration is halved) Lipid solubility: pKa 7.7 Uses: infiltration and nerve block Complications: - Very safe, used for a long time - Occasional allergic reactions (see next slide) - High doses: toxic doses: first pass effects Mepivacaine Dental formulation: 2.2ml 3% plain (30mg mepivacaine); 2.2ml 2% special (20mg mepivacaine, 10μg adrenaline) (ScandonestTM) - Safe dose = 400mg Onset: fast onset Duration of action: short duration Lipid solubility: pKa 7.6 Uses: infiltration and block, not used much in dentistry Prilocaine Dental formulation: 4% prilocaine plain (no adrenaline); prilocaine forte (with adrenaline), 3% prilocaine with octapressin (CitanestTM) -Safe dose 600mg (8 X 2.2ml) cartridges Onset: fast onset Duration of action: short/medium approx. 2.5 hours (slightly less duration and potency than lignocaine) Lipid solubility: pKa 7.7 Uses: infiltration and nerve block Complications: - In high doses may cause methamoglobinaemia (high metHb ® tissue hypoxia) - Avoid octapressin (felypressin) in pregnancy Articaine Dental formulation: 4% articaine + 1,100,000 or 1:200,000 adrenaline (SeptonestTM) Onset: Fast onset Duration of action: short/medium duration Lipid solubility: pKa 7.8 Uses: popular for infiltration, intra-ligamental Complications: infiltration, may diffuse through bone better than other anaesthetics and be good maxillary LA, still uncertain for blocks, some early reported incidences of permanent sensation loss Bupivacaine Dental formulation: 0.25% bupivacaine, 1:200,000 adrenaline Onset: Slow onset (up to 30 min) Duration of action: long duration (6 hours; 8 hours with adrenaline present) (higher potency than lignocaine) Lipid solubility: pKa 8.1 Uses: epidurals Complications: - Can cause cardiotoxicity in high doses Benzocaine and lidocaine topical Dental formulation and uses: - Topical anaesthetics used in dentistry most commonly contain benzocaine or lidocaine, as either gels, ointments or sprays - Benzocaine (ethyl aminobenzoate) is an ester local anaesthetic, available in concentrations to 20% - Lidocaine is available as gels or ointment up to 5% and as sprays up to 10% concentration - Eutectic mixtures of local anaesthesia include EMLA cream, with a 1:1 mixture of 2.5% prilocaine: 2.5% lidocaine. Used as a cutaneous topical anaesthetic on skin, very occasional use in dentistry Benzocaine and lidocaine topical Onset: approx. 1-2 minutes; effective to a depth of 2-3mm Duration: approx. 15 minutes, peak at 5 minutes (Lee et al, 2016) Lipid solubility: poor water solubility, poor absorption into the systemic system Complications: relatively safe with few adverse reactions, rare allergic reactions, altered sense of taste, unpleasant oral sensations Further reading: Lee H. Recent advances in topical anesthesia. J Dent Anesth Pain Med. 2016 Dec; 16(4): 237–244. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564188/ Topical Anaesthetics OTC Topical anaesthetics Bonjela adult gel - No LA Formulated for minor mouth infections Contains Cetalkonium Chloride - an antiseptic and Choline Salicylate - for pain and inflammation Suitable >16 years Bonjela Junior Gel Contains Lidocaine Hydrochloride - local anaesthetic and Cetylpyridinium Chloride - antiseptic to prevent infections Not for use in teething infants. Suitable > 5 months (teething gel contacts Damascena Rose) Anbesol Contains Lidocaine Hydrochloride, Chlorocresol and Cetylpyridinium Chloride - antiseptics to help protect against infection Not for use by anyone under the age of 12. References Medical Pharmacology at a Glance Basic pharmacology of local anaesthetics - PMC (nih.gov) Local Anesthetics: Review of Pharmacological Considerations - PMC (nih.gov) https://www.nysora.com/topics/pharmacology/clinical-pharmacologylocal-anesthetics/