Conflicts of Interest Top 10 Prescribed Medications . Pharmaceutical Company Speakers Bureau: in Pediatrics None . Pharmaceutical Consulting: None . Medical Device or Lab Consulting: None Anthony J. Busti, MD, PharmD, BSN, FNLA, FAHA . Stock or Financial Interests in Pharmaceutical Faculty, High‐Yield MED Reviews and Medical Device Companies: None Editor‐in‐Chief, Pharmacology Weekly San Antonio, TX . Drug Company Funded Research: None Emergency Medicine Residency Program Johns Hopkins Hospital Baltimore, MD 2 Pediatrics: Absorption . Oral: The Pediatric Patient – Gastric fluids are essentially neutral in the first hrs of life; by the 2nd yr of life gastric output is equal to adult Pharmacokinetics & Pharmacodynamics on per kg basis. – pH‐dependent passive diffusion • full‐term infant: declines from 6‐8 at birth, 1‐3 after 24 hours – Gastric‐emptying time • Not significantly slower, though may not reach adult times until 6‐8 months. 3 4 Pharmacokinetics Pharmacokinetics: Clearance Pathways . First Pass Metabolism: NAT – Clinical Application: Esterase FMO • Lidocaine vs. mexiletine (Mexitil) MAO • Propranolol (Inderal) • Meperidine (Demerol) UGT ≈ 35% CYP450 – Influenced by: • Influx & efflux transporters • Phase I (CYP450) mediated metabolism • Phase II mediated metabolism FMO = flavin monooxygenase MAO = monoamine oxidase NAT = n-acetyltransferase UGT = Uridine glucuronosyltransferase 6 5 Williams J et al. Drug Metab Disp 2004;32:1201-08. NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on the charge and degree NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on of lipophilicity. 7 the charge and degree of lipophilicity. 8 Pediatrics: Distribution Pharmacokinetics . Distribution: . Volume of distribution: – To understand where drug can be and is measured, one – Influence on hydrophilic & lipophilic needs to have a basic understanding of the various “fluid – Ex. Aminoglycosides: are hydrophilic and distribute more into extracellular space so more needed to achieve plasma compartments” in the body where drug can reside. levels. Total Body Water (60% of body weight; 70kg = 42 L) . Plasma protein binding: Intracellular Extracellular (40% or 2/3 of body weight; 28 L) (20% or 1/3 of body weight; 14 L) – In neonates, albumin 80% of an adult and ‐1 acid (mainly K+, Mg+) (mainly Na+, Cl‐, HCO‐_ glycoprotein also less than adult – Bilirubin can compete with binding sites on albumin with Plasma Interstitial other meds. (5% or 1/4 of body weight; 3L) (15% or 3/4 of body weight; 10 L) (mainly protein) (No protein) 9 10 Pharmacokinetics Pharmacokinetics . Phase I Metabolism: . Phase I Metabolism: – Oxidation / Reduction via primarily the CYP450 – Oxidation / Reduction via primarily the CYP450 enzyme system. enzyme system. • Found in the liver (mainly), intestine, lungs and kidneys. • The major groups in drug metabolism & drug interactions • Purpose is for microsomal (CYP450) enzymes to give/add a include 1,2,3, and 4; they are then further divided into functional group to the drug molecule in preparation for groups by chemical structure A,B,& C. These are then sub‐ phase II metabolism and/or elimination. Those functional divided into sub‐groups 1,2,3, etc… groups are: • Most common: CYP 1A2, 2C9, 2C19, 2D6, 3A4 – COOH – CYP2B6 (3% of meds) – OH – CYP2E1 (4% of meds) – NH2 – CYP2C19 (8% of meds) – SH – CYP1A2 (11% of meds) • Metabolite can be active or inactive – CYP2C9 (16% of meds) • Require presence of NADPH, O2 to function – CYP2D6 (19% of meds) – CYP3A4 (36% of meds) 11 12 Pharmacokinetics Pharmacokinetics . Phase II Metabolism: . Phase I Metabolism: – Conjugation reactions carried out by mainly – Oxidation / Reduction via primarily the CYP450 nonmicrosomal enzymes that add a compound to the enzyme system. drug to increase hydrophilicity (these compounds to be highly polar or ionized). Almost always inactive • Subject to induction and inhibition metabolites. • Are subject to genetic polymorphisms. • Glucuronidation (e.g., via UDP‐glucuronosyltransferases; – Examples: 2C9 (warfarin), 2C19 (clobazam; clopidogrel), 2D6 UGT1A1) (tamoxifen; psych meds; beta‐blockers) – Most common one – Only one in Phase II metabolism that is microsomal enzyme as CYP450 • Sulfation: sulfotransferases (SULT) • Acetylation: N‐acetyltransferase (NAT) • Glutathione conjugation (e.g. for acetaminophen) • Methylation – methyltransferase (MT) 13 14 Pharmacokinetics: UGT Enzymes Pediatrics: Elimination UGT1A6 UGT1A3 UGT1A6 . Glomerular filtration, tubular secretion, tubular UGT1A10 UGT2B7 reabsorption may take several weeks to 1 year UGT1A8 to develop fully . Results in decreased dose requirement UGT1A4 UGT1A1 15 Williams J et al. Drug Metab Disp 2004;32:1201-08. 16 17 18 Factors Affecting Therapy Pharmacokinetics . Creatinine Clearance: Zero‐order Kinetics (Elimination) 1st‐order Kinetics (Elimination) Rate of drug elimination per hour is Rate of drug elimination per hour is – Schwartz Method: CLcr = K x L/Scr “independent” of drug concentration (i.e. “dependent” on drug concentration (i.e., • L = length (cm), Scr = serum creatinine in mg/dL the same “amount” is eliminated per the more drug in body the more hour regardless of how much drug is in eliminated per hour) • K = age specific proportionality constant: the body – LBW < 1 yr = 0.33, Full term < 1 yr = 0.45, 2‐12 yr 0.55, 13‐21 yr Cp decreases “linearly with time” Cp decreases “exponentially with time” female = 0.55, 13‐21 yr male = 0.70 1half‐life = 50% of original dose gone 2 half‐lives = 75% of original dose gone – Traub Method: CLcr = 0.48 x height (cm)/Scr 3 half‐lives = 87.5% of original dose gone 4 half‐lives = 93.75% of original dose gone • CLcr = creatinine clearance in mL/min/1.73m2, Scr = serum Examples: aspirin, ethanol, phenytoin Examples: gentamicin, vancomycin creatinine in mg/dL Note: Will see a straight line with a graph NOT using logarithmic scale. 19 20 Top Medical Conditions . The Top Medical Conditions in Pediatrics: The Pediatric Patient – Asthma The Top Medical Conditions & – GI complications Medications Prescribed – Allergies – Infectious Problems – Now = Hyperlipidemia 21 22 Top 10 Drugs in Pediatrics Top 10 Drugs in Pediatrics . The 10 Most Commonly Prescribed Medications: . The 10 Most Commonly Prescribed Medications: 1. Amoxicillin 1. Amoxicillin 2. Cefdinir 2. Cefdinir 3. Azithromycin 3. Azithromycin 4. Cipro/Dex Otic 4. Cipro/Dex Otic 5. Albuterol 5. Albuterol 6. Mometasone 6. Mometasone 7. Budesonide 7. Budesonide 8. Cetrizine 8. Cetrizine 9. Montelukast 9. Montelukast 10. Ibuprofen 10. Ibuprofen 23 24 Beta‐Lactams Beta‐Lactams . Mechanism of action take home points: . Bactericidal – Beta‐lactam antibiotics inhibit cell wall synthesis in bacteria . Time dependent killing by inhibiting the enzyme transpeptidase (or also called Beta‐lactam ring penicillin binding protein). This eventual causes lysis of the bacteria and release of intracellular contents – Bacteriocidal – Time dependent killing • We only need to achieve a certain drug concentration and keep it there; more drug is not necessarily better. • This is different that “concentration dependent killing” where more drug or higher concentrations work better. Beta‐lactam ring is subject to attack by beta‐lactamases made from bacteria 25 26 Beta‐Lactams Beta‐Lactams . Aminopenicillins: . Aminopenicillins: – General Uses: • Otitis media, bacterial sinusitis, Lower UTI, Salmonella (amox), Shigella (amp), H. – Are more hydrophilic facilitating passage through porins. pylori, and infective endocarditis prophylaxis in dental procedures (2 g x 1) for – Expanded gr‐ coverage to include H. influenza; E. coli, and high risk patients. – Women’s Health/Pregnancy: PCN and ampicillin are also used for culture Proteus species due to better penetration of outer cell wall of + for group B streptococcus from a vaginal/rectal swab at 35‐37 weeks gr‐ bacteria (via the porins) and greater binding to gestation. transpeptidase, but ring is still open to penicillinase attack • This is done to reduce risk for GBS pneumonia, sepsis, & meningitis. (compare side groups on nafcillin). – DOC in Listeria (meningitis) – ampicillin • Also recommended in empiric treatment of meningococcal meningitis caused by – Good activity against PCN‐resistant pneumococci one of few Neisseria meningitidis which can be life threatening if left untreated (Waterhouse – Friderichsen syndrome). Add to 3rd generation cephalosporin (ceftriaxone). of antibiotics effective against enterococcus. – Memory tool: – Coverage against anaerobes • H: Haemophilus influenza • E: Escherichia coli • L: Listeria monocytogenes • P: Proteus mirabilis • S: Salmonella; Shigella 27 28 Beta‐Lactams Top 10 Drugs in Pediatrics Dosage Drug Usual Dose Misc. Form . The 10 Most Commonly Prescribed Medications: Adjust for renal fx. F=0.4 results 1. Amoxicillin in diarrhea (may cause more 2. Cefdinir C.diff); > absorption if on empty Adults: 250-500 mg q stomach; good for Shigella; not Ampicillin 6hrs 3. Azithromycin PO/IV as good for Salmonella; SE: rash (Principen) Peds: 50-100mg/kg/d (especially if given for 4. Cipro/Dex Otic in 4 divided doses viral/mononucleosis (EBV) viral infection). 5. Albuterol Preg Cat: B; Lact Cat: L1 6. Mometasone Adjust for renal; F = 0.95; good Adults: 250-500 mg for Salmonella; poor for Shigella; 7. Budesonide Amoxicillin q8h SE: rash (especially if given for (Amoxil; PO 8. Cetrizine Peds: 20-50 mg/kg/d in viral/mononucleosis (EBV)