Lecture 2: Pharmacology of Vasoconstrictors and Local Anesthetics PDF

1  Pharmacology of Vasoconstrictors and of specific LA agents!  After local anesthetic injection, blood vessels (arterioles and capillaries primarily) dilate & increased perfusion at the site, leading to: 1. increased absorption rate of LA into CVS removes LA from the site (redistributio...

1  Pharmacology of Vasoconstrictors and of specific LA agents!  After local anesthetic injection, blood vessels (arterioles and capillaries primarily) dilate & increased perfusion at the site, leading to: 1. increased absorption rate of LA into CVS removes LA from the site (redistribution) 2. Higher plasma levels of LA increase risk of toxicity (overdose) 3. LA diffuses away from the site more rapidly ↓ depth and duration of anesthesia 4. Increased bleeding at the site of treatment due to increased perfusion  Vasoconstrictors: constrict blood vessels and control tissue perfusion, added to local anesthetic to oppose vasodilatory actions of LA (all except cocaine cause vasodilation).  Vasoconstrictors functions in LA: 1. Vasoconstriction decrease blood flow (perfusion). 2. Slowed Absorption of LA into CVS lower anesthetic blood levels decrease risk of LA toxicity 3. More local anesthetic enters the nerve & remains for longer periods increase (in significantly or minimally) duration of action of most local anesthetics. 4. decrease bleeding useful when increased bleeding is anticipated (during a surgical procedure) Types of Vasoconstrictors - Chemically identical or similar to sympathetic - Epinephrine Catecholamines nervous system mediators epinephrine & - Norepinephrine norepinephrine. Contain aromatic ring with - Levonordefrin hydroxyl group and amine group attached to (synthetic) side chain - Isoproterenol - Epinephrine, norepinephrine, & dopamine: (synthetic) naturally occurring catecholamines of - Dopamine sympathetic nervous system. - Rarely used in LA in dental practice Noncatecholamines - Amphetamine, Methamphetamine, Ephedrine, Mephentermine, Hydroxyamphetamine, Metaraminol, Methoxamine, Phenylephrine - synthetic analog of vasopressin (ADH) Felypressin - Predominant effect on venous rather than arterial circulation (not used as hemostatic agent to reduce bleeding) 2 Modes of Action  Three categories of sympathomimetic amines are known: a) direct-acting drugs: directly act on adrenergic receptors Adrenergic Receptors: α & β, Found in most tissues of the body  α receptors: smooth muscle contraction in blood vessels (vasoconstriction).  β receptors: smooth muscle relaxation (vasodilation & bronchodilation) & cardiac stimulation (↑ heart rate & strength of contraction). b) indirect-acting drugs: release catecholamine norepinephrine from adrenergic nerve terminals  Ex: tyramine and amphetamine (also may exert direct action on α and β receptors) c) mixed-acting drugs: both direct & indirect  Epinephrine (Adrenalin) - Direct acting on both alpha and beta receptors, - Most desired to be used in dentistry - Most effective and most used vasoconstrictor in medicine and dentistry. - Cause Feeling of palpitation. - Powerful but fragile Subjects to oxidation cartridge contains sodium betasulfite (scavenge oxygen, and release hydrogen ions prevent oxidation).  Pharmacological action of the epinephrine  Myocardium: stimulates β1 receptors & ↑ force of contraction (positive inotropic) and ↑ rate of contraction (positive chronotropic)  Pacemaker Cells: stimulates β1 receptors. ↑ Irritability of pacemaker cells, ↑ incidence of dysrhythmias. Ventricular tachycardia (VT) and premature ventricular contractions (PVCs) are common.  Blood Pressure: Systolic blood pressure is increased. Diastolic pressure is decreased. (Act on Skeletal muscle Beta-2 & cause vasodilation). IMPORTANT  Vasculature: Peripheral vasoconstrictors (alpha-1).  Bronchial dilation (Beta-2)  CNS: if cross BBB 3   Symptoms of epinephrine overdose OD - CNS stimulation: ↑ fear & anxiety, tension, restlessness, throbbing headache, tremor, weakness, dizziness, pallor, respiratory difficulty, and palpitation. - Cardiac dysrhythmias: (especially ventricular) become more common;  Ventricular fibrillation is a rare but possible consequence.  Dramatic increases in both systolic (>300 mm Hg) & diastolic (>200 mm Hg) pressures may led to cerebral hemorrhage.  Anginal episodes may be precipitated in patients with coronary artery insufficiency. - rapid inactivation of epinephrine stimulatory phase of the overdose (toxic) reaction usually is brief.  Other vasoconstrictors - Norepinephrine (used in medicine) - Phenylephrine - Felypressin:  Has no effect on adrenergic receptors  Has minimum cardiovascular stimulatory action and nondysrhythmogenic  Used if there is contraindication to epinephrine  Used mainly to ↓ LA absorption and ↑ duration of action.  Contraindicated in pregnancy, why? ADH analog uterine contractions & reduce uterine blood flow miscarriage or harm the fetus. Clinical Implications of pH and Local Anesthetic Activity Most LA without a vasoconstrictor a pH between 5.5 and 7. When injected buffering capacity of tissue returns pH at injection site to a normal 7.4. LA with a vasopressor (e.g., epinephrine) is acidified through the addition of sodium (meta) bisulfite to retard vasoconstrictor oxidation & prolonging period of effectiveness of the drug (e.g., increased shelf life). pH of local anesthetic containing epinephrine may range from 2.8 to 5.5. - Even in this situation, buffering capacity of tissues tends to maintain a normal tissue pH - require a longer time During this time, LA is not able to function with full effectiveness 4  - Result in a slower onset for local anesthetics with vasoconstrictors compared with their plain counterparts. Dilutions of Vasoconstrictors  allowed dose of both vasoconstrictors and local anesthetics is very low diluted in a solvent to be dispensed easily  adrenaline isn’t used in dental practice except in emergency  The dilution of vasoconstrictors is referred to as a ratio (e.g., 1 to 1000 [written 1:1000]).  maximum doses of vasoconstrictors are presented in milligrams, or more commonly as micrograms μg ‘mcg in hand writing’  1:1000: 1 g (1000 mg) of solute (vasoconstrictor / drug) is contained in 1000 mL of solution  1:1000 dilutions contain 1000 mg in 1000 mL or 1.0 mg/mL of solution (1000 mcg/mL).  To produce a 1:100,000 concentration, 1 mL of a 1:10,000 concentration is added to 9 mL of solvent; therefore 1:100,000 = 0.01 mg/mL (10 mcg/mL).  If 1:100,000 = 0.01 mg/mL (10 mcg/mL), then 1.8 ml (dental cartridge volume) would contain 0.018 mg. (IMPORTANT)  1 mg = 1000 mcg (μg)  It is recommended to limit total epi in ASA I and II to 0.2 mg/appointment. And in ASA III or higher to 0.04 mg/appointment  ASA classification: risk-stratifying system used by anesthesiologists to predict preoperative risks. ASA I: Medically fit ASA II: controlled systematic disease ASA III: severe systemic disease/ unstable medical condition ASA IV: life-threatening/ uncontrolled medical condition ASA V: bed-bound patient/ just waiting for their organs to be donated (‫)ميت رسيريا‬ 5 Contraindications to vasoconstrictors Significant cardiovascular disease (ASA 3 and 4). thyroid dysfunction: mainly hypothyroidism diabetes mellitus: not absolute contraindication, vasoconstrictor may ↑ blood glucose level sulfite sensitivity: (sodium metabisulfite) Patients receiving MAO inhibitors, tricyclic antidepressants, and phenothiazines.  severity of disorder determine whether a vasoconstrictor may be safely included or be excluded from LA  the best thing to do is to limit the amount of vasoconstrictor that will go to blood circulation (avoid intravascular administration) Adequate pain control of sufficient clinical duration and depth is difficult to achieve without vasoconstrictors in the local anesthetic solution. Unless specifically contraindicated by a patient's medical status (ASA 4 or above) or by the required duration of treatment (short), inclusion of a vasoconstrictor should be considered routinely. avoid unintended intravascular administration of the vasoconstrictor (as well as the local anesthetic) through multiple aspirations and slow administration of minimum concentrations of both vasoconstrictor and local anesthetic Clinical Action of Specific Agents Specific LA agents Specific LA agents Selection of Local Anaesthetic agents depend on: - The duration of pulpal (hard tissue) and soft tissue (total) anaesthesia needed (Length of time pain control is necessary) - Possibility of self-mutilation in the postoperative period - Need for Postoperative pain management - Need for Hemostasis - Absolute and relative C/I Approximate Duration of Action of Local Anesthetics  Short Duration: Pulpal Anesthesia Approximately 30 Minutes - Mepivacaine HCl 3% 6  - Prilocaine HCl 4% (by infiltration)  Intermediate Duration: Pulpal Anesthesia Approximately 60 Minutes - Articaine HCl 4% + epinephrine 1:100,000 - Articaine HCl 4% + epinephrine 1:200,000 - Lidocaine HCl 2% + epinephrine 1:50,000 - Lidocaine HCl 2% + epinephrine 1:100,000 - Mepivacaine HCl 2% + levonordefrin 1:20,000 - Prilocaine HCl 4% (via nerve block only) - Prilocaine HCl 4% + epinephrine 1:200,000  Long Duration: Pulpal Anesthesia Approximately 90+ Minutes - Bupivacaine HCl 0.5% + epinephrine 1:200,000 (by nerve block) Duration Duration of pulpal (hard tissue) & soft tissue (total) anesthesia for each drug is an approximation. Factors affect both the depth and the duration of a drug's anesthetic action, prolonging or (much more commonly) decreasing it: 1. Individual response to the drug (follow “bell- shaped” curve) 2. Accuracy in deposition of LA 3. Status of tissues at the site of drug deposition (vascularity, pH) 4. Anatomic variation 5. Type of injection administered (supraperiosteal [ “infiltration”] or nerve block) - The same local anesthetic has a longer duration of action when administered via a block technique compared to an infiltration technique - Bupivacaine gives up to 12 hrs in block technique: used to control postoperative pain 7 Maximum doses of L.A Unlikely to be reached. (mg/kg) or (mg/lb). Only estimated values (Bell-shaped curve): Normal responders, Hypo-responders, Hyper- responders Always minimize drug doses and use smallest clinically effective dose Decreased in medically compromised, debilitated, or elderly persons Overdose (OD) When MRD is exceeded, no guarantee that OD will occur, but greater likelihood of its occurrence. Hyper-responders people : experience OD on lower dose than calculated MRD Another factor in determining whether an OD will occur: time over which the local anesthetic dose was administered. Maximum Recommended Dosages (MRDs) of Local Anesthetics How to calculate maximum dosages and numbers of local anesthetic cartridges to be administered to various patients. o 2% lidocaine: Each 1 ml contains 20.0 mg of lidocaine hydrochloride. o 0.5% lidocaine: Each 1 ml contains 5.0 mg of lidocaine hydrochloride. o 4% articaine: Each 1 ml contains 40.0 mg of articaine hydrochloride. o 3% mepivacaine: Each 1 ml contains 30 mg of mepivacaine hydrochloride  Multiply concentration by 10 8  Calculation of Maximum dosage and Number of Cartridges (single drug):  Keep in mind that we can’t exceed the allowed epinephrine dose in single visit  Patient: 22 years old, Healthy, Female, 50 kg L.A: Lidocaine HCL 2% + Epinephrine 1:100,000 - MRD Lidocaine: 7 mg/kg - Lidocaine 2% → 2/100 x 1000 = 20 mg/ml - Cartridge contains 1.8 ml solution → 20 x 1.8 = 36 mg/cartridge - Maximum dose for this patient is: 7 mg/kg x 50 = 350 mg - Number of cartridges= 350/36 = ~10 cartridge  Patient: 40 Years Old, Healthy, Male, 90 kg Articaine HCl 4% + Epinephrine 1:200,000 - Articaine 4%: 40*1.8 = 72 mg/cartridge - Articaine: 7.0 mg/kg  7 * 90 = 630 mg (MRD) - Number of cartridges: 630/72 = ≈9.0  Patient: 6 Years Old, Healthy, Male, 20 kg Mepivacaine HCl 3%, No Vasoconstrictor - Mepivacaine 3%: 30 * 1.8 = 54 mg/cartridge - Mepivacaine: 6.6 mg/kg  6.6 * 20 = 132 mg (MRD) - Number of cartridges: 130/54 = ≈2.5 MRD, Maximum recommended dose  Calculation of Maximum Dosage and Number of Cartridges (Multiple Drugs)  Patient: 45-kg Female, Healthy Mepivacaine 2% + Levonordefrin 1:20,000 - Mepivacaine 2% = 36 mg/cartridge - Mepivacaine: 6.6 mg/kg = 297 mg (MRD) - Above patient receives 2 cartridges (72 mg), but anesthesia is inadequate. Doctor wishes to change to articaine 4% + epinephrine 1:100,000. How Much Articaine Can This Patient Receive? - Articaine 2% = 72 mg/cartridge Articaine: 7.0 mg/kg = 315 mg (MRD) 9   Total dose of BOTH local anesthetics should not exceed the lower of the two calculated doses, or 297 mg in the example. - Patient has received 72 mg (mepivacaine), thus can still receive 225 mg of articaine. - Therefore, 225 mg/72 mg per cartridge = ≈3.0 cartridges of articaine 4% + epinephrine 1:100,000.  Ensure that the total dose of both local anesthetics does not exceed the lower of the two maximum doses for the individual agents.  Easter, Metabolism in Blood plasma (Pseudocholinesterase) & 2% of it Excreted unchanged in urine  Slow Onset of action (6-10 min) Procaine HCL  Effective concentration: 2%-4%  Does not have Topical anaesthetic action  Not very potent: 2% procaine (plain) provides essentially no pulpal anaesthesia and from 15 to 30 minutes of soft tissue anaesthesia.  The greatest vasodilation of all clinically used local anaesthetics.  Immediate management of inadvertent intra-arterial (IA) injection of a drug  Effective concentration: 2%  Rapid Onset of action (3-5 mins), half-life 90 min  Has Topical anaesthesia  Metabolized in Liver into two metabolites & Excreted in Kidney  Vasodilation properties: Procaine > Lidocaine > Prilocaine > Mepivacaine  60 minutes pulpal & 3 to 5 hours of soft tissue anaesthesia. Lidocaine  Pregnancy classification is B & Safe during lactation  Lidocaine replaced procaine (Novocaine) as the most widely used LA in both medicine and dentistry. Compared with procaine, lidocaine possesses : - more rapid onset of action (3 to 5 minutes vs. 6 to 10 minutes), longer duration of action - produces more profound anaesthesia, greater potency, Allergy to amide local anaesthetics is virtually non-existent! 10   Lidocaine Preparations - For most procedures in a typical dental patient, 2% lidocaine with 1:100,000 epinephrine is preferred to 2% lidocaine with 1:50,000 epinephrine. - 1:50,000 solution provides excellent haemostatic action. (1:100,000 may be used for hemostasis, but not as effective). - Rebound vasodilation: epinephrine concentration decreases. - The only recommended use of 2% lidocaine 1:50,000 epinephrine concentration is for hemostasis (small volumes into the surgical site). - 2% lidocaine with 1:200,000 or 1:300,000 epinephrine provides the same duration of pulpal and soft tissue anaesthesia, although not the same level of haemostasis, their use is recommended in elderly patients or hyper-responders to epinephrine.  Lidocaine Overdose - Same as other agents (CNS stimulation followed by CNS depression). - Stimulatory phase may be brief or may not develop at all. - Although muscle tremor and seizures commonly occur with overly high lidocaine blood levels, the first signs and symptoms may include drowsiness, leading to loss of consciousness and respiratory arrest.  Rapid Onset of action (3-5 mins), Anaesthetic half-life 1.9 hours  Effective concentration: 3% plain, 2% with vasoconstrictor. (concentration of plain form is always higher in all LA)  Metabolized in Liver & Excreted in Kidney  Vasodilation properties: Slightly vasodilator Mepivacaine HCl  Has no Topical anaesthesia form  Duration of action: 20-40 minutes pulpal anaesthesia for plain (compared to 10-20min Lidocaine plain)  Three Percent Mepivacaine Without a Vasoconstrictor uses: - For patients in whom vasoconstrictor is not indicated - For Dental procedures requiring neither lengthy nor profound pulpal anaesthesia. - Most used LA in paediatric when treating doctor is not a pediatric dentist (GP) and often is quite appropriate in the management of geriatric patients. 11   Vasodilating Properties: Lidocaine > Prilocaine > Mepivacaine  Onset of Action: Slightly slower than that of lidocaine (3 to 5 minutes).  Effective Dental Concentration 4%.  Anaesthetic Half-Life: 1.6 hours.  Topical Anaesthetic Action: Prilocaine, in its uncharged base form, is an integral part of EMLA cream  Metabolism is significantly different from lidocaine and mepivacaine; it undergoes more rapid and complete biotransformation (in lung).  Orthotoluidine: by-product which induce methemoglobinemia → observable cyanosis.  Limiting the total prilocaine dose to 600 mg (FDA recommendation) avoids symptomatic cyanosis.  Excreted in kidneys. (Renal clearance of prilocaine is faster than other amides)  Infiltration with Prilocaine 4% plain provides short durations of pulpal (10 to 15 minutes) Prilocaine HCL and soft tissue ( to 2 hours) anesthesia, whereas regional nerve block provides 40 to 60 minutes & soft tissue anesthesia for 2 to 4 hours.  Prilocaine plain =lidocaine or mepivacaine with a vasoconstrictor.  Prilocaine with epinephrine provides lengthy anaesthesia while offering a less concentrated epinephrine dilution: 1:200,000.  In epinephrine-sensitive patients requiring prolonged pulpal anesthesia (≥60 minutes), prilocaine plain or with 1:200,000 epinephrine is strongly recommended  Rapidly biotransformed  safe, lower toxicity  C/I of Prilocaine - Relatively contraindicated in patients with idiopathic or congenital methemoglobinemia, hemoglobinopathies (sickle cell anemia), anemia, or cardiac or respiratory failure evidenced by hypoxia  increased methemoglobin levels = ↓oxygen-carrying capacity. - Relatively contraindicated in patients receiving acetaminophen or phenacetin,  both produce elevations in methemoglobin levels. - Neurotoxicity and paresthesia Prilocaine has been implicated in a higher incidence of paresthesia associated with nerve block injections compared with lidocaine. (contraindicated as block agent) 12   Classification: Hybrid molecule. Classified as an amide; possesses both amide and ester characteristics.  Potency 1.5 times that of lidocaine; 1.9 times that of procaine.  Toxicity Similar to lidocaine and procaine.  Metabolized in both plasma and liver & Excreted Via kidneys  Vasodilating Properties: Articaine = lidocaine.  Onset of Action: - Articaine 1:200,000, infiltration 1 to 2 minutes, mandibular block 2 to 3 minutes; - Articaine 1:100,000, infiltration 1 to 2 minutes, mandibular block 2 to 3 minutes.  Effective Dental Concentration: 4% with 1:100,000 or 1:200,000 epinephrine.  Anaesthetic Half-Life: 0.5 hours [27 minutes].  Has Topical Anaesthetic Action Articaine HCl  Articaine, newest LA marketed, is able to diffuse through soft and hard tissues more reliably than other local anesthetics.  Clinically: following maxillary buccal infiltration, articaine may provide palatal soft tissue anesthesia, obviating the need for palatal injection  Significant success of articaine administered by mandibular buccal infiltration in adult.  Reports of paraesthesia following local anaesthetic administration. Most reported cases occurred following inferior alveolar nerve block and primarily involved the lingual nerve.  Articaine HCL relative C/I - Used with caution in hepatic disease and significant impairment in cardiovascular function. - Class C during pregnancy. - Use with caution in females who are breast-feeding - Administration to children younger than 4 years is not recommended (insufficient data to support such usage).  MRD bupivacaine is 90 mg, available as a 0.5% solution with 1:200,000 epinephrine Bupivacaine HCL  Two primary indications: 1. Lengthy dental procedures (pulpal or deep anesthesia > 90 minutes)  full mouth reconstruction, implant surgery, extensive periodontal procedures) 2. Management of postoperative pain (e.g., endodontic, periodontal, post implant, surgical). The patient's requirement for postoperative opioid analgesics is considerably lessened 13   Relative C/I - not recommended in younger patients or in those for whom the risk of postoperative soft tissue injury produced by self-mutilation is increased (physically and mentally disabled persons) - rarely indicated in children (pediatric dental procedures usually of short duration). Summary Amides are preferred to esters whenever possible A minimum of two drugs is recommended for most offices. Topical anaesthetic for tissue preparation before injection of local anaesthetic Short-duration pulpal anaesthetic (≈30 minutes) Intermediate-duration pulpal anaesthetic (≈60 minutes) Long-duration pulpal anaesthetic (90 or more minutes) Anesthetics For Topical Application Conventional topical anesthetics: unable to penetrate intact skin but do diffuse through abraded skin and any mucous membranes. Concentration of topical LA is greater than the same local anaesthetic administered by injection.  Higher concentration increases risk of toxicity (Do not contain vasoconstrictors) Many local anesthetics used effectively via injection prove ineffective when applied topically. As a general rule, topical anesthetics are effective only on surface tissues (2 to 3 mm).  EMLA (Eutectic Mixture of Local Anesthetics) EMLA cream (composed of lidocaine 2.5% and prilocaine 2.5%) provide surface anesthesia for intact skin Used primarily before painful procedures such as venepuncture EMLA must be applied 1 hour before the procedure, and lasts for 1 to 2 hours after removal. “EMLA is not recommended for use on mucous membranes or ulcers / un-intact skin  has high concentration & could be absorbed rapidly causing toxicity 14  Lidocaine Lidocaine is available in two forms for topical application: a) lidocaine base: poorly soluble in water, used as a 5% concentration, indicated for use on ulcerated or abraded tissue b) Lidocaine hydrochloride: water-soluble preparation, used as a 2% concentration and penetrates tissue more efficiently than the base form  greater risk of toxicity than the base form. MRD following topical application is 200 mg. Availability: - Lidocaine base is available as an aerosol spray, ointment, patch, and solution in various dosage forms. - Lidocaine HCl is available as an oral topical solution in 20 mg/mL (viscous) and 40 mg/mL (solution). Used in dental practice prior to LA injection to relief pain in needle phobic patient 15