W7 Local Anaesthesia Agents PDF

BOH1 Local Anaesthesia Local Anaesthetic Agents Presented by Ashleigh Ayo BOH Discipline Coordinator – Local Anaesthesia Sydney Dental School Credits to : Dr Rex Huang The University of Sydney 2  COMMONWEALTH OF AUSTRALIA...

BOH1 Local Anaesthesia Local Anaesthetic Agents Presented by Ashleigh Ayo BOH Discipline Coordinator – Local Anaesthesia Sydney Dental School Credits to : Dr Rex Huang The University of Sydney 2  COMMONWEALTH OF AUSTRALIA › › Copyright Regulations 1969 › WARNING › This material has been reproduced and communicated to you › by or on behalf of the University of Sydney pursuant to Part › › › VB of the Copyright Act 1968 (the Act).The material in this ›communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice The University of Sydney 1 We recognise and pay respect to the Elders and communities – past, present, and emerging – of the lands that the University of Sydney's campuses stand on. For thousands of years they have shared and exchanged knowledges across innumerable generations for the benefit of all.  Objective – To understand the local anaesthetics which are available and know about their properties – Topics covered: – common local anaesthetics and their properties – pharmacodynamics, and pharmacokinetics of LAs – effect of vasoconstrictors – topical anaesthetic The University of Sydney 3 W7: LA Agents LEARNING OBJECTIVES/OUTLINE To understand the local anaesthetics which are available and know about their properties 1. Common local anaesthetics and their properties 2. Pharmacodynamics, and pharmacokinetics of LAs 3. Effect of vasoconstrictors 4. Topical anaesthetic NOTES LA AGENTS Differ by their intermediate chains: Esters; “one i in the name) ○ Procaine ○ Benzocaine ○ Cocaine ○ Tetracaine Amides; AMIDES MORE COMMONLY USED “ 2 i’s in the name” ○ Lignocaine ○ Articaine ○ Mepivacaine ○ Prilocaine ○ Bupivacaine ○ Roprivacaine ESTERS VS AMIDES ESTERS PROCAINE “Brand name - Novocaine” Introduced 1905 Slow onset (6-10 mins) ○ High pKa Short duration (60 mins) ○ Rapid pseudocholinesterase (carboxylesterase) metabolism in plasma (98%) ○ Enables higher dose (10 mg/kg) ○ Short half life Vasodilating Problems: ○ Hypersensitivity rxns to inactive metabolite para-aminobenzoate (PABA) ○ Pseudocholinesterase deficiency: cannot break down certain ester anaesthetics, affecting 1 in 2800-3000 ppl Abnormally slow metabolism Risk of methemoglobinemia; not enough O2 circulating w/in blood Available as 2% w/ no vasoconstrictor, available in 2ml ampoule (40 mg in 2ml) SUMMARY; Typically NOT USED bc of hypersensitivity & more effective amides ○ Risks causing allergic rxn ○ Amide-linked LAs are: Relatively stable in solution Slowly metabolised by hepatic amidases Hypersensitivity rxns to amide LAs are extremely rare BENZOCAINE Used in some topical applications ○ Sore throat lozenges ○ Mouthwash ○ Throat spray ○ Gel, paste Can also be used for earache, sunburn etc Overuse of high concentrations have led to methaemoglobinaemia AMIDES (MOST COMMONLY USED IN DENTISTRY) NOTE: 5 AND 6 NOT COMMONLY USED 1. Lignocaine No.1 Gold standard 2% plain or with adrenaline (27.5 mcg) 1:80,000 Half life is 1.5-1.8 hours ○ Takes a couple hours to completely wear off + have feeling Lignospan Special 2. Articaine 4% 1:100,000 adrenaline Half life is 1.8 hours (little bit longer) Septanest 3. Prilocaine 2.2ml OR 1.8ml cartridges 3% w/ or w/o felypressin (vasoconstrictor); generally w/ felypressin Plain Half life similar to lignocaine Citanest 4. Mepivacaine 3% plain Longer half life of 2-3 hours; raises peak plasma levels (the highest concentration in the blood after a dose) Scandonest/Carbocaine 5. Bupivacaine 0.5% plain OR 1:200,000 adrenaline Half life 1.5-5.5 hours Long lasting; used for surgeries 6. Ropivacaine 0.5%, 0.75%. 1% Plain 1. LIGNOCAINE  MOST WIDELY USED: ○ Consistent ○ Predicable ○ Effective ○ Safe results Also comes in other concentrations: plain/with vasoconstrictor, in diff. Volumes, in glass ampules ○ 0.5%-2% for injection ○ 4%-10% for topical anaesthetic FEATURES Rapid onset (2-4 minutes), moderate duration ○ pKa 7.8 Allergies extremely rare 90% metabolised in liver (CYP 3A4) Excreted in urine (90% metabolites, 10% as free drug) Very few contraindications for use ○ Eg. pt w/ cirrhosis of liver (chronic liver damage); contraindication 2. ARTICAINE NOT USED FOR BLOCK INJECTIONS; works very well for infiltration (better than lignocaine) Safe to use in children over the age of 4 Should not be used during pregnancy (category B3 drug) Avoid when breastfeeding: pts should not breastfeed for at least 4 hrs following injection FEATURES Similar onset and duration to lignocaine Metabolised by cholinesterases in plasma (90%)  ○ Consider use in patients w/ decreased liver function; won't be metabolised by liver where it will cause stress 90% secreted as articainic acid 3. PRILOCAINE Less binding affinity to sodium channels vs lignocaine Prilocaine undergoes biotransformation in liver, kidney and lungs Orthotolidine is a metabolite produced → can cause methemoglobinemia Excretion via kidneys Pregnancy Category A drug Prilocaine/Felypressin not as effective as Lignocaine/Adrenaline → L/A first choice is pt has not contraindications 4. MEPIVACAINE Use in ppl above 4 yo Maximum dose 6.6mg/kg Rapid onset and medium duration No vasoconstrictor → less vasodilator effect → less effective on muscle cells; 5. BUPIVACAINE  Comes in vials in AUS NOT CARPULES → have to draw it up ourselves Higher pKa, protein binding, lipid solubility ○ Slower onset ○ Increased duration (soft tissue 8-12 hours+ → won’t use as OHT) ○ More potent than lignocaine Often used in addition to lignocaine for oral surgery Greater muscle affinity than lignocaine ○ Higher cardiotoxicity Half life 1.5-5.5 hours PHARMACODYNAMICS - EFFECT OF DRUG ON THE BODY Vasodilation LAs on their own are vasodilators; dilate blood vessels Cocaine is only LA which produces a vaso-constricting effect Procaine most potent CNS Depression Anticonvulsant at low levels; medication used to prevent or treat seizures (convulsions), BUT Can induce seizures at high levels (inhibitory neurons inhibited) CVS Decreases excitability of myocardium, “direct action of local anaesthetics decreases conduction rate (heart rate), on the heart when they enter the decreases force of contraction bloodstream in significant Causes hypotension (low blood pressure) amounts; immediate blocking of sodium channels” PHARMACOKINETICS - EFFECT OF BODY ON THE DRUG Absorption Vasodilation; if no added vasoconstrictor → blood vessels remain wide open → blood flows freely carrying LA quickly away from application site: ○ Increases rate of absorption ○ Decreases duration of LA ○ Increases potential for overdose Rate also depends on vascularity of site; more vascular area → more absorption → taken away  Absorbed poorly from GIT Very well absorbed trans-mucosally (but poorly from intact skin) Distribution LA binds to α-1 acid glycoprotein (AAG) ○ AKA orosomucoid, a carrier protein for neutral, positively charged basic drugs (albumin is carrier for acidic, negatively charged drugs) LA is distributed to all tissues once in bloodstream ○ More in highly perfused organs (eg. brain, liver, kidneys etc.) ○ Less in elderly, medically compromised patients bc of decreased circulation Elimination ½ life = time required for a 50% reduction of drug level w/in blood Metabolism Esters are hydrolysed in the plasma by (biotransformation) pseudocholinesterase (P) ○ 1 in 2800 ppl will have some atypical form of P → can’t metabolise ester LAs in body → issues Procaine hydrolysed to para-aminobenzoic acid (PABA) and diethylamino alcohol ○ PABA is an allergen Amides are primarily metabolised in the liver (except articaine; plasma) ○ Liver function and hepatic perfusion (hypotension, congestive heart failure, cirrhosis) can affect blood levels and toxicity ○ Prilocaine metabolite, orthotoluidine, if left to accumulate, can produce methemoglobinemia Prilocaine has some extra-hepatic metabolism (in the lungs) Articaine primarily metabolised by tissue and plasma cholinesterases (95%); the rest in the liver METABOLIC PATHWAYS!! EXCRETION  Both esters and amides are excreted via kidneys w/ small amounts being eliminated as the parent compound → urine Kidneys for both LA and metabolites ○ 10% of cocaine found in urine ○ ↳ eg pt. – 90% metabolised in liver (CYP 3A4) – Excreted in urine (90% as metabolites, 10% as free drug) – Half life 1.5 - 1.8 hours [] of LA in bloodstream to reduce by half time it takes for hours to completely wear off t have feeling again trakes couple The University of Sydney 17  4 % Sol 1 : 100 000 adrenaline , Articaine not used for block injections - infiltration ; works more efficiently for infiltration than lignocaine very well for -works The University of Sydney 18  Articaine – Synthesised in 1969 as “Carticaine” – Used in Germany since 1975, in Canada since 1983 – Safe to use in children over the age of 4 – Should not be used during pregnancy (category B3 drug) – Avoid when breastfeeding: patients should not breastfeed for at least 4 hours following injection – Much literature and debate on articaine: – ‘Superior’ drug to lignocaine – Lingual and inferior alveolar nerve damage The University of Sydney 19  Articaine – Has been widely adopted in Europe and North America – Comes as 4% solution with vasoconstrictor (1:100,000 or 1:200,000) – Similar onset and duration to lignocaine – Half-life 1.8 hours (little longer ~ bit be better suited for articaine articaine is metabolised in plasma - pt's wo/ liver issues good thing !; may of way it's metabolised , not going through liver + causing stress – Metabolised by cholinesterases in plasma (90%) be – Consider its use in patients with decreased hepatic function – 90% excreted as articainic acid The University of Sydney 20  Prilocaine – Manufactured as 2.2ml or 1.8ml (Euro) cartridges generally, seen / Gelypressin ~ brand name f – Marketed as "Citanest" with or without felypressin as vasoconstrictor & brand name S – Less binding affinity to sodium channels (c.f. lignocaine) – Half life similar to lignocaine The University of Sydney 21  Prilocaine – Prilocaine undergoes biotransformation in liver, kidney and lungs – Orthotoluidine a metabolite: can cause methaemoglobinaemia – Excretion via kidneys – Pregnancy Category A drug if pt has first choice no - contraindications – Prilocaine / felypressin not as effective as lignocaine /adrenaline – Newcomb, G. M., & Waite, I. M. (1972). The effectiveness of two local analgesic preparations in reducing haemorrhage during periodontal surgery. Journal of Dentistry, 1(1), 37–42. The University of Sydney 22  effect/duration Mepivacaine added to prolong generally be it doesn't vasoconstrictor t trends to wear off much quicker delivered plain who -generally it have vasoconstricter in – Less effect on muscle cells – Less vasodilator effect half life - longer – Half-life 2-3 hours – Raises peak plasma levels The University of Sydney 23  Mepivacaine – Other names: – Carbocaine – Scandonest – Rapid onset and medium duration – Use in people above 4 years of age – Maximum dose 6.6mg/kg The University of Sydney 24  Bupivacaine won't OHT use as lasts 8-11 hours -> it in Aus NOT carpuses + have to draw up ourselves Comes in vials The University of Sydney 25  Bupivacaine – *Cannot purchase dental cartridges in Australia – Need drawing-up needle and syringe – Higher pKa, protein binding, lipid solubility – Slower onset – Increased duration (soft tissue 8-12 hours +) – More potent than lignocaine – Often used additional to lignocaine for oral surgery – Greater muscle affinity than lignocaine – higher cardiotoxicity – Half-life 1.5-5.5 hours The University of Sydney 26  Pharmacodynamics – effect of drug on the body As on their own are vasodilators ; dialate blood vessels - Vasodilation (procaine most potent) constrict blood vessels – Cocaine only LA which produces vaso-constricting effect r don't cocaine – CNS ↳ we use – Depression – Anticonvulsant at low levels – Can induce seizures at high levels (inhibitory neurons inhibited) – CVS cardiovascular – Decreases excitability of myocardium, decreases conduction rate, decreases force of contraction Lignocaine (IV) has been used to treat ventricular tachycardia (VT) - can decrease conduction rate in heart (doesn't happen to everyone and premature ventricular contractions (PVCs) – Causes hypotension ; low blood pressure The University of Sydney 27  Pharmacokinetics – effect of body on the drug – Absorption no vasoconstrictor-> blood vessels remain wide open blood flows freely carrying LA quickly away ↑from application site -↑ rate of absorption – Vasodilation; if no added vasoconstrictor: increases rate of absorption, decreases duration of anaesthesia and increases potential for overdose area to more vascular – Rate also depends upon vascularity of site more ; absorption > - taken away – Absorbed poorly from GIT – Very well absorbed trans-mucosally (but poorly from intact skin) The University of Sydney  Pharmacokinetics – effect of body on the drug – Distribution – LA binds to α-1 acid glycoprotein (AAG) – AKA orosomucoid, a carrier protein for neutral, +vely charged basic drugs (albumin is carrier for acidic, -vely charged drugs) La once injected is distributed to all tissues once in bloodstream-> Lance CUS CNS Kidney brain – LA is distributed to all tissues once in bloodstream , , , erc. effects – More in highly perfused organs (brain, liver, kidneys etc) – Less in elderly, medically compromised patients 3 bc of circulation t – Elimination ½ life = time required for a 50% reduction of drug level in blood The University of Sydney  Pharmacokinetics – effect of body on the drug – Metabolism (biotransformation) lin -3000ppI will have some form of P-s can't metabolise ester a typical in body -> issues ↑ – Esters are hydrolysed in the plasma by pseudocholinesterase (P) Procaine hydrolysed to para-aminobenzoic acid (PABA) and diethylamino alcohol PABA is an allergen 1/2800 people have an atypical form of pseudocholinesterase – They will not metabolise ester local aanesthetics and other esters such as succinylcholine (muscle relaxant) properly The University of Sydney 30  Pharmacokinetics – Metabolism (biotransformation) – Amides are primarily metabolised in the liver except (metabolised articaine plasma) in Liver function and hepatic perfusion (hypotension, congestive heart failure, cirrhosis) can affect blood levels and toxicity Prilocaine metabolite, orthotoluidine, if left to accumulate, can produce methaemoglobinaemia* Prilocaine has some extra-hepatic metabolism (in the lungs) Articaine primarily metabolised by tissue and plasma cholinesterases (95%); the rest in the liver *Other amides can also cause methaemoglobinaemia The University of Sydney 31  Metabolic pathways exam ?! Agent Site Enzyme/Process Lignocaine liver de-ethylation CYP 450 Prilocaine liver/kidneys/lung amidase Articaine plasma carboxyesterase* Bupivacaine liver glucuronic acid conjugation Procaine plasma cholinesterase* *this is the same enzyme The University of Sydney 32  Excretion – Both esters and amides are excreted via kidneys with small amounts being eliminated as the parent compound & lost in some capacity in urine https://secure.i.telegraph.co.uk/multimedia/archive/02766/kidney_2766748b.jpg The University of Sydney  Excretion – Excretion: for dialysis pr contact their renal specialist for safe pathway – Kidneys for both the local anaesthetic and metabolites , 7 – 10% of cocaine found in urine – < 3% lignocaine present in urine – Significant renal impairment can result in increased potential for toxicity – Eg. dialysis patients – Glormerulonephritis/polynephritis The University of Sydney 34  Additional agents to LA drug I must add acid to LA be Lt on its own is fairly clinically insignificant Buffering agents – Sodium hydroxide, hydrochloric acid and EDTA etc may be added to adjust the pH of the solutions (especially if adrenaline present) – pH of plain solutions adjusted to between 4-7 – pH of adrenaline containing solutions adjusted to between 3.5-5 of morth tissue : 7 3-7 4 - put.. – pH is a prime factor in the burning sensation of LA The University of Sydney 35  Additional agents to LA drug Antioxidant – Commonly sodium metabisulfite – Prevents oxidation of vasoconstrictor – Also tends to lower the pH this patients may be allergic to – The addition of adrenalin and sodium metabisulfite lowers the local anaesthetic solution pH, resulting in a slower onset of action and increased ‘burning’ sensation during injection The University of Sydney 36  Additional agents to LA drug Sodium chloride – To adjust the solution to make them isotonic The University of Sydney 37  What about vasoconstrictors? vaso-activity of any LA influences : of LA - potency - duration of action https://3fybkfrr10x3tgp41p45lr3a-wpengine.netdna-ssl.com/wp-content/uploads/2016/01/cold.jpg The University of Sydney 37  Vasoconstrictors – All amide local anaesthetics are vasodilators – Vasoconstrictors are added to – counter effects of vasodilation ( – slow local absorption of drug ! increase duration of action ! reduce toxicity be won't > - have “Local Analgesia in Dentistry”, Roberts & Sowray 3rd ed. to give as much LA :. LA is where we injected it/ where we want it The University of Sydney 39  Dentistry without a vasoconstrictor – Paterakis, K., et al. (2018). "Efficacy of epinephrine-free articaine compared to articaine with epinephrine (1:100 000) for maxillary infiltration, a randomised clinical trial." J Oral Rehabil 45(6): 467-475. – Duration of anaesthesia: longer with vasoconstrictor – Recovery of sensation: faster without vasoconstrictor – Pulpal anaeshtesia was more reliable with articaine and vasoconstrictor – Soft tissue anaesthesia was deeper and longer when epinephrine was used –“Epinephrine-containing articaine delivers a longer, more effective anaesthesia and is preferable for caries treatments and longer invasive treatments of the soft tissue.” – “A pain-free treatment of the soft tissue up to 15 minutes can be performed under the vasoconstrictor-free anaesthetic without causing long-lasting numbness.” The University of Sydney 40  Adrenaline (epinephrine) – Acts on alpha, beta receptors – CVS: "Think adrenaline in Sight/flight" peripheral vasoconstriction increases rate and force of contraction of myocardium ; hear dilation of coronary vessels i a harder increase in blood pressure – Respiratory: Potent bronchodilator (smooth muscle) j open Lung airways-pf breathe – CNS: not a potent stimulator – ‘There are no absolute contraindications to the use of vasoconstrictors in dental local anaesthetics, since epinephrine is an endogenously produced neurotransmitter.’ inamorale produce it all be – Pallasch TJ, Vasoconstrictors and the heart. J Cal Dent Assoc 26:668-76, 1998. time - Cavitriny be allergic uxu The University of Sydney 41  Felypressinof adrenaline form Syndic – Synthetic analogue of vasopressin (antidiuretic hormone, released from posterior pituitary) wa – No direct effects on myocardium used pr on a... can be heart issues – Can cause coronary artery spams, (constriction) leading to angina, if given intravenously in - Won't use pregnancy - Vasopressin derivative related to oxytocin - ? induce premature labour - theoretical risk (avoid in pregnancy) – No evidence that felypressin is safer than adrenaline loter than it doesn't have effect on myocardion) – Scully's Medical Problems in Dentistry (Seventh Edition) 2014, Pages 51-96 – Bronzo, A. L. A., Cardoso, C. G., Ortega, K. C., & Décio, M. (2012). Felypressin increases blood pressure during dental procedures in hypertensive patients. Arquivos Brasileiros de Cardiologia. h The University of Sydney 42  Adrenaline injected into the blood stream could result in: – Adverse reactions include, palpitations, tachycardia, arrythmias, anxiety, headache, tremor, hypertension – Increased oxygen demands on myocardium – increased heart rate and contractility – Effect usually lasts for a few minutes The University of Sydney 43 Topical anaesthetics https://www.therecoveryvillage.com/wp-content/uploads/2019/05/CveF_u68.jpeg The University of Sydney 44  Topical anaesthetics – Penetrates mucous membranes, not intact skin* – Depth of penetration ~2-3mm of needle in enough getlip I just to get that pain to away – Ingredients: – Benzocaine – Lignocaine of – Prilocaine 3 combination one we generally use is a nese 2 – Unflavoured topical has a bitter taste - have suction - shir parch * Except for EMLA (lignocaine/prilocaine mixture, non-ionised base form) Lastof scope The University of Sydney 45  Topical anaesthetics - available – Topical applicators – “Oraqix” – “Cetacaine” – Lee, H.-S. (2016). Recent advances in topical anesthesia. Journal of Dental Anesthesia and Pain Medicine, 16(4), 237. https://doi.org/10.17245/jdapm.2016.16.4.237 The University of Sydney 46  > binds vi Saliva - mucosa - ointment on Topical anaesthesia gen runnue Unrowr goes to back of pr - ointment/adhesive Soi – Xylocaine 5% Ointment – 5% lignocaine ↑ Adheres huoor – Need to apply to dry mucosa for any topical LA – Does not work on intact skin – Onset of action 3-5 minutes – Duration of action 15-20mins The University of Sydney 47  “Oraqix” -ligoid very runny ; can't ointment inho ger an solcus , space not big enough - blunt lip – Lignocaine 25mg/g – Prilocaine 25mg/g – Intrasulcular - warning: do not inject! workingirona : – Liquid which gels at body temperature – Use: apply to periodontal sulcus prior to scaling/cleaning – Onset 30s – Duration 17-20mins – Friskopp et. al. J Clin Periodontol. 2001 May;28(5):453-8. The anesthetic onset and duration of a new lidocaine/prilocaine gel intra-pocket anesthetic (Oraqix) for periodontal scaling/root planing. won't numb effective pup won't get DEEP be - , to ovely The University of Sydney  4 main : or/or wo adrenaline I. Lignocaine Arlicaine we adrenaline 2.. 3 mepivicaine (plain) 4. Prilocaine w/ felypressin Ashleigh Ayo Lecturer – Discipline of Oral Health Sydney Dental School Faculty of Medicine and Health University of Sydney [email protected] [email protected]