Pharmacologic Agents for the Pediatric Patient

1. Oral Pharmacologic Agents for the Pediatric Patient Patrick D. McCarty, DDS

2. Objectives Review important principles of basic and clinical pharmacology Examine developmental considerations in children and their relationship to pharmacology Explore the advantages and disadvantages of enteral sedation Review the pharmacology of enteral sedative-hypnotic drugs used for children

3. General Principles of Pharmacology Pharmocodynamics The actions of the drug on the body � Pharmocokinetics The actions of the body on the drug

4. Components of Pharmacokinetics and Pharmacodynamics Pharmacokinetic Variables Absorption Volume of Distribution Clearance Half-Life Bioavailability Pharmacodynamic Variables Maximum Effect Sensitivity

5. Pharmacokinetics Volume of Distribution Vd = Amount of Drug in Body C (Vd = volume of distribution, C = concentration)

6. Pharmacokinetics CL = Rate of Elimination C (CL = clearance, C = concentration)

7. Pharmacokinetics Half-Life The time required to change the amount of drug in the body by one-half during elimination

8. Pharmacokinetics Bioavailability The fraction of unchanged drug that reaches the systemic circulation

9. Pharmacokinetics Factors that Influence Bioavailability First-pass hepatic metabolism Solubility of the drug Chemical Instability Nature of the drug formulation

10. Pharmacodynamics Maximum Effect All pharmacologic responses must have a maximum effect (E max)

11. Pharmacodynamics Sensitivity The sensitivity of the target organ to drug concentration is reflected by the concentration required to produce 50% of maximum effect

12. Developmental Considerations in Children �Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but has its own independent range and horizon.� Abraham Jacobi, MD (Father of American Pediatrics)

13. The goal of sedation is DISTRACTION

14. Target organ of sedation is the

15. Sedation

16. Goals of Sedation The goals of sedation in a pediatric patient for diagnostic & therapeutic procedures are; 1) to guard the patient�s safety & welfare 2) to minimize physical discomfort & pain 3) to control anxiety, minimize psychological trauma, and maximize the potential for amnesia 4) to control behavior & movement so as to allow the safe completion of the procedure 5) to return the patient to a state in which safe discharge from medical supervision, as determined by recognized criteria, is possible

17. The Concept of Rescue Because sedation & general anesthesia are a continuum, it is not always possible to predict how an individual patient will respond. Hence, practitioners intending to produce a given level of sedation should be able to diagnose and manage the physiological consequences (rescue) for patients whose level of sedation becomes deeper than initially intended.

18. Route of administration does NOT determine depth of anesthesia (sedation)

19. Enteral Sedation for Children Advantages Generally accepted and easy to administer No needles Usually makes for a cooperative and comfortable child Adverse reactions are usually less

20. Enteral Sedation for Children Disadvantages Depends on patient�s ability or willingness to take the medication Long latent period Variable absorption from the gastrointestinal tract Unable to titrate to effect Failure rate can be high

21. Oral Sedation & Nitrous Oxide Oral Sedation can be made more effective with the addition of nitrous oxide carefully titrated to achieved the desired level of conscious sedation. This allows for some degree of titration along with a safer, more conservative dosage of oral medications

22. Tips on How Not to Sedate Your Patient!

23. Formulas for Pediatric Drug Dosages Young�s Rule: Dose = Adult dose x Age (years) Age + 12

24. Formulas for Pediatric Drug Dosages Clark�s Rule: Dose = Adult dose x Weight (kilograms) 70 OR Dose = Adult dose x Weight (pounds) 150

25. Sedative � Hypnotic Drugs Sedative Should reduce anxiety and exert a calming effect Hypnotic Should produce drowsiness and an increased tendency to sleep

26. Sedative � Hypnotic Drugs for the Pediatric Patient Classification Benzodiazepines Antihistamines Midazolam (Versed) Hydroxyzine Lorazepam (Ativan) Promethazine Triazolam (Halcion) Diazepam (Valium) Opioids Meperidine (Demerol) Fentanyl

27. Sedative � Hypnotic Drugs for the Pediatric Patient Classification (continued) Barbituates Nonbarbituates Phenobarbital Chloral hydrate Secobarbital

28. Benzodiazepines Mechanism of Action Targets for benzodiazepine actions are the gamma-aminobutyric acid (GABA) receptors GABA is the major inhibitory neurotransmitter in the central nervous system The receptors are composed of a, �, and ? subunit families Benzodiazepines modulate the GABA effects by binding to a specific, high-affinity site

29. Midazolam (Versed�) Class Benzodiazepine Mechanism of Action Depresses all levels of the central nervous system (CNS) Indications Sedation, anxiolysis, amnesia Contraindications Hypersensitivity to midazolam or any component Side Effects Neurologic: drowsiness, dizziness, sedation, amnesia, paradoxical excitement, involuntary movement Cardiovascular: bradycardia Respiratory: respiratory depression, respiratory arrest, cough Gastrointestinal: nausea, vomiting

30. Midazolam (Versed�) Onset of Action Oral: within 10-20 minutes Dosage Oral: 0.25 - 0.5 mg/kg (20mg maximum) Intranasal (injection solution) 1mg/mL (2mL, 5mL), 5mg/mL (1mL, 2mL)

31. Lorazepam (Ativan�) Class Benzodiazepine Mechanism of Action Depresses all levels of the CNS Indications Sedation, anxiolysis, amnesia Contraindications Hypersensitivity to lorazepam or any component Side Effects Neurologic: sedation, drowsiness, lethargy, transitory hallucinations Cardiovascular: bradycardia Respiratory: respiratory depression Gastrointestinal: nausea, vomiting

32. Lorazepam (Ativan�) Onset of Action Oral: within 60 minutes Dosage Oral: 0.05mg/kg (2mg maximum) Dosage Form Oral solution 2mg/ml, alcohol and dye free

33. Triazolam (Halcion�) Class Benzodiazepine Mechanism of Action Depresses all levels of the CNS Indications Sedation, short-term treatment of insomnia Contraindications Hypersensitivity to triazolam or any component Side Effects Neurologic: drowsiness, dizziness, agitation, anterograde amnesia Gastrointestinal: nausea, vomiting

34. Triazolam (Halcion�) Onset of Action Oral: within 15 - 30 minutes Dosage Oral: (elixir) 0.02mg/kg (investigational dose) Dosage Form Tablet 0.125 mg, 0.25 mg

35. Comparison of Triazolam to a Chloral Hydrate/Hydroxyzine CombinationIn the Sedation of Pediatric Dental PatientsMeyer M, Mourino A, Farrington FPediatric Dental 1990; 12:283-7

36. Diazepam (Valium�) Class Benzodiazepine Mechanism of Action Depresses all levels of the CNS Indications Sedation, anxiolysis, amnesia Contraindications Hypersensitivity to diazepam or any component Side Effects Neurologic: drowsiness, confusion, dizziness, fatigue Cardiovascular: bradycardia Respiratory: respiratory depression, respiratory arrest

37. Diazepam (Valium�) Onset of Action Oral: within 30 minutes Dosage Oral: 0.2 � 0.3 mg/kg (10 mg maximum) Dosage Form Oral solution 1mg/mL, 5 mg/mL (contains 19% alcohol)

38. Hydroxyzine (Atarax�, Vistaril�) Class Antihistamine Mechanism of Action Competes with histamine for H1-receptor sites on effector cells in the GI tract, blood vessels, and respiratory tract Indications Sedation, anxiolysis, antihistamine, antipruritic Contraindications Hypersensitivity to hydroxyzine or any component Side Effects Neurologic: drowsiness, dizziness, ataxia Cardiovascular: hypotension Gastrointestinal: xerostomia

39. Hydroxyzine (Atarax�, Vistaril�) Onset of Action Oral: within 15 - 30 minutes Dosage Oral: 0.6 mg/kg Dosage Form Oral syrup (hydrochloride) 10mg/5 mL (contains 0.5% alcohol and sodium benzoate; mint flavor) Oral suspension (pamoate) 25 mg/ 5mL (lemon flavor)

40. Promethazine (Phenergan�) Class Antihistamine Mechanism of Action Competes with histamine for H1-receptor Indications Sedation, antiemetic, allergic reactions, motion sickness Side Effects Neurologic: drowsiness, confusion, excitation, extra-pyramidal reactions, dystonia Cardiovascular: tachycardia, bradycardia, palpitations Respiratory: thickening of bronchial secretions, pharyngitis Gastrointestinal: nausea, diarrhea, abdominal pain

41. Promethazine (Phenergan�) Onset of Action Oral: within 20 minutes Dosage Oral: 0.5mg/kg (25mg maximum) Dosage Form Oral syrup 6.25 mg/5mL (contains alcohol)

42. Meperidine (Demerol�) Class Opioid Mechanism of Action Binds to opiate receptors in the CNS Produces generalized CNS depression Indications Sedation, management of moderate to severe pain Contraindications Hypersensitivity to meperidine or any component, use of MAO inhibitors within 14 days Side Effects Neurologic: dizziness, drowsiness, active metabolite may precipitate twitches, tremors or seizures Cardiovascular: tachycardia, bradycardia, palpitations Respiratory: respiratory depression Gastrointestinal: nausea, vomiting Ocular: miosis Dermatologic: pruritus

43. Meperidine (Demerol�) Onset of Action Oral: within 10 - 15 minutes Dosage Oral: 1 � 2 mg/kg (100 mg maximum) Dosage Form Syrup as hydrochloride 50 mg/5mL (contains sodium benzoate), Demerol� 50 mg/5mL (contains benzoic acid, banana flavor)

44. Fentanyl (Sublimaze�) Class Opioid Mechanism of Action Binds with stereospecific opioid mu receptors at many sites within the CNS Indications Sedation, analgesia Contraindications Hypersensitivity or intolerance to fentanyl or any component Side Effects Neurologic: CNS depression, dizziness, drowsiness, euphoria Cardiovascular: hypotension, bradycardia, Respiratory: respiratory depression, apnea Gastrointestinal: nausea, vomiting Ocular: miosis Dermatologic: erythema, pruritus

45. Fentanyl (Sublimaze�) Onset of Action Oral: within 5 - 30 minutes 15-20�g/kg orally Dosage Intranasal: 1 � 2 �g/kg Dosage Form Intranasal (injection solution): 0.05 mg/mL (2mL) Respiratory depression is a significant risk and may outlast opioid effects by as much as 60-90 minutes.

46. Pentobarbital (Nembutal�) Class Barbiturate Mechanism of Action Depresses CNS activity by binding to barbiturate site at GABA-receptor complex enhancing GABA activity Indications Sedation Contraindications Hypersensitivity to barbiturates or any component Side Effects Neurologic: CNS excitation or depression, drowsiness, lethargy Cardiovascular: arrhythmias, bradycardia, Respiratory: respiratory depression, apnea Gastrointestinal: nausea, vomiting

47. Pentobarbital (Nembutal�) Onset of Action Oral: within 10 - 25 minutes Dosage Intranasal: 2 � 6 mg/kg/dose (150 mg maximum) Dosage Form Elixir: 18.2 mg/5mL (contains saccharin and 18% alcohol)

48. Secobarbital (Seconal�) Class Barbiturate Mechanism of Action Depresses CNS activity by binding to barbiturate site at GABA-receptor complex enhancing GABA activity Indications Sedation Contraindications Hypersensitivity to secobarbital or any component Side Effects Neurologic: dizziness, drowsiness, CNS depression or paradoxical excitation Cardiovascular: cardiac arrhythmias, bradycardia, Respiratory: respiratory depression, apnea Gastrointestinal: nausea, vomiting Dermatologic: exfoliative dermatitis, Stevens-Johnson syndrome

49. Secobarbital (Seconal�) Onset of Action Oral: within 15 - 30 minutes Dosage Oral: 2 � 6 mg/kg (100 mg maximum) Dosage Form Capsule: 100mg

50. Chloral Hydrate (Somnote�) Class Nonbarbiturate Mechanism of Action Central nervous system depressant effects are primarily due to its active metabolite, trichloroethanol, mechanism unknown Indications Sedation and hypnosis Contraindications Hypersensitivity to chloral hydrate or any component Side Effects Neurologic: dizziness, disorientation, excitement (paradoxical) Respiratory: respiratory depression Gastrointestinal: nausea, vomiting, gastric irritation

51. Chloral Hydrate (Somnote�) Onset of Action PO Onset 30 � 60 minutes Dosage Oral: 25 � 100 mg/kg (2g maximum) Dosage Form Syrup: 250, 500 mg/mL (contains < 0.4% alcohol and sodium benzoate, orange flavor) Elimination Hepatic & Renal

52. Chloral Hydrate (Somnote�) Warnings!!! Death and permanent neurologic injury from respiratory compromise have been reported in children sedated with chloral hydrate Respiratory obstruction may occur in children with tonsillar and adenoidal hypertrophy Trichloroethanol (TCE) is an active metabolite of chloral hydrate and a carcinogen in mice It was largely displaced in the mid-20th century by barbiturates and subsequently by benzodiazepines. It was also formerly used in veterinary medicine as a general anesthetic. Today, it is commonly used as an ingredient in the veterinary anesthetic Equithesin

53. The Effect of Chloral Hydrate on Genioglossus and Diaphragmatic ActivityHershenson et al.Pediatr Res 1984; 18:516-519

54. Flumazenil (Romazicon�) Class Benzodiazepine antagonist Mechanism of Action Antagonizes the effect of benzodiazepines on the GABA-benzodiazepine receptor complex Indications Reverse sedative effects of benzodiazepines Contraindications Hypersensitivity to flumazenil or any component, or benzodiazepines Side Effects Neurologic: dizziness, headache, agitation, anxiety, abnormal crying Cardiovascular: arrhythmias, bradycardia, tachycardia, hypertension, hypotension Gastrointestinal: nausea, vomiting

55. Flumazenil (Romazicon�) Onset of Action Intravenous (IV): within 1 � 3 minutes Dosage IV: first dose 0.01 mg/kg (0.2 mg maximum) given over 15 seconds, may repeat 0.01 mg/kg after 45 seconds, and subsequent doses every minute to a maximum total cumulative dose of 0.05 mg/kg or 1 mg, whicever is lower Dosage Form Injection: 0.1 mg/mL (5, 10 mL)

56. Naloxone (Narcan�) Class Narcotic antagonist Mechanism of Action Competes and displaces narcotics at narcotic receptor sites Indications Reverse CNS and respiratory depression 2� to narcotic overdose Contraindications Hypersensitivity to naloxone or any component Side Effects Neurologic: agitation, seizures Cardiovascular: hypertension, hypotension, tachycardia, ventricular arrhythmias Respiratory: pulmonary edema Gastrointestinal: nausea, vomiting

57. Naloxone (Narcan�) Onset of Action IV: within 2 minutes Dosage IV: children (< 5 years or < 20 kg), 0.1 mg/dose may repeat every 2 - 3 minutes IV: children (> 5 years or > 20 kg), 2 mg/dose may repeat every 2 � 3 minutes Dosage Form Injection: 0.4 mg/mL (1, 10 mL), 1 mg/mL (2, 10 mL)

58. Summary Sedative-hypnotic agents for the pediatric patient in the dental setting have proven to be quite beneficial Understanding the basic and clinical pharmacology of these drugs is essential to the dental provider Acceptable success rates can be achieved in expectations are reasonable