Pediatric Pharmacology & Therapeutics PDF

P E D I AT R I C PHARMACOLOGY & THERAPEUTICS Yasmin Alayyoubi, DMD, DMSc, MSD, CAGS PHARMACOKINETICS PK: How the body interacts with a drug after administration Differences from adults due to immature organs, body composition, protein binding, and unique receptor patterns...

P E D I AT R I C PHARMACOLOGY & THERAPEUTICS Yasmin Alayyoubi, DMD, DMSc, MSD, CAGS PHARMACOKINETICS PK: How the body interacts with a drug after administration Differences from adults due to immature organs, body composition, protein binding, and unique receptor patterns Dose adjustments are needed to avoid toxicity and achieve the desired effect Drug effects can vary due to altered organ response (e.g., heart, lungs) PHARMACOKINETICS IN CHILDREN Involves absorption, distribution, metabolism, and elimination of drugs Age-related variations impact these processes, requiring dose adjustments in children ABSORPTION Several factors affect gastric absorption in children: Reduced gastric acid → ↑ acid-labile drug bioavailability (e.g., penicillin) Reduced bile salts → ↓ lipophilic drug absorption (e.g., diazepam) Microbial flora: Alters drug metabolism and absorption Slower gastric emptying/motility → delayed drug absorption (particularly in infants < 3 months) DISTRIBUTION Age-related changes in drug distribution due to: Body composition changes (extracellular & total body water) Plasma protein binding Water-soluble drugs: Younger children need higher doses (per kg) due to higher body water % Older children need lower doses to avoid toxicity as body water decreases Children with obesity: Higher total body water, body volume, lean mass, and fat mass compared to non- obese children M E TA B O L I S M The cytochrome P-450 (CYP450) enzyme system in the liver and small intestine is crucial for drug metabolism. CYP450 enzymes inactivate drugs via: Phase I Metabolism: oxidation, reduction, hydrolysis Phase II Metabolism: hydroxylation, conjugation Phase I metabolism is reduced in neonates and progressively increases during the first six months of life E L I M I N AT I O N Drug metabolites are eliminated primarily through bile or kidneys Renal elimination depends on: Plasma protein binding Renal blood flow Glomerular filtration rate Tubular secretion All factors can vary with age U N D E R S TA N D I N G PA I N I N C H I L D R E N Pain is a distressing physical and emotional experience, uniquely felt by each child because of differences in how they perceive it or children ≥ 3 years old to assess severity of pain ensuring appropriate management can be p *https://wongbakerfaces.org T Y P E S O F PA I N Nociceptive pain arises when pain receptors in the body are triggered by harmful stimuli such as heat, cold, vibration, stretching, or chemicals. It is caused by the stimulation of intact nociceptors due to tissue injury and inflammation Common causes of nociceptive pain include burns, bruises, fractures, sprains Nociceptive pain can be divided into two types: Somatic pain: Originates from Visceral pain: Arises from internal the skin, bones, muscles, organs or nearby structures. It is connective tissues, or joints. It typically described as a dull, diffuse often starts as sharp, stabbing, ache in areas like the abdomen or chest localized pain but can evolve into a dull ache. Examples include cuts & headaches  PHARMACOLOGIC PA I N M A N A G E M E N T NON-OPIOID ANALGESICS Nonopioid analgesics include Acetaminophen and NSAIDs These analgesics are effective in treating mild to moderate pain The use of aspirin has decreased since the 1970s due to its link to Reye’s syndrome M O D E R AT E / S E V E R E PA I N The use of codeine and its alternatives, oxycodone, hydrocodone, morphine, and tramadol, for children as an analgesic is not recommended by the American Academy of Pediatrics “A 2013 systematic review found a combination of acetaminophen and ibuprofen provides effective analgesia without the adverse side effects associated with opioids; the combination of acetaminophen and ibuprofen was shown to be more effective in combination than either medication alone.” – AAPD Policy on Pediatric Pain Management, 2022 A C E TA M I N O P H E N Aka Tylenol Generally considered very safe for children Contraindicated in known hypersensitivity to paracetamol, and in hepatic & renal failure Has analgesic and antipyretic properties Mechanism of action: Inhibits cyclooxygenase-3 (COX-3) which is found mostly in the brain Antipyresis occurs from inhibition of the hypothalamus Onset of action: 3 months of age up to 40 kg: 25-45 mg/kg/day in doses divided every 12 hours (maximum single dose 875 mg; maximum daily dose 1,750 mg) Use 200mg/5ml or 400mg/5ml oral suspension or 200mg or 400mg chewable tablets Children ≥ 40 kg, adolescents, and adults: 500-875 mg every 12 hours CLINDAMYCIN Alternative for patients with Type I allergy to penicillin and/or cephalosporin antibiotics Effective for infections (e.g., abscesses) with gram-positive aerobic bacteria and gram- positive or gram-negative anaerobic bacteria No longer recommended for endocarditis prophylaxis for dental procedures C. difficile colitis is a serious adverse reaction Forms: Suspension, capsule, injectable Oral dosage for soft tissue infections: Infants, children, and adolescents: 20-30 mg/kg/day in divided doses every 8 hours (maximum single dose 450 mg) for 7- 10 days Adults: 300-450 mg every 6-8 hours (maximum daily dose 1,800 mg) AZITHROMYCIN An alternative for patients with Type I allergy to penicillin and/or cephalosporin antibiotics Can cause cardiac arrhythmias in patients with pre-existing cardiac conduction defects Can be used as an alternative to penicillin for endocarditis prophylaxis for dental procedures Forms: Tablet, capsule, suspension, injectable Infants, children, and adolescents: 10-12 mg/kg on day 1, single dose, (maximum 500 mg), followed by 5-6 mg/kg once daily for remainder of treatment (2-5 days) Adults: 500 mg on day 1, single dose, followed by 250 mg daily as a single dose CLARITHROMYCIN An alternative for patients with Type I allergy to penicillin and/or cephalosporin antibiotics Can cause cardiac arrhythmias in patients with pre-existing cardiac conduction defects Can be used as an alternative to penicillin for endocarditis prophylaxis for denta procedures Forms: Suspension, tablet Infants, children, and adolescents: 7.5 mg/kg/dose every 12 hours (maximum single dose 500 mg) Adults: DOXYCYCLINE Important: Tetracycline antibiotics may cause permanent tooth discoloration and enamel hypoplasia in developing teeth, as well as hyperpigmentation of soft tissues Not recommended for children 12 years Active ingredient: 20% Benzocaine Carrier: Gelatin, pectin, and carboxymethylcellulose sodium in a plasticized hydrocarbon gel, a polyethylene and mineral oil gel base Does not contain benzocaine Main ingredients include water, glycerin, propylene glycol for short term relief of pain associated with teething  LOCAL ANESTHETICS Max Dose 300mg 500mg 300mg  Benzocaine (topical): Not for children < 2 years Articaine: Not recommended for children < 4 years Bupivacaine: Not recommended for children < 12 years Important: Doses of amide local anesthetics should be decreased by 30% in infants younger than six months Self-induced soft tissue trauma (e.g., lip, cheek biting) is a clinical complication of local anesthetic use. Most lesions of this nature are self- limiting and heal without complications, although potential risks are bleeding & infection It is necessary to properly advise parents/caregivers about post-operative precautions and provide a realistic duration of numbness P E D I AT R I C S E D AT I O N P E D I AT R I C S E D AT I O N Sedation is commonly used in children to help manage behavior during dental procedures Deeper sedation is often required for children under 5 or those with special health care needs to ensure cooperation There is a frequent risk of unintentional deeper sedation than planned In older children, basic behavioral management techniques are often effective alternatives to sedation  Basic behavior guidance Advanced behavior guidance Tell-Show-Do Protective stabilization (active and passive) Distraction Sedation (e.g. Nitrous oxide, oral, IV) Positive reinforcement General anesthesia Desensitization Parental presence/absence Sensory adapted dental environment Animal assisted therapy Children may present with behavioral considerations that require more advanced techniques, due to inability to cooperate due to lack of psychological or emotional maturity and/or mental, physical, or medical disability G O A L S O F S E D AT I O N ( A A P D ) Safeguard the patient’s safety and welfare Minimize physical discomfort and pain Manage anxiety, reduce psychological trauma, and maximize the potential for amnesia Modify behavior and movement to ensure the safe completion of the procedure Return the patient to a state that allows for safe discharge from medical supervision, as determined by established criteria M I N I M A L S E D AT I O N Nitrous oxide sedation A drug-induced state in which patients respond normally to verbal commands Although cognitive function and coordination may be impaired, ventilation and cardiovascular functions remain unaffected Responsiveness: patients are less anxious, calmer, and less overtly reactive to clinical stimuli, while still purposefully interacting with the clinician Monitoring: Requires clinical observation of skin color, respiratory effort, and pulse oximetry (now mandated by state regulations) M O D E R AT E S E D AT I O N Drug-induced depression of consciousness where patients purposefully respond to verbal commands (e.g., “open your eyes”), either alone or with light tactile stimulation For older patients, this indicates an interactive state For younger patients, age-appropriate behaviors like crying are expected Commonly used drugs include Midazolam (Versed), Hydroxyzine, Meperidine – dosed per kg, administered in office Airway intervention is not typically required; spontaneous ventilation remains adequate Cardiovascular function is usually maintained I N D I C AT I O N S F O R M O D E R AT E S E D AT I O N Pre-school children and those unable to cooperate due to insufficient psychological or emotional maturity Individuals who cannot cooperate because of cognitive, physical, or medical disabilities Patients who struggle to cooperate due to anxiety and fear Those requiring dental work who would benefit from a prolonged visit, and whose treatment may have been ineffective with minimal sedation GENERAL ANESTHESIA Drug-induced loss of consciousness in which patients are not arousable, even in response to painful stimulation The ability to independently maintain ventilatory function is often impaired, and positive pressure ventilation may be necessary due to depressed spontaneous ventilation or drug-induced neuromuscular function impairment Assistance is often required to maintain a patent airway Cardiovascular function may also be compromised I N D I C AT I O N S F O R G E N E R A L ANESTHESIA Lack of psychological or emotional maturity, and/or complex medical disabilities Need for extensive dental treatment, or immediate surgical procedures Protection of the developing psyche A S A C L A SS I F I C AT I O N The American Society of Anesthesiologists (ASA) physical status classification system is a tool used by anesthesiologists to assess a patient's physical health and risk of complications before surgery ASA I: Healthy patient ASA II: Mild systemic disease ASA III: Severe systemic disease ASA IV: Severe systemic disease that is a constant threat to life ASA V: A moribund person who is not expected to survive without the operation ASA VI: A declared brain-dead person whose organs are being removed for donor purposes  Patients who are in ASA classes I and II are frequently considered appropriate candidates for minimal, moderate, or deep sedation Children in ASA classes III and IV, children with special health care needs, and those with anatomic airway abnormalities or moderate to severe tonsillar hypertrophy present issues that require additional and individual consideration, particularly for moderate and deep sedation Patients who are in Mallampati classes I and II are considered appropriate candidates for moderate sedation CASES Case 1: If a 20-month-old patient weighs 22 pounds, what is the maximum number of carpules of 2% lidocaine that may be administered? Lidocaine 2% with 1:100,000 epinephrine Maximum dose of lidocaine: 4.4mg/kg 22lb ÷ 2.2lb/kg = 10kg 10kg X 4.4mg/kg = 44mg 44mg ÷ 34mg lido per 1.7ml cartridge = 1.3 carpules Case 2: 14-month-old child weighing 9kgs presents with teething pain. How much Tylenol should the patient take per dose? Dose = 120mg Tylenol Suspension is 160mg/5ml = 32mg/1ml 120mg ÷ 32mg/ml = 3.75ml Alternatively, you can use 10-15mg/kg/ dose so maximum recommended dose would be 9kg x 15mg/kg = 135mg Tylenol per dose Case 3: 4-year-old healthy patient weighing 41lbs presents with a localized parulis of tooth #E. What is your treatment plan? Presents a localized fluctuant buccal swelling/ draining fistula Antibiotics not necessary for a localized fistula Pt may require pain medication Tx: Ext of #E or pulpectomy/crown Case 3 (cont): 4-year-old healthy patient weighing 41lbs presents with a localized parulis of tooth #E. What is your treatment plan? 41lbs ÷ 2.2kg/lbs = 18.6kg Dose = 150mg Ibuprofen Suspension is 100mg/5ml = 20mg/1m 150mg ÷ 20mg/ml = 7.5ml Alternatively, you can use 4-10mg/kg/ dose so maximum recommended dose would be 18.6kg x 10mg/kg = 186mg Tylenol per dose Case 4: 5-year-old 50lb healthy patient presents facial swelling as a result of grossly decayed #I. What antibiotics will you prescribe & what dose? Convert to Kg 50lb ÷ 2.2kg/lbs = 22.7kg Augmentin: Dose is 25-45mg/kg 22.7kg x 45mg/kg = 1021.5mg/day (maximum daily dose is 1,750 mg) Concentrations: 2 doses/day regimen: 200mg/5ml or 400mg/5ml oral suspension, or 3 doses/day regimen: 125mg/5ml or 250mg/5ml oral suspension 1021.5 mg/day ÷ 200mg/5ml = 25.5 ml/ day ÷ 2 doses/day = 12.8ml/dose 1021.5 mg/day ÷ 400mg/5ml = 12.8 ml/day ÷ 2 doses/day = 6.4ml/dose  American Academy of Pediatric Dentistry Reference Manual, 2023-2024 Brian J. Anderson, Jerrold Lerman, Charles J. Coté, Pharmacokinetics and Pharmacology of Drugs Used in Children, Editor(s): Charles J. Coté, Jerrold Lerman, Brian J. Anderson, A Practice of Anesthesia for Infants and Children (Sixth Edition), Elsevier,2019, Pages 100-176.e45, ISBN 9780323429740. Van Den Anker J, Reed MD, Allegaert K, Kearns GL: REFERENCE Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol 58 (supplement 10):S10– S S25, 2018. doi: 10.1002/jcph.1284 Vaughns JD, Conklin LS, Long Y, et, al.: Obesity and pediatric drug development. J Clin Pharmacol 58(5):650–661, 2018. doi: 10.1002/jcph.1054 Blake JB, Abdel-Rahman SM, Pearce RE, et, al.: Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res 60(6):717–723, 2006. doi: 10.1203/01.pdr.0000245909.74166.00 THANK YOU [email protected]