Dental Local Anaesthesia & Vasoconstrictors Lecture PDF

Pharmacology of Dental Local Anaesthesia & Vasoconstrictors Dr. B Rogers DDS  OBJECTIVES Describe the systemic action of local anaesthetic drugs. Explain the Pharmacology and classification of Local Anaesthetic Drugs, Vasoconstrictors, and other constituents...

Pharmacology of Dental Local Anaesthesia & Vasoconstrictors Dr. B Rogers DDS  OBJECTIVES Describe the systemic action of local anaesthetic drugs. Explain the Pharmacology and classification of Local Anaesthetic Drugs, Vasoconstrictors, and other constituents of Local Anaesthetic solution  Kinetics of Local Anaesthetic Onset and Duration of Action Barriers to Diffusion  Barriers to Diffusion Cont’d Factors which decrease LA concentration outside Nerve: 1. Absorption by non-neural tissues 2. Dilution in interstitial fluid 3. Lost to capillary & lymphatic circulation 4. Hydrolysis of ester LA’s Induction of Local Anaesthesia  Induction Time The period from deposition of the anesthetic solution to complete conduction blockade Factors Affecting induction time: LA concentration* LA solution pH* Diffusion constant of LA** Anatomical diffusion barriers in nerve** *Operator can control ** Operator can't control  Physical Properties and Clinical Actions affecting Induction of LA dissociation constant (pKa): drugs with a lower pKa possess a more rapid onset of action than those with a higher pKa Lipid solubility: appears to be related to its intrinsic potency. Greater lipid solubility 🡺 increased potency protein binding: responsible for the duration of anesthetic activity. more securely to the protein receptor sites and to possess a longer duration of clinical activity. Vasodilator activity: affects both the potency and the duration of  Factors Affecting Local Anesthetic Action Factor Action Description Affected Lower pKa 🡺 more rapid onset of action. More RN pKa Onset (free base LA) molecules present to diffuse through the nerve sheath 🡺 faster onset LA Lipid Solubility Potency Greater the lipid solubility = greater potency Increased protein bindings allows LA cations (RNH+) Protein Binding Duration to attach more firmly to proteins at receptor sites 🡺 increases duration of action Non-nervous tissue Onset Increases diffusability = decreased onset time diffusability LA Greater vasodilator activity 🡺 increased blood flow to Vasodilator Potency & region 🡺 rapid removal of LA molecules from injection Activity Duration site 🡺 reduced LA potency & duration Recovery from Local Anesthetic Block  Readministration of Local Anaesthetic Recurrence of Immediate Profound Anaesthesia: Ideal scenario Difficulty Re-achieving Profound Anaesthesia = Tachyphylaxis Tachyphylaxis: increasing tolerance to a drug that is administered repeatedly. much more likely to develop if nerve function is allowed to return before reinjection (e.g., if the patient complains of pain). The duration, intensity, and spread of anesthesia with reinjection are greatly reduced  Duration of Anaesthesia As LA is removed from the nerve, the function of the nerve returns rapidly at first, but then it gradually slows In a nerve block, onset is rapid, but recovery is much slower because the local anesthetic is bound to the nerve membrane Longer acting local anaesthetics are more firmly bound in the nerve membrane (increased protein binding) than are shorter acting drugs and therefore are released more slowly from receptor sites SYSTEMIC ACTIONS OF LOCAL ANESTHETICS  Central Nervous System - CNS CNS DEPRESSANTS: Readily cross blood-brain barrier At low (therapeutic, nontoxic) blood levels 🡺 no CNS effects of any clinical significance At higher (toxic, overdose) levels 🡺 primary clinical manifestation is a generalized tonic–clonic convulsion Properties: Anticonvulsant, analgesic, euphoric  CNS – Anticonvulsant Action Drugs: procaine, lidocaine, mepivacaine, prilocaine, even cocaïne Blood concentration: occur at a blood level considerably below that at which the same drugs produce seizure activity  CNS – Anticonvulsant Action Cont’d - Therapeutic doses: 2 to 3 mg/kg, given at a rate of 40 to 50 mg/min - Effects: temporarily arresting seizure activity in a majority of human epileptic patients. effective in interrupting status epilepticus - Mechanism of Anticonvulsant Action : LA 🡺 CNS Depression 🡺 raise the seizure threshold by decreasing the excitability of the hyperexcitable neurons of epileptic pt.s 🡺 preventing or terminating seizures.  CNS – Preconvulsive Signs and Symptoms of Central Nervous System Toxicity Signs (objectively observable) Symptoms (subjectively felt) Slurred speech Numbness of tongue Shivering and circumoral region Muscular twitching Warm, flushed feeling of Tremor of muscles of face and distal extremities skin Generalized light-headedness Pleasant dreamlike state Dizziness Visual disturbances (inability to focus) Auditory disturbance (tinnitus) Drowsiness Disorientation  CNS – Convulsive Phase Duration of seizure activity is related to the local anesthetic blood level and is inversely related to the arterial partial pressure of carbon dioxide (pCO2) level. At a normal pCO2, a lidocaine blood level between 7.5 and 10 μg/mL usually results in a convulsive episode.  CNS – Convulsi ve Phase Cont’d  CNS - Analgesia Administered IV 🡺 increase the pain reaction threshold and a degree of analgesia. 1940s – 1950s procaine IV used for chronic pain in arthritis. ⮚ “Procaine unit” = 4 mg/kg of body weight administered over 20 minutes ⮚ technique was ineffective for acute pain ⮚ relatively narrow safety margin between the analgesic actions of procaine and the occurrence of signs and symptoms of overdose, this technique is no longer in use today  CNS - Euphoria Historically used for mood elevation (euphoria) & rejuvenation (fatigue-lessening) Cocaine: dating back to the chewing of coca leaves by Incas and other South American natives leads to habituation Benign, but unsubstantiated use of procaine (Novocain) as a rejuvenating drug: clinics operate primarily in central Europe and Mexico, where procaine is used under the proprietary name Gerovital.  Cardiovascular System Direct Action on the Myocardium = ANTIDYSRHYTHMIC ACTION Mechanism: Myocardial depression (through reduced depolarization) 🡺 decreased conduction rate 🡺 decreased force of contraction Therapeutic benefits: managing hyperexcitable myocardium (cardiac dysrhythmias)  Cardiovascular System Drugs: - Lidocaine = most widely used (therapeutic blood levels) 1.8 - 6μg/mL - Procainamide = procaine with an amide linkage - Tocainide = chemical analog of lidocaine that can be taken PO NB: Signs and symptoms of local anesthetic overdose will be noted if the blood level rises beyond 6 μg/mL of blood  Cardiovascular System Direct Action on the Peripheral Vasculature = VASODILATION direct depression of the myocardium and smooth muscle relaxation in the vessel walls by the local anaesthetic. Therapeutic benefits: Hypotensive Drugs: procaine vasodilation > lidocaine Minimal to Moderate Overdose Levels *blood level rises beyond 6 μg/mL of blood  Local Tissue Toxicity Skeletal muscle appears to be more sensitive than other tissues to the local irritant properties of local anesthetics longer-acting local anesthetics cause more localized skeletal muscle damage than shorter-acting drugs. E.g. articaine, lidocaine, mepivacaine, prilocaine, bupivacaine, and etidocaine Effects are reversible, muscle regeneration being complete within 2 weeks after local anesthetic administration  Respiratory System Dual effect on respiration ▪ direct relaxant action on bronchial smooth muscle at high therapeutic levels (near overdose) ▪ produce respiratory arrest due to generalized CNS Depression with overdose Generally, respiratory function is unaffected until near- overdose levels are achieved.  Miscellaneous Actions Malignant Hyperthermia/ hyperpyrexia: pharmacogenic disorder in which a genetic variant, alters pt.'s response to certain drugs 🡺 tachycardia, tachypnea, unstable blood pressure, cyanosis, respiratory and metabolic acidosis, fever (as high as 42° C [108° F] or more), muscle rigidity, and death. Mortality ranges from 63% to 73%. Many commonly used anesthetic drugs can trigger MH in certain individuals.  Miscellaneous Actions Neuromuscular Blockade: may lead to abnormally prolonged periods of muscle paralysis, unlikely to occur in the dental outpatient. Drug Interactions: Potentiation: + CNS depressants 🡺 potentiation of the CNS-depressant actions of LA + drugs that share a common metabolic pathway/ induce the production of hepatic microsomal enzymes 🡺 increased blood plasma/ delayed excretion 🡺 Potentiation + other adverse reactions  Pharmacology of Vasoconstrictors  Chemical structure −  Mode of Action Three categories of sympathomimetic amines 1. Direct acting = Exert their action directly on Adrenergic Receptors 2.Indirect-acting = Release of Catecholamines from adrenergic nerve terminals 3.Mixed-acting drugs = both direct and indirect actions  Mode of Action - Adrenergic Receptors Two types based on inhibitory or excitatory actions of catecholamines on smooth muscle: 1. alpha (α) receptors 🡺 response that includes contraction of smooth muscle in blood vessels (vasoconstriction). α1 receptors = excitatory-postsynaptic, α2 receptors = inhibitory-postsynaptic  Mode of Action - Adrenergic Receptors 2. beta (β) receptors 🡺 smooth muscle relaxation (vasodilation and bronchodilation) and cardiac stimulation (increased heart rate and strength of contraction) β 1 receptors =in the heart and small intestines and 🡺 cardiac stimulation and lipolysis β 2 receptors = in the bronchi, vascular beds, and uterus, produce bronchodilation and vasodilation  Mode of Action - Adrenergic Receptors +, Increase; −, decrease; 0, no effect.  Mode of Action – Catecholamines Release Other sympathomimetic drugs, such as tyramine and amphetamine, act indirectly by causing the release of the catecholamine norepinephrine from storage sites in adrenergic nerve terminals. These drugs may exert direct action on α and β receptors. (Mixed) clinical actions of this group of drugs therefore are quite similar to the actions of norepinephrine. Successively repeated doses of these drugs will prove to be less effective than those given previously because of depletion of norepinephrine from storage sites TACHLYPHYLAXIS  Concentration/ Dilution Expressed as a ratio maximum doses of vasoconstrictors are presented in mg, micrograms (μg) Interpreting the ratio: concentration of 1 : 1000 = 1 g (1000 mg) of solute (drug) is contained in 1000 mL of solution 🡺 1 : 1000 dilution = 1000 mg in 1000 mL or 1.0 mg/mL of solution (1000 μg/mL). concentration of 1 : 10,000 = 1 mL of a 1 : 1000 solution is added to 9 mL of solvent 🡺1 : 10,000 = 0.1 mg/mL (100 μg/mL). concentration of 1 : 100,000 = 1 mL of a 1 : 10,000 concentration is added to 9 mL of solvent 🡺 1 : 100,000 = 0.01 mg/mL (10 μg/mL). Concentration/ Dilution/ Ratio Pharmacology of Specific Agents  Epinephrine Proprietary Name. Adrenalin(e) Chemical Structure: acid salt is highly soluble in water. Shelf life of LA cartridge w/vasoconstrictor = 18 months w/o = 36 months Source: synthetic and from the adrenal medulla of animals Mode of Action. Epinephrine acts directly on both α- and β-adrenergic receptors; β effects predominate.  Epinephrine - Systemic Actions Myocardium: cardiac output and heart rate are increased. Pacemaker Cell: Ventricular tachycardia (VT) and premature ventricular contractions (PVCs) Coronary Arteries: increasing coronary artery blood flow Blood Pressure: small dose 🡺 Systolic blood pressure is increased. Diastolic pressure is decreased (1-2 cartridges 1:100,000 epi) larger dose 🡺 Diastolic pressure is increased (4 cartridges 1:100,000 epi)  Epinephrine - Systemic Actions Cardiovascular Dynamics: Direct Stimulation 🡺 overall decrease in cardiac efficiency Vasculature: act on smaller arterioles & precapillary sphincters. Stimulate α receptors 🡺 vasoconstriction in skin, mucosa & kidneys. β2 receptors🡺 vasodilation in skeletal muscle Haemostasis: α receptor stimulation 🡺 vasoconstriction & haemostasis  Epinephrine - Systemic Actions Respiratory System: β2 effect 🡺 dilation of bronchial smooth muscle Central Nervous System: in therapeutic dosages, not a potent central nervous system (CNS) stimulant Metabolism: β action 🡺 increases oxygen consumption in all tissues. (4 cartridges 1:100,000) Termination of Action and Elimination: action is terminated primarily by its reuptake by adrenergic nerves  Epinephrine - Systemic Actions Side Effects and Overdose: CNS stimulation 🡺 increasing fear and anxiety, tension, restlessness, throbbing headache, tremor, weakness, dizziness, pallor, respiratory difficulty, and palpitation. CVS🡺 cardiac dysrhythmias, especially ventricular - ventricular fibrillation is rare but possible. Dramatic increases in both systolic (>300 mm Hg) and diastolic (>200 mm Hg) pressures may be noted and have led to cerebral hemorrhage. Angina  Epinephrine - Clinical Applications Management of acute allergic reactions Management of refractory bronchospasm (status asthmaticus) Management of cardiac arrest As a vasoconstrictor, for haemostasis As a vasoconstrictor in local anesthetics, to decrease absorption into the CVS As a vasoconstrictor in local anesthetics, to increase depth of anaesthesia As a vasoconstrictor in local anesthetics, to increase duration of anaesthesia To produce mydriasis  Selection of a Vasoconstrictor Two vasoconstrictors are available in local anesthetic solutions in Americas: epinephrine and levonordefrin. Factors to consider when choosing vasoconstrictor (if any) with your LA: 1. length of the dental procedure 2. need for haemostasis during and after the procedure 3. Requirement for postoperative pain control 4. medical status of the patient  Length of the Dental Procedure The addition of any vasoconstrictor to LA prolongs its duration (and depth) of pulpal and soft tissue anesthesia.  Requirement for Haemostasis Vasoconstrictors must be deposited locally into the surgical site (area of bleeding) to provide hemostasis Epinephrine: effective surgical haemostatic. However, it also produces a rebound vasodilatory effect as the tissue level of epinephrine declines 🡺 possible bleeding postop., potentially interfering with wound healing Phenylephrine: longer acting  Requirement for Haemostasis Norepinephrine: potent but documented cases of tissue necrosis. NOT USED IN DENTISTRY Felypressin: constricts the venous circulation more than the arteriolar circulation and therefore is of minimal value for haemostasis. NOT USED IN THE AMERICAS  Medical Status of the Patient Contraindications: Patients with more significant cardiovascular disease (ASA 3 and 4) Patients with certain non-cardiovascular diseases (e.g., thyroid dysfunction, diabetes, sulfite sensitivity) Patients receiving MAO inhibitors, tricyclic antidepressants, and phenothiazines NB: Patients with a resting blood pressure (minimum 5-minute rest) of > 200 mm Hg systolic or >115 mm Hg diastolic should not receive elective dental care until their more significant medical problem of high blood pressure is corrected  Treatment Definition Examples Recommendations Routine dental ASA I Healthy pt. Healthy, non-smoking, no/minimal alcohol use management ▪ Pregnancy ▪ asthma ▪ Current smoker Pt. w/ no mild ▪ thyroid dysfunction Elective care okay; ASA II ▪ Social alcohol drinker systemic disease ▪ BP 140-159/ 90-05 mmHg consider treat. mods ▪ well controlled DM type II ▪ BMI 30 3 mths ▪ Poorly ctrl HTN 160-199/ 95-114 mm Pt. w/ severe ▪ Post CVA > 3 mths Hg systemic disease Elective care okay; serious ▪ Post TIA > 3 mths ▪ ESRD undergoing scheduled dialysis ASA III that limits consideration of treat. ▪ Post CAD/stents > 3 mths ▪ Morbid obesity BMI >= 40 activity but isn’t mods ▪ Active hepatitis ▪ Alcohol dependence/ abuse incapacitating ▪ Exercise induced asthma ▪ Implanted pacemaker ▪ COPD ▪ Moderate reduction of ejection fraction ▪ Severe reduction of Ejection fraction ▪ Recent MI < 3mths ▪ ARD or ESRD not under scheduled Pt. w/ Elective care ▪ Recent CVA < 3mths dialysis incapacitating contraindicated; ▪ Recent TIA < 3mths ▪ Shock ASA IV sys. Disease emergency care: non- ▪ Recent CAD/stents < 3mths ▪ Sepsis that’s a constant invasive or in a controlled ▪ Ongoing cardiac ischaemia ▪ Uncontrolled epilepsy threat to life environment ▪ Severe valve dysfunction ▪ Uncontrolled HTN. BP >200/ >115 mm Hg ▪ Ruptured abdominal/ thoracic aneurysm ▪ Multi organ/ system dysfunction Moribund pt. ▪ Massive trauma ▪ End-stage cancer ASA V Won’t survive 24 ▪ Intracranial bleed Palliative care ▪ End-stage infectious disease hrs ▪ Ischaemic bowel ▪ End-stage hepatic dysfunction ▪ Significant/ end- stage cardiac pathology Pt. declared brain-dead. Organ donor ASA VI  References Malamed, Stanley. F (2014) Handbook of Local Anesthesia, 6th ed. Mosby, Inc.