Challenges of Treating Children Taking Psychotropic Drugs

Update on Medications and Drug Interactions for the Pediatric Dentist

Pamela J. Sims, Pharm.D., Ph. D.Professor

Department of Pharmaceutical, Social and Administrative SciencesMcWhorter School of Pharmacy

Samford Universityand

Adjunct ProfessorDepartment of Pediatric Dentistry

University of Alabama School of Dentistry

Topics

Pharmacokinetic differences between children and adults

Preventing infection Managing behavior Interactions with local anesthesia Treating pain Treating nausea

Pediatric Pharmacokinetic Changes Absorption

– increased pH– Variable motility– Frequent presence of food and/or milk– Affects rate and extent

Distribution

Body composition– Primarily lean body mass– Increased V of water soluble drugs

• increased LD on mg/kg basis

– Decreased V of fat soluble drugs• decreased LD on mg/kg basis

Fluid compartments as a function of age (% of weight)

Age TBW ECF ICF Fat

PrematureNeonate

85 50 33 1-10

Neonate 78 45 35 12-16

4-6months

65 35 37 20-25

Adult 55-60 19 40 >25

Distribution

Altered Protein Binding– Decreased plasma protein concentrations– Lower binding capacity– Decreased affinity

Comparative protein binding of certain drugs

Drug % PB in newborn % PB in adult

Acetaminophen 37 48

Diazepam 84 99

Morphine 46 66

Phenobarbital 32 51

Phenytoin 80 90

Theophylline 36 56

Metabolism

Phase I– Alternative pathways

– Develops slowly• concentration same,

activity reduced

– Affected by diet and drugs

• Inhibitors

• Inducers

Phase II– Glucuronidation

slowest to develop• 3-4 years of age

Excretion

Glomerular Filtration– Neonate

• RBF 5-6% of CO

• 30% of adult

Tubular Secretion and Reabsorption– decreased RBF

– Small, undeveloped tubules

Creatinine not as helpful a predictor of renal function as in adults– still one way of

monitoring nephrotoxic drugs

Preventing Infection

Prophylaxis against endocarditis Prophylaxis for joint replacement patients Prophylaxis for solid organ transplant patients Prophylaxis for immunocompromised patients

– Rheumatoid arthritis

– Type I diabetes

– Lupus

– Oncology patients

Dental Procedures and Endocarditis Prophylaxis Recommended (1997)

– Dental extractions – Periodontal procedures– Dental implant placement and

reimplantation of avulsed teeth– Endodontic treatment beyond apex– Subgingival placement of

antibiotic fibers and strips– Initial placement of orthodontic

bands– Intraligamentary local anesthetic

injections– Prophylactic cleaning of teeth or

implants where bleeding is anticipated

Recommended 2007– All dental procedures

that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa*

Dental Procedures and Endocarditis Prophylaxis Not Recommended (1997)

– Restorative dentistry– Nonintraligamentary local anesthetic

inj.– Post placement and buildup intracanal

endodontic tx.– Placement of rubber dams– Postoperative suture removal– Placement of removable prosthodontic

or orthodontic appliances– Taking of oral impressions– Fluoride treatments– Taking of oral radiographs– Orthodontic appliance adjustment– Shedding of primary teeth

*Not Recommended 2007– Routine anesthetic injections

through noninfected tissue– Taking dental radiographs– Placement of removable

prosthodontic or orthodontic appliances

– Adjustment of orthodontic appliances

– Placement of orthodontic brackets

– Shedding of deciduous teeth– Bleeding from trauma to the

lips or oral mucosa

Cardiac Conditions Associated with Endocarditis High-risk category 1997

– Prosthetic cardiac valves, including bioprosthetic and homograft valves

– Previous bacterial endocarditis

– Complex cyanotic congenital heart disease

– Surgically constructed systemic pulmonary shunts or conduits

Moderate-risk category 1997– Most other congenital cardiac

malformations

– Acquired valvar dysfunction (eg, rheumatic heart disease)

– Hypertrophic cardiomyopathy

– Mitral valve prolapse with valvar regurgitation and/or thickened leaflets

Highest Risk of Adverse Outcome 2007– Prosthetic cardiac valve– Previous infective endocarditis– Congenital heart disease (CHD)*

• Unrepaired cyanotic CHD, including palliative shunts and conduits

• Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention during the first six months after the procedure**

• Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization)

– Cardiac transplantation recipients who develop cardiac valvulopathy

Cardiac Conditions for which Endocarditis Prophylaxis Not Recommended

Negligible-risk category (no greater risk than the general population) (1997)

– Isolated secundum atrial septal defect

– Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 mo)

– Previous coronary artery bypass graft surgery

– Mitral valve prolapse without valvar regurgitation

– Physiologic, functional., or innocent heart murmurs

– Previous Kawasaki disease without valvar dysfunction

– Previous rheumatic fever without valvar dysfunction

– Cardiac pacemakers and implanted defibrillators

2007– *Except for the conditions

listed, antibiotic prophylaxis is not longer recommended for any other form of CHD

– **Prophylaxis is recommended because endothelialization of prosthetic material occurs within 6 months after the procedure

Prophylactic Regimens for Dental, Oral, Respiratory Tract, or Esophageal Procedures (1997)

Standard generalprophylaxis

Amoxicillin Adults: 2.0 gChildren: 50 mg/kg

1 hour before procedureAllergic to pencillin Clindamycin

orAdults: 600 mgChildren: 20 mg/kg

1 hour before procedure

Cephalexin orcefadroxil

Adults: 2.0 gChildren: 50 mg/kg

1 hour before procedureAzithromycin orClarithromycin

Adults: 500 mgChildren: 15 mg/kg1 hour before procedure

Prophylactic Regimens for a Dental Procedure 2007

Standard general prophylaxis

Amoxicillin Adults: 2.0 g Children: 50 mg/kg

30-60 minutes before procedure

Allergic to pencillin Clindamycin or

Adults: 600 mg Children: 20 mg/kg

30-60 minutes before procedure

Cephalexin**† Adults: 2.0 g Children: 50 mg/kg

30-60 minutes before procedure

Azithromycin or Clarithromycin

Adults: 500 mg Children: 15 mg/kg 30-60 minutes before procedure

Amino-penicillinsBroader Spectrum

Ampicillin Amoxicillin

– 125, 200, 250, 400 mg chewable tablets

– 250, 500 mg capsules– 500, 875 mg filmcoated

tablet– 125mg/5cc, 200 mg/5cc ,

250 mg/5cc, 400 mg /5cc suspension

– 50 mg/ml drop Bacampicillin

(Spectrobid)

Gram + and some Gram - coverage

More stable in GI tract Amoxicillin

– May be taken with food, milk or juice

– Food may delay peak concentrations

Cephalosporins

**or other first or second generation oral cephalosporin in equivalent adult or pediatric dosage.

†Cephalosporins should not be used in an individual with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin

First Generation CephalosporinsGood Gram+, Moderate Gram -

Parenteral: Cephalothin, Cefazolin, Cephapirin, Cephradine

Oral: Cephalexin (Keflex, Keftab), Cephradine (Anspor, Velosef, Eskacef), Cefadroxil (Duricef, Ultracef)

Similar spectrum to ampicillin and amoxicillin

Not affected by food More slowly absorbed in

children Higher bone penetration

than penicillins

Oral First Generation Cephalosporins Cephalexin

Monohydrate (Keflex)– 250, 500 mg capsule

– 250,500 mg tablet

– 125mg/5cc, 250 mg/5cc oral susp

Cephalexin HCl Monohydrate (Keftab)– 250, 500 mg tablet

Cephradine (Anspor, Velosef, Eskacef)– 250, 500 mg capsule

– 250 mg/5cc oral susp

Cefadroxil (Duricef)– 500 mg capsule

– 1 g tablet

– 250 mg/5cc, 500 mg/5cc oral susp

Second Generation CephalosporinsIncreased activity against Gram-

Parenteral: Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefoxitin, Cefuroxime

Oral: Cefaclor(Ceclor, Ceclor CD), Cefprozil(Cefzil), Cefuroxime Axetil(Ceftin), Loracarbef(Lorabid)

Oral Second Generation Cephalosporins Cefaclor (Ceclor)

– 250, 500 mg capsules– 125/5, 187/5, 250/5

and 375/5 susp and chewables

– 20-40 mg/kg/day Cefaclor (Ceclor CD)

– 375, 500 mg extended release tablets

– 375-500 mg q 12 h

Cefprozil (Cefzil)– 250,500 mg tablets

– 125,250/5cc susp

– 250-500 mg q 12 h

– Children: 7.5 - 10 mg/kg q 12 h

Cefuroxime axetil (Ceftin)– 125, 250, 500 mg tablets

– 125/5cc susp

– 125-500 mg bid

– Children: 125-250 mg bid

Drug-related Concerns of Penicillin and Cephalosporin Antibiotics

Allergy– Cross-sensitivity between penicillins and cephalosporins. If a

person is truly allergic to penicillin, 10-25% patients will be allergic to cephalosporins. If a person is allergic to cephalosporins, the patient will generally be allergic to penicillins.

Increased bleeding in patients taking warfarin (Coumadin)– Antibiotics can decrease local flora responsible for

synthesis of Vitamin K (Vitamin K is the antagonist to warfarin and warfarin exerts its anticoagulant effects by inhibition of Vitamin K dependent clotting factors)

Drug-related Concerns of Penicillin Antibiotics Decreased efficacy of oral contraceptives

– Today’s low dose BCP’s require endogenous GI flora to conjugate hormone to allow absorption. If bacteria are absent, hormone which prevent egg implantation will be absent. Patients utilizing oral contraceptive agents should use another form of BC during the entire “cycle” in which antibiotics were administered.

Macrolides Azithromycin (Zithromax)

– 250 mg, Z-pak (250 mg), 500, Tri-pak (500 mg) 600 mg tablet

– 100 mg/5cc, 200 mg/5cc susp

– 1 g susp

Clarithromycin (Biaxin)– 250, 500 mg tablet

– 125 mg/5cc, 250 mg/5cc susp

– 500 mg XL

Erythromycin

– Base (E-mycin, Ery-Tab, Ilotycin, PCE)

– Estolate (Ilosone)

– Ethylsuccinate (EES)

– Stearate (Erythrocin) Troleandomycin (Tao)

– 250 mg capsules

Drug-related Concerns of Macrolides Active Metabolite

– Clarithromycin

GI upset– Erythromycin

Hepatic Enzyme Inhibition– Erythromycin– Clarithromycin

Drug-related Concerns of Macrolides Hepatic Enzyme

Inhibition– Increases blood levels– Increases risk of toxicity– Decreases clearance

Cisapride (Propulcid) Phenytoin (Dilantin) Carbamazepine (Tegretol) Cyclosporine Warfarin (Coumadin) Corticosteroids Theophylline Benzodiazepines Digoxin

Lincosamides Lincomycin

(Lincocin)– 500 mg capsules

Clindamycin (Cleocin)– (HCl) 75, 150, 300 mg

capsules

– (Palmitate) 75mg/5cc solution

ADR– Pseudomembranous

Colitis (Clostridium difficile)

Patients at increased risk of hematogenous total joint infection

Immunocompromised/Immunosuppressed

– Inflammatory arthropathies, rheumatoid arthritis, systemic lupus

– disease, drug or radiation-induced

Insulin dependent diabetics

First 2 years post-replacement

Previous joint infections

Malnourishment Hemophilia

Higher Incidence of Bacteremic Dental Procedures Dental Extractions Periodontal

procedures Dental implant

placement and reimplantation of avulsed teeth

Endodontic beyond the apex

Initial orthodontic bands/not brackets

Intraligamentary local anesthetic injections

Prophylactic cleaning of teeth or implants where bleeding is anticipated

Suggested Prophylaxis Regimens Patients not allergic to

penicillin:– Cephalexin,

Cephradine or Amoxicillin

• 2 gm orally 1 hour prior to procedure

Patients allergic to penicillin:– Clindamycin 600 mg

orally 1 hour prior to the dental procedure.

Fen-Phen, Pondimin or Redux PatientsFenfluramine or dexfenfluramine w or w/o phentermine

If a patient needs to undergo a dental procedure for which the AHA recommends prophylaxis against endocarditis, patient needs an echo.

If no echo must prophylax

If valvar disease discovered, must prophylax

Oral Infections

Acute endodontic abscess– Augmentin– Clindamycin

Acute periodontal infections – Augmentin

Gingival abscess– Amoxicillin

ANUG– Metronidazole

Localized juvenile periodontitis– Doxycycline and scale and

root planing– Augmentin

• Can add metronidazole– Ciprofloxacin

Abscessed teeth to be extracted– Augmentin– Clindamycin– Ceftin

Chlorhexidine mouthwash

Antibiotics

Augmentin– Amoxicillin/clavulanic acid

– 20 – 40 mg/kg/day amoxicillin in divided doses q 8 h

– 20 – 45 mg/kg/day amoxicillin in divided doses q 12 h

– Use lowest doses of clavulanic acid

• GI ADE

For oral susp– For bid: 200/28.5, 400/57,

600/42.9

– 125/31.5, 250/62.5

Chewable– For bid: 200/28.5, 400/57

– 125/31.25, 250/62.5

Tablet– 250/125, 500/125

– For bid: 875/125

Tetracyclines Demeclocycline

(Declomycin)– 150 mg capsule– 150, 300 mg tablet

Doxycycline (Vibramycin)– 50,100 mg capsule,

tablet– 25 mg/5cc oral susp– 50 mg/5cc syrup

Minocycline (Minocin)– 50, 100 mg tablet,

capsule– 50 mg/5cc susp

Oxytetracycline– 250 mg capsule

Tetracycline– 100, 250, 500 mg capsule– 125 mg/5cc susp– 250, 500 mg tablet

Drug-related Concerns of Tetracyclines Bacteriostatic Photosensitivity Chelation with any di or trivalent cation

– antacids– mineral supplements (Ca, Fe, Mg)– Dairy products– Sucralfate (Carafate)– Stains teeth

Quinolones Ciprofloxacin (Cipro)

– 100, 250, 500, 750 mg tablet– 5, 10 g/100 mg susp– 20-30 mg/kg/day in two divided

doses Cinoxacin (Cinobac)

– 250, 500 mg capsules Enoxacin (Penetrex)

– 200, 400 mg tablet Gatifloxacin

– 20, 400 mg tablets Grepafloxacin (Raxar)

– 200 mg tablet Levafloxacin (Levaquin)

– 250, 500 mg tablet

Lomefloxacin (Maxaquin)– 400 mg tablet

Moxifloxacin– 400 mg tablets

Norfloxacin (Noroxin)– 400 mg tablet

Ofloxacin (Floxin)– 200, 300, 400 mg tablet

Sparfloxacin (Zagam)– 200 mg tablet

Trovafloxacin (Trovan)– 100, 200 mg tablets

Drug-related Concerns of Quinolones Primarily Gram - spectrum Resistance develops quickly All contraindicated in pregnant and nursing

women All cause photosensitivity

Metronidazole Enters cells which contain

nitroreductase, where its nitro group is reduced

Unstable intermediate compounds bind to DNA and inhibit synthesis causing cell death

Active against anaerobes and protozoa

Flagyl– Active against anaerobes and

protozoa

– 250, 500 mg tablet

– 750 mg extended release tablet

– 375 mg capsule

– Bacterial vaginosis• 500 mg bid for 7 days

• 2 g

– Giardiasis• 250 mg tid for 7 day

Drug-related Concerns of Metronidazole Increased

Metronidazole levels– Cimetidine

Disulfiram-like reaction– Ethanol

Acute psychosis or confusional state– Disulfiram

Hepatic Enzyme Inhibition– Anticoagulants

– Hydantoins

Decreased renal excretion– Lithium

Behavior Management

Antihistamines Anxiolytic Antihistamines Anxiolytic Benzodiazepines Sedative/Hypnotic Benzodiazepines Anesthetic Benzodiazepines

ADA Old Definitions Conscious Sedation

– A controlled, pharmacologically induced, minimally depressed level of consciousness that retains the patient’s ability to maintain a patent airway independently and continuously and respond appropriately to physical stimulation and/or verbal command.

– Drugs, dosages and techniques used should carry a margin of safety which is unlikely to render the child non-interactive and non-arousable.

Deep Sedation– A controlled, pharmacologically-induced state of depressed consciousness from

which the patient is not easily aroused which may be accompanied by a partial loss of protective reflexes, including the ability to maintain a patent airway independently and/or respond purposefully to physical stimulation or verbal commands.

General Anesthesia– A controlled, state of unconsciousness, accompanied by a partial or complete loss

of protective reflexes, including ability to independently maintain an airway or respond purposefully to physical stimulation or verbal command.

ADA New Definitions Minimal Sedation

– (Previously associated with anxiolysis and conscious sedation)– A minimally depressed level of consciousness that retains the patient’s

ability to independently and continuously maintain an airway and respond appropriately to physical stimulation or verbal command and that is produced by a pharmacological or non-pharmacological method or a combination thereof. Although cognitive function and coordination may be modestly impaired, ventilatory and cardiovascular functions are unaffected.

• Note: In accord with this particular definition, the drug(s) and/or techniques used should carry a margin of safety wide enough to render unintended loss of consciousness unlikely. Further, patients whose only response is reflex withdrawal from repeated painful stimuli would not be considered to be in a state of minimal sedation.

• When the intent is minimal sedation for adults, the appropriate dosing of enteral drugs is not more than the maximum recommended dose of a single drug that can be prescribed for unmonitored home use.

ADA New Definitions

Moderate sedation– A drug-induced depression of consciousness during which patients

respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. No interventions are required to maintain a patent airway, and spontaneous ventilation is adequate. Cardiovascular function is usually maintained.

• Note: In accord with this particular definition, the drugs and/or techniques used should carry a margin of safety wide enough to render unintended loss of consciousness unlikely. Repeated dosing of an agent before the effects of previous dosing can be fully appreciated may result in a greater alteration of the state of consciousness than is the intent of the dentist. Further, a patient whose only response is reflex withdrawal from a painful stimulus is not considered to be in a state of moderate sedation.

ADA New Definitions Deep sedation

– A drug-induced depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation. The ability to independently maintain ventilatory function may be impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

General anesthesia– A drug-induced loss of consciousness during which patients are not

arousable, even by painful stimulation. The ability to independently maintain ventilatory function is often impaired. Patients often require assistance in maintaining a patent airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

ADA New Definitions Note: Because sedation and general anesthesia are a continuum, it is not

always possible to predict how and individual patient will respond. Hence, practitioners intending to produce a given level of sedation would be able to diagnose and manage the physiologic consequences (rescue) for patients whose level of sedation becomes deeper than initially intended.

For all levels of sedation, the practitioner must have the training, skills and equipment to identify and manage such an occurrence until either assistance arrive (emergency medical service) or the patient returns to the intended level of sedation without airway or cardiovascular complications.

All areas in which local anesthesia and sedation are being used must be properly equipped with suction, physiologic monitoring equipment, a positive pressure oxygen delivery system suitable for the patient being treated and emergency drugs. Protocols for the management of emergencies must be developed and training programs held at frequent intervals.

Levels of Sedation

Level 1 Level 2 Level 3 Level 4 Mild Sedation (Anxiolysis)

Interactive Non-Interactive Arousable with Mild/Moderate Stimulus

Non-Interactive Non-Arousable except with Intense Stimulus

Totally Awake Responds to verbal commands Eyes open or temporarily closed

Mimics Sleep Responds to physical stimuli May require airway re-adjustment

Depressed vitals in Sleep-like state Airway requires constant monitoring

ASA Physical Status Scale Class I Normal Healthy individual Class II Mild systemic disease

– (eg, controlled diabetes or hypertension) Class III Severe systemic disease that is not

incapacitating

– (eg, COPD, mental retardation, hemophilia) Class IV Incapacitating disease that is a constant

threat to life– (eg, unstable angina or renal failure)

Class V Moribund patient not expected to survive 24 hours

Class E Emergency

Considerations for the Pediatric Patient Patient’s age Level of cognitive and coping skills ASA Class

– I or II candidate for level 1,2, 3 or 4– III or IV should be treated in a hospital setting

Antihistamines Diphenhydramine

(Benadryl)– Dosage forms

• Capsules 25, 50 mg

• Elixir 12.5 mg/tsp

– Dose• 5 mg/kg/day

• <5 yo 12.5-25 mg

• >5 yo 25-50 mg

Advantages– drowsiness

– dry mouth

– low respiratory depression

– no dependence

Disadvantages– paradoxical excitement

Anxiolytic Antihistamines

Hydroxyzine– Atarax (HCl)

• tablets 10,25,50,100 mg

• syrup 2 mg/ml (10mg/tsp)

– Vistaril (Pamoate)• capsules 25,50,100 mg

• susp 5 mg/ml (25mg/tsp)

• Inj 25 mg/ml as HCl

Anxiety– 50 - 100 mg qid

– Children: 12.5 - 25 mg qid

Sedation– 50 - 100 mg

– Children: 0.6 mg/kg

Pre-operative adjunct– 50 - 100 mg

– Children: 1.1 mg/kg

Hydroxyzine

Advantages– Sedative– Dry mouth– H1 antagonist in GI tract– No dependence– Antagonizes vasopressor

effects of epinephrine– No respiratory depression

• May protect from respiratory depression of meperidine

– No effect on QT interval

Disadvantages– No IV dosage form

Benzodiazepines

Controlled substance– potential for abuse and

dependence

Anterograde amnesia Muscle relaxant Potentiated by enzyme

inhibitors

Reversal agent available– Flumazenil

(Romazicon)

Good margin of safety– Respiratory depression

– Reduce dose with opiates

Anxiolytic Benzodiazepines

Speed of Onset Elimination Half-life

Active Metabolites

Alprazolam (Xanax)

Intermediate 6.3-26.9 No

Chlordiazepoxide (Librium)

Intermediate 5-30 Yes

Clorazepate (Tranxene)

Fast 40-50 Yes

Diazepam (Valium)

Very Fast 20-80 Yes

Halazepam (Paxipam)

Slow 14 Yes

Lorazepam (Ativan)

Intermediate 10-20 No

Oxazepam (Serax)

Slow 5-20 No

Prazepam (Centrax)

nd 50-100 Yes

Anxiolytic Benzodiazepines Lorazepam

– Ativan• tablets 0.5,1,2 mg

– Lorazepam Intensol• conc. oral sol. 2 mg/ml,

30 ml dropper

– Adults:• 2-4 mg

• 0.5 - 1 mg tid

• increase dose as needed

– Pediatric dose:• 0.05 mg/kg

• Doses > 0.09 mg/kg produce inc. ataxia w/o inc. sedation

• Safety of oral lorazepam in children < 12 yo not established

Anxiolytic Benzodiazepines

Lorazepam– Ativan– Intermediate onset

– No active metabolites

– Short acting

• 10-20 hour half-life

– sublingual absorption more rapid than oral

Anxiolytic Benzodiazepines Diazepam

– Valium– 2,5,10 mg tablets

– 5 mg/5ml solution

– 5 mg/ml Intensol sol

– 5 mg/ml inj

– Adult:• 5-10 mg

– Pediatric:• 0.2-0.3 mg/kg 90

minutes prior to procedure

Anxiolytic Benzodiazepines

Diazepam– History of use in children

– Rapid onset

– Active metabolites• desmethyldiazepam

• temazepam

• oxazepam

– Long Acting• 20-80 hr half-life

Anesthetic Benzodiazepines Midazolam

– Versed

– 1 mg/ml inj

– 5 mg/ml inj

– 2 mg/ml syrup• peds 2-16 yo only

Adult– IM 0.07-0.08 mg/kg up to 1 hr

before procedure

– IV dilute 1mg/ml with NaCl or D5W and administer slowly

Pediatric:– IM 0.1-0.15 mg/kg, 30-60 min prior

– IV

• <5 yo:0.05-0.1 mg/kg

• 5-12 yo 0.025-0.05 mg/kg

• >12 yo 1-5 mg, titrate slowly over 10-20 min

– Oral

• 0.2-0.4 mg/kg, 30-45 min prior

– Rectal

• 0.3 mg/kg

– Nasal

• 0.2-0.3 mg/kg

Drug-related Effects of Benzodiazepines Additive effects with other CNS

depressants Amnesia Paradoxical reactions Flumazenil (Romazicon)

Benzodiazepine Antagonist– 0.01 mg/kg (max 0.2 mg) over 15 seconds, may

repeat after 45 seconds

Drug Interactions of Benzodiazepines Effect increased by other CNS depressants Effect increased by enzyme inhibitors

– Cimetidine (Tagamet), Macrolides (Erythromycin, Biaxin), Oral contraceptives, Disulfiram (Antabuse), Isoniazid

Effect decreased by enzyme inducers

– Rifampin, Smoking, Phenytoin Effect antagonized by CNS stimulants

– Theophylline

Sedative/Hypnotic

Chloral Hydrate (Noctec)

– 250, 500 mg capsules

– 250, 500 mg/5cc syrup

– Adults• Sedative 250 mg tid• Hypnotic 500-1000 mg 15-30 minutes before procedure

– Pediatric• Sedative 25 mg/kg/day up to 500 mg single dose• Hypnotic 50 mg/kg/day up to 1 g single dose

• Doses of 75 mg/kg uses for dental sedation with NO

Chloral Hydrate Good margin of safety Low respiratory

depression No anxiolytic

properties Agitation before

sedation and after

Controlled substance– abuse and dependence

No reversal agent

Interactions with Local Anesthesia

Patients treated for ADD/ADHD

Patients treated for narcolepsy

Patients treated for obesity Patients treated for

depression Patients treated for

enuresis

Stimulants Antidepressants Antipsychotics Beta-Blockers Monoamine Oxidase

Inhibitors (MAOIs)

Dental Issues

Local anesthesia– Contents of a Local Anesthetic Cartridge

• Local Anesthetic– Esters

– Amides

• Vasoconstrictor

• Preservative– Sodium Metabisulfite

• Sodium Chloride and Sterile Water

Systemic side effects

Local anesthetic– CNS excitation

• seizures

• depression

– CV excitation• arrhythmias

Vasoconstrictor– Increase heart rate

– Increase blood pressure

Distribution and Activity of Receptors

Organ function Receptor Response tostimulation

Heart rate 1 Increase

Cardiac contractility 1 Increase

Peripheral Resistance 2

VasoconstrictionVasodilation

ADD/ADHD Treatment in Alabama insured by The Oath

Methylphenidate Amphetamine Antidepressants Clonidine

1-5 yo(n=40)

8 20 0 5

6-12 yo(n=2641)

1354 833 198 127

13-18 yo(n=1677)

644 597 286 79

19+(n=924)

220 189 466 11

Psychostimulants for ADD/ADHD and Narcolepsy Methylphenidate

– Standard methylphenidate

– Ritalin SR®

– Concerta®• Coated with immediate release • contains an osmotic pump

providing gradual release over 10 hours

• produces slightly ascending serum concentrations

• tablet remains intact and leaves GI tract as an empty shell

• take qd

Amphetamines– Dextroamphetamine

– Adderall®

– Dexedrine Spansules®

Pemoline (Cylert®)

Vasoconstrictor Interactions with CNS Stimulants

Additive CNS stimulation with other sympathomimetic agents

Decongestants Diet aids Psychostimulants

– Methylphenidate• Ritalin®• Concerta®

– Amphetamines• d-Amphetamine• Adderall®

Bronchodilators Albuterol® Theophylline

Antidepressants

ADD/ADHD– Atomoxetine (Strattera®)

Anxiety– Social Phobia– Panic Disorder– OCD

Depression Enuresis Sleep Disorders Premenstrual Dysphoric Disorder

Vasoconstrictor Interactions with Antidepressants Antidepressants

– Block reuptake of norepinephrine and/or serotonin

Interaction– Increased and prolonged

effects on receptors

Increased alpha and beta stimulation– increased heart rate

– increased cardiac contractility

– increased peripheral resistance

Interacting Antidepressants

Tricyclic Antidepressants Tertiary Amines

• Amitriptyline (Elavil)• Clomipramine (Anafranil)• Doxepin (Adapin, Sinequan)• Imipramine (Tofranil)• Trimipramine (Surmontil)

Secondary Amines• Amoxapine (Asendin)• Desipramine (Norpramin,

Pertofrane)• Maprotiline (Ludiomil)• Nortriptyline (Aventyl,

Pamelor)• Protriptyline (Vivactil)

Miscellaneous – Amoxapine (Asendin)– Venlaxafine (Effexor)– Mirtazapine (Remeron)

Selective norepinephrine reuptake inhibitors– Atomoxetine (Strattera)

Vasoconstrictor Interactionswith Antipsychotics and Antiemetics

blockade of alpha adrenergic receptors– orthostatic

hypertension

– reflex tachycardia

– potentiation of antihypertensives

predominance of beta adrenergic effects– increased heart rate

– increased cardiac contractility

– peripheral vasodilation

Interacting Antipsychotics and Antiemetics Phenothiazines

– Acetophenazine (Tindal)– Chlorpromazine (Thorazine)– Fluphenazine (Prolixin)– Mesoridazine (Serentil)– Perphenazine (Trilafon) – Prochlorperazine (Compazine) – Promazine (Sparine)– Promethazine (Phenergan)– Thioridazine (Mellaril)– Trifluoperazine (Stelazine)

Thiothixene (Navane) Haloperidol (Haldol) Clozapine (Clozaril) Loxapine (Loxitane) Molindone (Moban) Risperdal (Risperidone) Zyprexa (Olanzapine) Seroquel (Quetiapine)

Beta-adrenergic blockers

Hypertension Arrhythmias Mitral Valve Prolapse Migraine Performance anxiety

– Stage fright

Vasoconstrictor Interactions with Beta-adrenergic Antagonists

Blockade of beta 1 and beta 2 receptors

Causes unopposed alpha peripheral vasoconstriction

Initial hypertensive episode followed by bradycardia

Interacting Beta-adrenergic Antagonists

Selective beta 1 antagonists– Acebutolol (Sectral)

– Atenolol (Tenormin)

– Betaxolol (Kerlone)

– Bisoprolol (Zebeta)

– Metoprolol (Lopressor)

Non-selective beta antagonists– Carteolol (Cartrol)– Nadolol (Corgard)– Penbutolol (Levatol)– Pindolol (Visken)– Propranolol (Inderal)– Sotalol (Betapace)– Timolol (Blocadren)– Labetalol (Trandate,

Normodyne)

Monoamine Oxidase Inhibitors (MAOIs) Social Phobia Panic Disorder Depression

Monoamine Oxidase Inhibitors (MAOIs) Social Phobia Panic Disorder Depression Parkinsons

Antidepressants– Isocarboxazid (Marplan)– Phenelzine (Nardil)– Tranylcypromine (Parnate)– Selegiline (Emsam)

• Transdermal 6, 9, 12 mg/24h)

Antiparkinson– Selegiline

• Eldepryl 5 mg capsule• Carbex 5 mg tablet• Zelapar 1.25 mg orally

disintegrating tablet

Vasoconstrictors and MAOIs

MAOIs potentiate indirect or mixed-acting sympathomimetic substances– by inhibiting metabolism of

MAO B – severe headache,

hyperpyrexia, hypertension

Interaction with direct-acting agents is minimal– EMSAM inhibits

MAO A and therefore is contraindicated with epinephrine and levonordefrin

Sympathomimetic Agents

Direct acting-directly stimulates receptor– epinephrine

– norepinephrine

– levonordefrin

– isoproterenol

– dopamine

– methoxamine

– phenylephrine

Indirect-acting-releases norepi from nerve terminal– tyramine

– amphetamine

– methamphetamine

Mixed-acting-both direct and indirect actions– ephedrine

Treating Pain

Mild to moderate– Acetaminophen– Aspirin– NSAIDs

Moderate– Acetaminophen/Codeine

Moderate to severe– Acetaminophen/Hydrocodone– Acetaminophen/Oxycodone– Meperidine

Acetaminophen Pediatric Dosing

Weight(lb)

Age(yr)

Doseq 4-6 hr

(mg)24-35 2-3 160

36-47 4-5 240

48-59 6-8 320

69-71 9-10 400

72-95 11 480

Acetaminophen

Not NSAID– not anti-inflammatory

– no cross-hypersensitivity

Pregnancy– generally safe

Lactation– generally safe

Central action on prostaglandins– no renal effects

• safest in pregnancy

• safest in renally compromised

– no GI effects

– no platelet effects• safest with

anticoagulants

AcetaminophenAdverse effects Hepatotoxicity

– overdose• 10-15 g

• children less susceptible

• chronic alcoholics more susceptible– not a contraindication

– Chronic toxicity• Adults 3 g per day

Aspirin Dosages in Children

Age(yrs)

Wt(lbs)

Dosage(mg q 4 h)

No. of 81 mgtabs q 4 h

No. of 325 mgtabsq 4 h

2-3 24-35 162 2 ½

4-5 36-47 243 3

6-8 48-59 324 4 1

9-10 60-71 405 5

11 72-95 486 6 1 1/2

12-14 >95 648 8 2

Ibuprofen Pediatric Dosing

Weight(lb)

Age(yr)

Dose(mg)

Dose(tsp)

24-35 2-3 100 1

36-47 4-5 150 1 ½

48-59 6-8 200 2

60-71 9-10 250 2 ½

72-95 11 300 3

Nonselective NSAIDs

Acetic Acids– Diclofenac (Voltaren)– Indomethacin– Nabumetone (Relafen)– Sulindac (Clinoril)– Tolmetin (Tolectin)

Oxicams– Piroxicam (Feldene)– Meloxicam (Mobic)

Pyranocarboxylic acid– Etodolac (Lodine)

Pyrrolizine carboxylicacid– Ketorolac (Toradol)

Propionic Acids– Fenoprofen (Nalfon)– Flurbiprofen (Ansaid)– Ibuprofen (Motrin)*– Ketoprofen (Orudis)– Naproxen /Naproxen Na

(Anaprox, Naprosyn)– Oxaprozin (Daypro)

Fenamates– Meclofenamate– Mefenamic acid (Ponstel)

Nonselective NSAIDs GI Effects Nausea

– Most 3-9%

– Ketorolac 12%

– Tolmetin 11%

Diarrhea– Ibuprofen , Piroxicam<3%

– Diclofenac, Etodolac, Flurbiprofen, Ketorolac, Oxaprozin, Sulindac, Tolmetin 3-9%

– Nabumetone 14%

Dyspepsia– Most 3-9%– Etodolac 10%– Ketoprofen 11.5%– Ketorolac 12%– Nabumetone 13%

Stomatitis– Most 1-3%

Additive effects with aspirin– GI toxicity

Nonselective NSAIDs Adverse drug effects and interactions Inhibits platelet

aggregation– reversibly

– normal function when drug eliminated

Potentiates the effects of anticoagulants

– Warfarin (Coumadin)– Anisindione (Miradon)

– Dicumarol Potentiates the effects of

other antiplatelet drugs– Dipyridamole (Persantine)– Ticlodipine (Ticlid)– Anagrelide (Agrylin)– Clopidogrel (Plavix)– Cilostazol (Pletal)

NSAIDs Adverse Effects Cross-hypersensitivity with aspirin allergy

– Contraindication– urticaria, asthma, nasal polyps

NSAIDsAdverse Drug Effects and Drug Interactions

Caution with reduced renal function– Do not prescribe for

renal transplant patients

Lithium– Increased toxicity

Methotrexate– Increased toxicity

Cyclosporine– Increased

nephrotoxicity

NSAIDs Drug Interactions Antihypertensives

– decrease effect– ACE Inhibitors

• Benazepril (Lotensin)• Captopril (Capoten)• Enalapril (Vasotec)• Fosinopril (Monopril)• Lisinopril (Prinivil,

Zestril)• Moexipril (Univasc)• Quinapril (Accupril)• Ramipril (Altace)• Trandolapril (Mavik)

Angiotensin II Receptor Antagonists– Candesartan (Atacand)– Eprosartan (Teveten)– Irbesartan (Avapro)– Losartan (Cozaar)– Telmisartan (Micardis)– Valsartan (Diovan

NSAIDs Drug Interactions

– Beta Blockers• Acebutolol (Sectral), Atenolol (Tenormin),

Betaxalol (Kerlone) Bisoprolol (Zebeta), Metoprolol (Lopressor, Toprol XL),

Carteolol (Cartrol), Nadolol (Corgard), Penbutolol (Levatol), Pindolol (Visken), Propranolol (Inderal) Sotalol (Betapace), Timolol (Blocadren), Labetalol (Normodyne, Trandate)

NSAIDs Drug Interactions Antihypertensives

– decrease effect

– Loop Diuretics• Furosemide (Lasix),

Bumetanide (Bumex), Ethacrynic acid (Edecrin), Torsemide (Demadex)

– Thiazide Diuretics• Bendroflumethiazide

(Naturetin), Benzthiazide (Exna), Chlorothiazide (Diuril), Hydrochlorothiazide (Hydrodiuril, Esidrix, Oretic), Hydroflumethiazide (Diucardin, Saluron), Indapamide (Lozol), Methyclothiazide (Enduron, Aquatensen), Metolazone (Zaroxolyn, Mykrox), Polythiazide (Renese), Quinethazone, (Hydromox) Trichlormethiazide (Metahydrin, Naqua, Diurese)

NSAIDs Drug Interactions Cimetidine

– Increased NSAIDs effect/toxicity

Probenecid– Increased NSAIDs effect/toxicity

Codeine Combinations with Acetaminophen (CIII) Tablets (300 mg)

– Tylenol #2,3,4

Capsules (325 mg)– Phenaphen #3,4

– Fioricet w codeine• 50 mg Butalbital

• 40 mg Caffeine

Codeine Dose– #2 15 mg

– #3 30 mg

– #4 60 mg

Acetaminophen Dose– 300 - 325 mg

Codeine Sensitivity– Nausea most prevalent

Codeine Combinations with Acetaminophen (CV) 12 mg codeine/ tsp

(5cc) 120 mg

acetaminophen/ tsp (5cc)

Adult dose: 15 ml (1 tablespoonful q 4 h)

Capital w/Cod susp Tylenol w/Cod elixir Acetaminophen w/cod

sol (various manuf)

Codeine Combinations with Acetaminophen (CV) Analgesic:

– 0.5 – 1 mg codeine/kg/dose every 4-6 hours

– 10-15 mg/kg/dose acetaminophen every 4-6 hours

3-6 yr:– 5 ml (1 tsp)

7-12 yr– 10 ml (2 tsp)

>12 yr– 15 ml (3 tsp)

Hydrocodone Combinations with Acetaminophen (CIII) 2.5/108 Solution

– Hycet 2.5/167 Elixir

– Lortab 2.5/500 tablets

– Lortab 2.5/500 5/325

– Norco 5/400

– Zydone 5/500 tablets

– Co-Gesic, Duocet, Hy-Phen, Lorcet, Lortab 5/500, Anexsia 5/500 Panacet 5/500, Vicodin

5/500 capsules– Bancap HC, Ceta-Plus,

Dolacet, Hydrocet, Hydrogesic, Margesic H, Lorcet HD, Stagesic, T-Gesic, Zydone

7.5/500 Tablets– Lortab 7.5/500

7.5/650 Tablets– Anexsia 7.5/650, Lorcet Plus

7.5/750 Tablets– Vicodin ES

10/650 Tablets– Lorcet 10/650

Hydrocodone

Children < 50 kg– 0.2 mg/kg every 4-6 hours

Children > 50 kg– 5-10 mg every 4-6 hours

Meperidine (CII)

Meperidine (Demerol)– 50, 100 mg tablets

– 50 mg/5cc syrup

– 50 - 150 mg q 3-4 h

– Children• 1-1.5 mg/kg/dose q 3-4

h

Meperidine/Promethazine (Mepergan Fortis)

– 50 mg Meperidine

– 25 mg Promethazine

– 1 q 4-6 h

Contraindications of Meperidine

Patients taking MAOIs within 14 days– Antidepressants

• Phenelzine (Nardil)

• Tranylcypromine (Parnate)

– Antiparkinson– Selegiline (Eldepryl)

– Hyperphenylalaninemia

Meperidine Drug InteractionsSerotonin Syndrome Serotonergic Drugs

– Selective Serotonin Reuptake Inhibitors (SSRIs)

• Fluvoxamine (Luvox)

• Fluoxetine (Prozac)

• Paroxetine (Paxil)

• Sertraline (Zoloft)

• Citalopram (Celexa)

• Escitalopram (Lexipro)

Cognitive-behavioral– Confusion/ disorientation (51%)

– Agitation/irritability (34%)

Autonomic Nervous System– Hyperthermia (45%)

– Diaphoresis (45%)

– Sinus Tachycardia (36%)

– Hypertension (35%)

Neuromuscular– Dilated pupils (28%)

– Tachypnea (26%)

– Nausea (23%)

Opioids

Phenanthrenes – Codeine

– Hydrocodone

– Oxycodone

– Morphine

– Hydromorphone

– Levorphanol

Phenylpiperidines– Meperidine

– (Fentanyl)

Diphenylheptanes– Propoxyphene

– (Methadone)

Opioid Pharmacologic Effects

CNS Effects– Analgesia

– Euphoria

– Sedation

– Respiratory Depression

– Cough Suppression

– Miosis

– Truncal Rigidity

– Nausea and Vomiting

CV System– Hypotension

GI Tract– Constipation

Biliary Tract– Colic

Genitourinary Tract– Urinary Retention– Decreased Renal Function

Warnings for Opioids

Asthma and Other Respiratory Conditions– Use with extreme caution with acute asthma,

bronchial asthma, COPD or cor pulmonale

Hypotensive Effect– Increased with coadministration of

phenothiazines or general anesthesia

Opioid Drug InteractionsDental Implications Phenothiazines

– Acetophenazine (Tindal)

– Chlorpromazine (Thorazine)

– Fluphenazine (Prolixin)

– Mesoridazine (Serentil)

– Perphenazine (Trilafon)

– Prochlorperazine (Compazine)

– Promazine (Sparine)

– Promethazine (Phenergan)

– Thioridazine (Mellaril)

– Trifluoperazine (Stelazine)

Additive Pharmacologic Effects– CNS Depression

– Respiratory Depression

– Orthostasis

Inhibitors of CYP3A4 increase opioid effects

Antifungals– Fluconazole– Itraconazole– Ketoconazole– Miconazole

Metronidazole Macrolides

– Erythromycin– Clarithromycin

Narcotic Antagonist

Naloxone (Narcan)– 0.4 mg/ml, 1 mg/ml– For OD:

• 0.4 - 2 mg IV q 2-3 minutes

– Partial reversal• 0.1-0.2 mg IV q 2-3 minutes repeat every 1-2 hrs

– Children:• 0.01 mg/kg IV, may repeat q 2-3 min

Treating Nausea

Anti-emetics Hydroxyzine

– Atarax, Vistaril Phenothiazines

– Chlorpromazine– Perphenazine

• Trilafon– Prochlorperazine

• Compazine– Promethazine

• Phenergan– Triflupromazine

• Vesprin– Triethylperazine

• Torecan

Metoclopramide – Reglan

Anticholinergics– Cyclizine

• Marezine– Meclizine

• Antivert, Bonine– Dimenhydrinate

• Dramamine Trimethobenzamide

– Tigan

Anti-emetics

5-HT3 Receptor Antagonists– Dolasetron

• Anzemet

– Gransetron• Kytril

– Ondansetron• Zofran

Droperidol– Inapsine

Dronabinol– Marinol

Anti-emetics

Hydroxyzine– 25-100 mg– Children: 1.1 mg/kg

Promethazine– 12.5 - 25 mg q 4-6 h– Children 0.25 - 0.5 mg/kg q 4-6 h– do not adm < 2 yo

Phenothiazines Prochlorperazine

– Compazine– 5, 10, 25 mg tablets– 10, 15, 30 mg capsules sustained

release– 5 mg/5 ml syrup– 5 mg/ml inj– 2.5, 5, 25 mg supp

Oral:– 5-10 mg 3-4 times daily

Rectal– 25 mg bid

IV – 5-10 mg 1-2 minutes before induction

Perphenazine– Trilafon– 2, 4, 8, 26 mg tablets– 16 mg/5 ml conc.– 5 mg/ml inj

Triethylperazine– Torecan– 10 mg tablets– 5 mg/ml inj– IM 2 ml, tid– Oral: 10 – 30 mg daily in divided doses

Triflupromazine– Vesprin– 10, 20 mg/ml inj– IM 5- 15 mg q 4 h– IV 1 mg, up to 3 mg daily

5-HT3 Receptor Antagonists

Ondansetron– Zofran– 4, 8, 24 mg tablets– 4 mg/5ml solution– 2 mg/ml inj– 32 mg/50ml premixed– IV (prevention)

• 4 mg undiluted over > 30 seconds

– Oral• 16 mg 1 hr before procedure

– Zofran ODT• 4, 8 mg

Dolasetron– Anzemet– 50, 100 mg tablets– 20 mg/ml inj– IV

• 12.5 mg• Children: 0.35 mg/kg

– Oral (prevention)• 100 mg 2 h before surgery• Children: 1.2 mg/kg

within 2 hr of surgery– Caution in patients with

QTc abnormalities

Anti-emetics Trimethobenzamide

– Tigan– 100, 250 capsule– 100 mg supp (ped)– 200 mg supp– 100 mg/ml inj– Adult

• Oral: 250 mg tid-qid• Rectal, IM: 200 mg tid-qid

– Pediatric• 30 – 90 lbs 100-200 mg tid-qid

– New indication: Post-op N & V associated with gastroenteritis

– 300 mg opaque purple capsule– 300 mg po tid – qid– Can be opened and sprinkled on

food or in liquids

Metaclopramide– Reglan– 5 mg/5 ml syrup– 5, 10 mg tablets– 5 mg/ml inj

Antiemetic Dental Implications

Increased CNS Depression– Sedation– Respiratory depression

Extrapyramidal effects Vasodilation

– Orthostatic hypotension Lower seizure threshold Increase cardiac arrhythmias Interaction with vasoconstrictors Anticholinergic effects

– dry mouth