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General Principles of Toxicology:

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1. No drug ever exerts a single action. 2. No clinically useful drug is entirely devoid of toxicity. 3. The potential toxicity of a drug rests in the hand of the user.

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Adverse Drug Reactions: Overdose

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absolute or relative over-administration of a drug which produces elevated levels in the blood; dose related

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Adverse Drug Reactions: Allergy

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hypersensitive state acquired through exposure to a particular allergen, re-exposure to which brings about a heightened capacity to react; not dose related

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Adverse Drug Reactions: Idiosyncrasy

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response that cannot be explained by any known pharmacological or biochemical mechanism

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Causes of adverse drug reactions: 1.Toxicity caused by direct extension of the usual pharmacological effects of the drug

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A. Side effects B. Overdose reactions C. Local toxic effects

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Causes of adverse drug reactions: 2.Toxicity caused by alteration in the recipient of the drug

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A. A disease process B. Emotional disturbances C. Genetic aberrations D. Idiosyncrasy 3. Toxicity caused by allergic responses to the drug

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OVERDOSE—99%

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of all true adverse drug reactions

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Predisposing Factors 1. Patient Factors

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A. Age—more common in old and young people B. Weight—greater (lean) body weight can tolerate larger dose of drug before overdose C. Other medications—if other drugs compete for protein binding sites, toxicity occurs at lower drug level (Meperidine, Phenytoin, Quinidine, Desipramine); competition for hepatic oxidative enzymes slow biotransformation of Lidocaine (Cimetidine) D. Presence of disease—hepatic and renal dysfunction, congestive heart failure impair ability to transform drug to inactive product E. Genetics—alters response to drug (atypical pseudocholinesterase) F. Mental attitude and environment—fear related to larger dose requirement and lower seizure threshold, increasing likelihood of overdose

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Predisposing Factors 2. Drug Factors

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A. Vasoactivity—vasodilation increases absorption into tissues and raises blood level B. Concentration—greater concentration increases circulating blood level C. Dose—larger dose increases circulating blood level D. Route of administration—inadvertent intravascular injection increases blood level of drug; rapid absorption of topical anesthetic can lead to overdose E. Rate of injection**(important)—rapid intravenous administration (60 seconds) F. Vascularity of injection site—more risk of overdose in highly perfused areas G. Presence of vasoconstrictors—reduces clinical toxicity

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Drug OVERDOSE Causes

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1. Biotransformation of the drug is unusually slow—esters faster than amides; atypical pseudocholinesterase contraindication for esters; significant liver disease relative contraindication for amides (use minimal volume) 2. The drug is too slowly eliminated from the body through the kidneys. 3. Too large a total dose is administered—do not exceed MRD (maximum recommended dose); consider patient's age, weight, and physical status; MOST FREQUENTLY SEEN CAUSE OF OVERDOSE 4. Absorption from the injection site is unusually rapid—use vasoconstrictor unless contraindicated or short procedure to reduce absorption, limit area of topical anesthetic coverage (especially amide) 5. Inadvertent intravascular administration—most common with IA (11.7%), Mental/incisive (5.7%), PSA (3.1%) Prevent by using larger gauge needles (i.e., 25 gauge), aspirating in at least 2 planes before injection, injecting slowly (**most important factor)

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Clinical Manifestations of Local Anesthetic Overdose Signs and Symptoms

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occur at varying rates depending on cause— Most rapid—rapid intravascular injection—in seconds Too large a dose or rapid absorption—3-5 minutes Slow biotransformation—10-30 minutes Least rapid—Slow elimination—10 minutes to several hours

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Clinical Manifestations of Local Anesthetic Overdose Intensity

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Most intense—rapid intravascular Gradual but can be severe—too large a dose or rapid absorption Gradual, slow increase—Slow biotransformation or elimination

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Clinical Manifestations of Local Anesthetic Overdose Duration

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Longest—Slow biotransformation or elimination 5-30 minutes—too large a dose or rapid absorption 2-3 minutes—rapid intravascular

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MINIMAL TO MODERATE OVERDOSE SIGNS

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Talkativeness Apprehension Excitability Slurred speech Generalized stutter, leading to muscular twitching and tremor in face and distal extremities Euphoria Dysarthria Nystagmus Sweating Vomiting Failure to follow commands or be reasoned with Disorientation Loss of response to painful stimuli Elevated blood pressure Elevated heart rate Elevated respiratory rate

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MINIMAL TO MODERATE OVERDOSE SYMPTOMS

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Light-headedness and dizziness Restlessness Nervousness Numbness Sensation of twitching before actual twitching Metallic taste Visual disturbances (inability to focus) Auditory disturbances (tinnitus) Drowsiness and disorientation Loss of consciousness

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MODERATE TO HIGH OVERDOSE LEVELS

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Tonic-clonic seizure activity followed by Generalized CNS depression Depressed blood pressure, heart rate, and respiratory rate

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MODERATE TO HIGH OVERDOSE LEVELS Pathophysiology

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Local anesthetics exert DEPRESSANT effect Adverse reactions UNCOMMON at non-overdose levels of <5 micrograms/ml (usual range of blood level is 0.5-2 micrograms/ml following administration of 40-160 mg of local anesthetic or 1-4 cartridges of Lidocaine, e.g.)

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MODERATE TO HIGH OVERDOSE LEVELS CNS Actions

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1. CNS extremely sensitive to actions of local anesthetics 2. Local anesthetics cross the blood-brain barrier producing CNS depression 3. Signs of toxicity appear at cerebral blood level > 4.5 micrograms/ml—agitation, talkativeness, irritability 4. Tonic-clonic seizures occur at levels >7.5 micrograms/ml 5. Generalize CNS depression occurs at higher levels, resulting in respiratory depression and arrest

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MODERATE TO HIGH OVERDOSE LEVELS CVS Actions

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1. Less sensitive to actions of local anesthetics than CNS 2. Develops later than CNS actions 3. Minor alterations in CVS occur at 5-10 micrograms/ml—myocardial depression, decreased cardiac output, peripheral vasodilation 4. At >10 micrograms/ml—massive peripheral vasodilation, marked reduction in myocardial contractility, severe bradycardia, possible cardiac arrest

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MANAGEMENT OF ANESTHETIC OVERDOSE

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is based on severity of reaction Most often mild and transitory, little or no specific treatment Only RARELY are drugs other than OXYGEN required to terminate reaction

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MANAGEMENT OF ANESTHETIC MILD OVERDOSE SLOW ONSET > 5 minutes after administration

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Reassure patient Administer oxygen Monitor and record vital signs (IV anti-convulsant if trained and if situation warrants it—optional) Permit recovery before leaving office unescorted

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MANAGEMENT OF ANESTHETIC MILD OVERDOSE SLOW ONSET SLOWER ONSET > 15 minutes after administration

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Reassure patient Administer oxygen Monitor and record vital signs Administer anti-convulsant—if trained Summon medical assistance Refer for medical evaluation including blood tests, and liver and hepatic function tests Do not let patient leave office alone Determine cause of reaction before administering any other anesthetics

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MANAGEMENT OF ANESTHETIC SEVERE OVERDOSE RAPID ONSET (within 1 minute)

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Remove syringe from mouth and place in supine position, feet slightly elevated Monitor and record vital signs Other steps IF CONVULSIONS present: Protect patient's arms, legs, head Loosen clothing Remove pillow from headrest Summon emergency assistance Basic life support—airway, oxygen Administer anti-convulsant BLS as needed; circulation assistance may be needed post-seizure Administer vasopressor if hypotension > 30 minutes Allow patient to recover before release with another adult; if seizure occurred or emergency medical services were summoned, medical evaluation

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MANAGEMENT OF ANESTHETIC SEVERE OVERDOSE SLOW ONSET (5-15 minutes)

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Terminate treatment Basic life support as needed Monitor and record vital signs Administer anti-convulsant Summon emergency assistance BLS and/or vasopressor post-seizure as needed Permit recovery before release to another adult or let emergency medical personnel transport and evaluate Determine cause of problem before attempting to administer local anesthetic again

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EPINEPHRINE OVERDOSE

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Precipitating Factors and Prevention— Happens with epinephrine more than with other vasoconstrictors Happens more commonly following use of gingival retraction cord with epinephrine

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EPINEPHRINE OVERDOSE CLINICAL MANIFESTATIONS Clinical SYMPTOMS:

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Fear, anxiety Tenseness Restlessness Throbbing headache Tremor Perspiration Weakness Dizziness Pallor Respiratory difficulty Palpitations

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EPINEPHRINE OVERDOSE CLINICAL MANIFESTATIONS SIGNS:

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Sharp elevation in blood pressure (systolic) Elevated heart rate Possible cardiac dysrhythmias

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EPINEPHRINE OVERDOSE MANAGEMENT

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Terminate dental procedure Position patient to semi-sitting or erect Reassure patient that effects are transient Monitor and record vital signs Oxygen if deemed necessary Permit patient to recover in dental chair Release only when able to care for self **Usually such short duration that no formal management is required

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Allergy

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Hypersensitive state acquired through exposure to a particular allergen, re-exposure to which produces a heightened capacity to react

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Allergy Classification Type 1

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anaphylactic - life threatening, immediate, with in seconds to minutes

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Allergy Classification Type 2

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cytotoxic

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Allergy Classification Type 3

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immune complex 6 to 8 hours

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Allergy Classification Type 4

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cell mediated, delayed,48 hours

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Predisposing Factors

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Poeple who have other allergies 15% of patients have other allergies that require medical management People have more allergies to esters than amides, incidence of allergies to local anesthetics has decreased since primarily amides are used in dentistry now Most amide reactions are overdose, idiosyncrasy, or psychogenic Allergic reactions are more frequentlt associated with OTHER contents of cartridge-methylparaben (preservative) no longr used in local anesthetic cartridges since 1984 sodium bisulfate or metabisulfate (antioxidant for vasoconstrictor) - steroid dependent asthmatics may be allergic to this which is also sprayed on fruits as perservative Topical anesthetics - may contain preservative and may result in local or systemic reaction

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Allergic responses to local anesthetics include

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dermatitis (most frequent), bronchospasm, systemic anaphylaxis (life-threatening, rare)

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Allergy Prevention

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Pay attention to allergy related questions on health history (allergies, asthma, hay fever, sinus trouble, hives, itching, swelling, adverse drug reactions)

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Allergy Prevention Protocol if patient relates a history of allergy to a drug

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assume patient is allergic and take steps to determine if reaction is truely an allergy avoid us of the drug (and any related drugs) until allergy can be absolutely disproved for almost all drugs, there are equally effective alternative drugs that should be used *** the exception is local anesthetics

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Allergy Prevention To determine the veracity of an alleged drug allergy

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expand on dialogue history with patient refer patient for more extensive medical consultation and through evaluation

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Describe what happened when alleged allergic reaction took place

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If it was an allergy, patient would report any or all of these signs and symptoms - itching, hives, rash, edema, cramping, diarrhea, nausea, vomiting, runny nose, watery eyes, wheezing, larnygeal edema, angioedema, vasodilation, hypotension Most reactions are psychogenic or related to vasoconstrictor Hyperventilation is anxiety induced - dizziness, lightheadness, peripheral paresthesias

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What treatment was given?

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3 drug categories are used to treat allergies - vasopressors (epinephrine), histamine blockers (chlorpeniramine or diphenhydramine), and corticosteroids (hydrocontisone sodium succinate) Anti-convulsants are to treat seizures from overdose Aromatic ammonia is to treat syncope O2 can be used for any or all

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What position were you in at the time of the reaction?

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If upright, more likely psychogenic (vasodepressor syncope), if supine, may be other causes

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What was the time sequence of the reaction?

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Most adverse reactions occur during or immediately after injection If dental treatment continued after the reaction and patient was discharged alone from the office, less likely to be allergy

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Were emergency personnel involved?

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If not, then it was probably psychogenic and less serious

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What specific drugs were used?

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Many patients only know Novocine. If they cannot be more specific, you need to further evaluate. Novocaine has not been used since the 1940's, so it is unlikely the causative agent

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What volume of drug was used?

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This is useful to determine if reaction was overdose. Patient is unlikely to know, but you may be able to get this from record from treating dentist at time of incident

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Was there a vasoconstrictor or perservative in the anesthetic solution?

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Again, patient will not usually know. Try to get info from treating dentist at time of incident

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Were you taking other drugs at the same time?

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It may have been a drug-drug reaction or side-effect. Many reactions are coincidental, however, and not related to the drug itself

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What is the name, address, and phone number of the dentist who treated you at the time of the incident?

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If you can consult with that individual, you may be able to find out exactly what happened and determine if it was a true allergy or something else

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Allergy Testing

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Skin test is primary mode of testing Intracutaneous test is 100 times more sensitive than cutaneous 0.1 ml of plain solution (with out vasoconstrictor or preservative) is injected into forearm If reaction occurs, it confirms allergy If no reaction, may try intraoral challenge-inject same solution as supraperiosteal injection; often patients experience psychogenic symptoms Testing must be done under careful conditions with access to emergency drugs and equipment and trained personnel, IV infusion, informed consent from patient

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Dental management in presence of alleged local anesthetic allergy

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assume allergy exist until absolutely disproved postpone elective care that my require anesthetic if emergency care is needed: N2O, analgesics, antibiotics, general anesthesia, histamine blockers as anesthesia (reserve of emergency use because of burning and stinging; provides 30 minutes of pulpal anesthesia; drowsiness), electronic dental anesthesia or hypnosis

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Dental management in presence of confirmed local anesthetic allergy

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If allergic to ester, use amide and do not use anesthetic with preservative. For all other allergies, follow alternative protocols listed above

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Time of onset symptoms

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More rapid onset of symptoms=more intense reaction More rapid rate of progression of signs and symptoms=more life threatening situation

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Dermatological signs and symptoms

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Urticaria (wheals-smooth elevated patches of skin) -most common Pruritus (intense itching) Angioedema (localized swelling in response to allergen - more common after exposure to topical anesthetic within 30-60 minutes)

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Dermatological reaction management

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If only sking reaction, not usually life threating, unless rapid progression to other reactions

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Dermatological immediate reaction management

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(conjunctivitis, rhinitis, urticaria, pruritux, erythema with in 60 minutes) Administer 0.3 epinephrine IM or subcutaneously. Administer IM histamine blocker. Obtain medical consult before dismissing patient - may be necessary for emergency evaluation to occur. Observe patient for at least 60 minutes and release with another adult if drugs have been adminstered. Prescribe oral histamine blocker for 3 days. Patient should be evaluated before further dental care

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Dermatological delayed reaction management

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(localized mild skin and mucous membrane reaction 60+ minutes after application of topical anesthetic) Oral histamine blocker for 3-4 days. Medical consultation before further treatment - complie list of all drugs and chemicals administered or used

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Respiratory Reaction signs and symptoms

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Bronchospasm (classic response - in lower airway) Respiratory distress, dyspnea, wheezing, flushing, cyanosis, perspiration, tachycardia, increase anxiety, use of accessory muscles of respiration

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Respiratory Reaction Management

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Bronchospasm- terminate dental therapy. Placepatient in semi-erect position. O2 (5-6 liters per minute) Epinephrine or bronchodilator every 5 minutes as needed. Observe paient for 60 minutes before discharge. If relapse, repeat epinephrine, call EMS. Histamine blocker. Medical consult - transfer to hospital or release, depending on advice. Prescribe oral histamine blocker and thorough allergy evaluation before subsequent dental therapy

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Respiratory Reaction Laryngeal Edema - Life-threatening signs and symptoms

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Upper airway swelling and subsequent obstruction of airway; partial obstruction results in stridor (high pitched crowning sound) Can lead to complete obstruction - silence. Unconciousness

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Respiratory Reaction Laryngeal Edema Management

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Place patient supine, feet slightly elevated. Summon medical assistance. Oxygen. 0.2 epinephrine IV or subcutaneously every 5 minutes as needed. Maintain airway. Histamine blocker and corticosteroid. Criothyrotomy-maintain airway, oxygen, artificial ventilation. Monitor vital signs. Hospitalization

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Generalized anaphylaxis reaction

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Most life-threatening. Clinical death can occur within a few minutes. Develops rapidly. Maximum intensity 5-30 minutes. Unlikely following administration of amide anesthetics

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Generalized anaphylaxis early phase skin reactions

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Patient complains of feeling sick, intense itching, flushing, giant hives over face and upper chest. Conjunctivitis. Vasomotor rhinitis. Pilomotor erection.

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Generalized anaphylaxis Gastrointestinal and or genitourinary reactions

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Severe abdominal cramps. Nausea and vomiting. Diarrhea. Fecal and urinary incontinence

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Generalized anaphylaxis respiratory reactions

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Substernal tightness or pain in chest. Cough may develope. Wheezing, Dyspnea. Cyanosis of mucous membranes and nail beds. Possible laryngeal edema

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Generalized anaphylaxis cardiovascular reactions

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Pallor. Light-headedness. Palpitations. Tachycardia. Hypotension. Cardiac dysrhythmias. Unconsciousness. Cardiac arrest. Death. ***Reaction may last minutes or days

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Generalized anaphylaxis Management

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Position patient (unconscious patient in supine position with legs elevated slightly) BLS as needed - airway, breathing, circulation Summon medical assistance Administer epinephrine 0.3 ml of 1:1000 IM of IV (second dose after 5 minutes if no improvement) Oxygen. Monitor vital signs. After improvement - not drug acute phase (wait until BP has increase and bronchospasm decreased) Histamine blocker. Corticosteroids If no sign of allergy, but patient loses consciouness. Terminate treatment. Position patent supine with legs slightly elevated. BLS as indicated. Summon medical assistance. Oxygen. Monitor vital signs. Definitive management once emergency medical personnel assess, stabilize and possibly transport to hospital if necessary

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Strategies to minimize or prevent systemic complications

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Thorough prelimary medical evaluation Recognition and management of fear and anxiety Administer injections with patient in supine position Apply topical anesthetic for at least one minute before injection Use weakest effective concentration and minimum effective volume of anesthetic Use anesthetic with appropriate duration for treatment comtemplated Use vasoconstrictor unless specifically contraindicated Use disposable, sharp, rigid, needles of appropriate length, capable of reliable aspiration. Use aspirating syringes Aspirate in at least two planes prior to injection Deposit solution slowly Observe patient during and after injection

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