Conflicts of Interest · • This is done to reduce risk for GBS pneumonia, sepsis, & meningitis....

Top 10 Prescribed Medications in Pediatrics

Anthony J. Busti, MD, PharmD, BSN, FNLA, FAHA

Editor‐in‐Chief, Pharmacology WeeklySan Antonio, TX

Emergency Medicine Residency ProgramJohns Hopkins Hospital

Baltimore, MD

Faculty, High‐Yield MED Reviews

Pharmaceutical Company Speakers Bureau: None Pharmaceutical Consulting: None Medical Device or Lab Consulting: None Stock or Financial Interests in Pharmaceutical and Medical Device Companies: None Drug Company Funded Research: None

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Conflicts of Interest

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The Pediatric PatientPharmacokinetics & Pharmacodynamics

Pediatrics: Absorption

Oral:– Gastric fluids are essentially neutral in the first hrs of life; by the 2nd yr of life gastric output is equal to adult 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.

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Pharmacokinetics

First Pass Metabolism:– Clinical Application:

• Lidocaine vs. mexiletine (Mexitil) • Propranolol (Inderal)• Meperidine (Demerol)

– Influenced by:• Influx & efflux transporters• Phase I (CYP450) mediated metabolism• Phase II mediated metabolism

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Pharmacokinetics: Clearance Pathways

Esterase FMONAT

MAO

CYP450UGT ≈ 35%

Williams J et al. Drug Metab Disp 2004;32:1201-08.

FMO = flavin monooxygenaseMAO = monoamine oxidaseNAT = n-acetyltransferase

UGT = Uridine glucuronosyltransferase6

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NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on the charge and degree of lipophilicity. 8

NOTE: NOT ALL drugs require transporters to get across cell membranes! Some will make it across by diffusion depending on the charge and degree of lipophilicity.

Pediatrics: Distribution

Volume of distribution:– Influence on hydrophilic & lipophilic– Ex. Aminoglycosides: are hydrophilic and distribute more into extracellular space so more needed to achieve plasma levels.

Plasma protein binding:– In neonates, albumin 80% of an adult and ‐1 acid glycoprotein also less than adult

– Bilirubin can compete with binding sites on albumin with other meds.

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Distribution:– To understand where drug can be and is measured, one needs to have a basic understanding of the various “fluid compartments” in the body where drug can reside.

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Pharmacokinetics

Total Body Water (60% of body weight; 70kg = 42 L)

Intracellular(40% or 2/3 of body weight; 28 L)

(mainly K+, Mg+)

Extracellular(20% or 1/3 of body weight; 14 L)

(mainly Na+, Cl‐, HCO‐_

Plasma(5% or 1/4 of body weight; 3L)

(mainly protein)

Interstitial(15% or 3/4 of body weight; 10 L)

(No protein)

Pharmacokinetics Phase I Metabolism:

– Oxidation / Reduction via primarily the CYP450 enzyme system.

• Found in the liver (mainly), intestine, lungs and kidneys.• Purpose is for microsomal (CYP450) enzymes to give/add a functional group to the drug molecule in preparation for phase II metabolism and/or elimination. Those functional groups are:

– COOH– OH– NH2– SH

• Metabolite can be active or inactive• Require presence of NADPH, O2 to function

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Pharmacokinetics Phase I Metabolism:

– Oxidation / Reduction via primarily the CYP450 enzyme system.

• The major groups in drug metabolism & drug interactions include 1,2,3, and 4; they are then further divided into groups by chemical structure A,B,& C. These are then sub‐divided into sub‐groups 1,2,3, etc…

• Most common: CYP 1A2, 2C9, 2C19, 2D6, 3A4– CYP2B6 (3% of meds)– CYP2E1 (4% of meds)– CYP2C19 (8% of meds)– CYP1A2 (11% of meds)– CYP2C9 (16% of meds)– CYP2D6 (19% of meds)– CYP3A4 (36% of meds)

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Pharmacokinetics

Phase I Metabolism:– Oxidation / Reduction via primarily the CYP450 enzyme system.

• Subject to induction and inhibition• Are subject to genetic polymorphisms.

– Examples: 2C9 (warfarin), 2C19 (clobazam; clopidogrel), 2D6 (tamoxifen; psych meds; beta‐blockers)

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Pharmacokinetics Phase II Metabolism:

– Conjugation reactions carried out by mainly nonmicrosomal enzymes that add a compound to the drug to increase hydrophilicity (these compounds to be highly polar or ionized). Almost always inactive metabolites.

• Glucuronidation (e.g., via UDP‐glucuronosyltransferases; UGT1A1)

– 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)

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Pharmacokinetics: UGT Enzymes

UGT1A3

Williams J et al. Drug Metab Disp 2004;32:1201-08.

UGT1A10

UGT1A8

UGT1A6UGT1A6

UGT1A1UGT1A4

UGT2B7

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Pediatrics: Elimination

Glomerular filtration, tubular secretion, tubular reabsorption may take several weeks to 1 year to develop fully

Results in decreased dose requirement

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Factors Affecting Therapy Creatinine Clearance:

– Schwartz Method: CLcr = K x L/Scr• L = length (cm), Scr = serum creatinine in mg/dL• K = age specific proportionality constant:

– LBW < 1 yr = 0.33, Full term < 1 yr = 0.45, 2‐12 yr 0.55, 13‐21 yr female = 0.55, 13‐21 yr male = 0.70

– Traub Method: CLcr = 0.48 x height (cm)/Scr• CLcr = creatinine clearance in mL/min/1.73m2, Scr = serum creatinine in mg/dL

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Zero‐order Kinetics (Elimination) 1st‐order Kinetics (Elimination)

Rate of drug elimination per hour is “independent” of drug concentration (i.e. the same “amount” is eliminated per hour regardless of how much drug is in the body

Rate of drug elimination per hour is “dependent” on drug concentration (i.e., the more drug in body the more eliminated per hour)

Cp decreases “linearly with time” Cp decreases “exponentially with time”

1 half‐life = 50% of original dose gone2 half‐lives = 75% of original dose gone3 half‐lives = 87.5% of original dose gone4 half‐lives = 93.75% of original dose gone

Examples: aspirin, ethanol, phenytoinNote: Will see a straight line with a graph NOT using logarithmic scale.

Examples: gentamicin, vancomycin

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Pharmacokinetics

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The Pediatric PatientThe Top Medical Conditions &

Medications Prescribed

The Top Medical Conditions in Pediatrics:– Asthma– GI complications– Allergies– Infectious Problems– Now = Hyperlipidemia

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Top Medical Conditions

The 10 Most Commonly Prescribed Medications:1. Amoxicillin2. Cefdinir3. Azithromycin4. Cipro/Dex Otic5. Albuterol6. Mometasone7. Budesonide8. Cetrizine9. Montelukast10. Ibuprofen

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Top 10 Drugs in Pediatrics The 10 Most Commonly Prescribed Medications:

1. Amoxicillin2. Cefdinir3. Azithromycin4. Cipro/Dex Otic5. Albuterol6. Mometasone7. Budesonide8. Cetrizine9. Montelukast10. Ibuprofen

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Top 10 Drugs in Pediatrics

Beta‐Lactams

Bactericidal Time dependent killing

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Beta‐lactam ring is subjectto attack by beta‐lactamasesmade from bacteria

Beta‐lactam ring

Beta‐Lactams Mechanism of action take home points:

– Beta‐lactam antibiotics inhibit cell wall synthesis in bacteria by inhibiting the enzyme transpeptidase (or also called 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.

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Beta‐Lactams

Aminopenicillins:– Are more hydrophilic facilitating passage through porins.– Expanded gr‐ coverage to include H. influenza; E. coli, and Proteus species due to better penetration of outer cell wall of gr‐ bacteria (via the porins) and greater binding to transpeptidase, but ring is still open to penicillinase attack (compare side groups on nafcillin).

– Good activity against PCN‐resistant pneumococci one of few of antibiotics effective against enterococcus.

– Coverage against anaerobes

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Beta‐Lactams Aminopenicillins:

– General Uses:• Otitis media, bacterial sinusitis, Lower UTI, Salmonella (amox), Shigella (amp), H.

pylori, and infective endocarditis prophylaxis in dental procedures (2 g x 1) for high risk patients.

– Women’s Health/Pregnancy: PCN and ampicillin are also used for culture + for group B streptococcus from a vaginal/rectal swab at 35‐37 weeks gestation.

• This is done to reduce risk for GBS pneumonia, sepsis, & meningitis.– DOC in Listeria (meningitis) – ampicillin

• Also recommended in empiric treatment of meningococcal meningitis caused by Neisseria meningitidis which can be life threatening if left untreated (Waterhouse – Friderichsen syndrome). Add to 3rd generation cephalosporin (ceftriaxone).

– Memory tool:• H: Haemophilus influenza• E: Escherichia coli• L: Listeria monocytogenes• P: Proteus mirabilis• S: Salmonella; Shigella

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Beta‐LactamsDrug Dosage

Form Usual Dose Misc.

Ampicillin(Principen)

PO/IV

Adults: 250-500 mg q 6hrsPeds: 50-100mg/kg/d in 4 divided doses

Adjust for renal fx. F=0.4 results in diarrhea (may cause more C.diff); > absorption if on empty stomach; good for Shigella; not as good for Salmonella; SE: rash (especially if given for viral/mononucleosis (EBV) viral infection). Preg Cat: B; Lact Cat: L1

Amoxicillin(Amoxil;Trimox)

PO

Adults: 250-500 mg q8h Peds: 20-50 mg/kg/d in 2-3 divided doses.

Adjust for renal; F = 0.95; good for Salmonella; poor for Shigella; SE: rash (especially if given for viral/mononucleosis (EBV) viral infection). Preg Cat: B; Lact Cat: L1

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Beta‐Lactams: Cephalosporins

Cephalosporins:– Bactericidal– Broken down into 5 generations; each generation essentially see greater gr‐ coverage and CNS penetration

• 1st generation has greatest affinity for PBPs in S aureus.• Cefuroxime, cefotaxime, ceftriaxone, ceftazidime, & cefepime have good CNS penetration when meninges are inflamed.

• With the exception of ceftaroline, they DO NOT work against MRSA. None of them cover for enterococcus.

• Their additional structure to protects against beta‐lactamases (i.e., penicillinases) but now more susceptible to cephalosporinases)

– Allergy cross‐sensitivity of about 1% with penicillin allergic patients

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Beta‐Lactams: CephalosporinsGr+ Coverage Gr‐ Coverage

& CNS penetration for most

Generation of Cephalosporin

1st generation

2nd generation

3rd generation

4th generation

5th generation


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Penicillin Cephalexin

Beta‐Lactams: Cephalosporins 3rd Generation Cephalosporins:

– See a reduction in gr+ coverage (especially with Staph. aureus), but may be slightly better against PCN‐resistant S. pneumoniae

– Not reliable against Enterobacter species– gr‐ coverage increases especially against Enterobacteriaceae (E. coli, Klebsiella, and Proteus spp.).

• Also improved activity against H. influenzae, N. gonorrheaand meningitidis.

• Ceftazidime has good coverage against P. aeruginosa• Ceftriaxone can be mixed with 1% lidocaine for IM injection

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3rd Generation Cephalosporins:– Oral formulations:

• Cefdinir (Omnicef)• Cefditoren (Spectracef)• Cefixime (Suprax)• Cefpodoxime (Vantin)• Ceftibuten (Cedax)

– Parenteral formulations:• Cefotaxime (Claforan)• Ceftazidime (Fortaz) • Ceftriaxone (Rocephin)

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Protein Synthesis Inhibitors

Macrolides Ketolides Tetracyclines Glycylcyclines Anaerobic agents Linezolid Streptogramins Aminoglycosides

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Macrolides Bacteriostatic MOA: Inhibit protein synthesis by binding to domain II & V on the 50S ribosomal subunit thereby interfering with the translocation reaction where the developing peptide chain is moved from the receptor to the donor site.– These sites of binding are also sites for inhibition by clindamycin, lincomycin, chloramphenicol, streptogramins and so should not be used together for that reason.

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Macrolides

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Erythromycin

Clarithromycin

Azithromycin(azalide class)

Telithromycin(ketolides class)

3‐L‐cladinosegroup

Macrolides General Uses:

– Oral drug delivery: Otitis media, pharyngitis, URI & LRI, CAP, PID (C. trachomatis; mainly azithromycin), bacterial exacerbations of COPD; H. pylori (clarithromycin only one FDA approved), mycobacterium avium complex (MAC); Legionnaires disease (erythromycin & azithromycin).

• With the increased number of people not immunizing, this class is useful at treating pertussis (“whooping cough” – inspiratory whoop after paroxysmal coughing)

– Ophthalmic drug delivery: Conjunctivitis and prophylaxis of ophthalmia neonatorum caused by Neisseria gonorrhoeae and Chlamydia trachomatis (erythromycin only)

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MacrolidesDrug Dosage


Azithromycin(Zithromax; Z-pak; Tri-pak; Zmax(extended release susp))

PO/IV

Adults: Z-pak: 500 mg day1; 250 mg day 2-5Tri-pak: 500 mg x 3 dayZmax (mild-Mod CAP & ABS): 2 g x 1Peds: 5-10 mg/kg/d

No CYP3A4 interaction; t1/2 =68hrs; S. pneumo resistance being seen. ER form: absorbed in small intestine vs stomach with IR. Mixed with 60 ml water & used in 12 hrs (1-2 hrs after meal). GI side effects = 17.2%

Clarithromycin(Biaxin; Biaxin XL)

PO

Adults: 250-500 mg q 12hrs; or 1000 mg qd for XLPeds: 7.5-15mg/kg/d in 2 divided doses

Adjust for renal fx; CYP3A4 inhibitor (mech based inhibition). Only one for H. pylori SE: bad taste, GI upset, QT prolongation

Erythromycin(Ery-Tab, E-Mycin)

PO/IVAdults: 250-500 mg q 6hrsPeds: 20-40mg/kg/d in 4 divided doses

SE: diarrhea, GI upset QT prolongation; CYP3A4 inhibitor, little H. influenzae coverage

Fidaxomicin(Dificid)

POAdults: C. difficile only: 200 mg bid x 10 daysPeds: None

No renal or hepatic dosing; not absorbed – do NOT treat systemic infx; No DDI. Treats C. difficile(including NAP1/B1/027 strain). No major SE. Does not cover gr-aerobes or gr- anaerobes.

Spiramycin (Rovamycine) PO Not available in US Used mainly for gonorrhea.

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Fluoroquinolones

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Ciprofloxacin

Piperazinyl group at 7; Antipseudomonal activity

fluorine

Carboxyl‐group: DDI

Fluoroquinolones

Bacteriocidal

MOA: Current agents are “fluorinated” analogs of nalidixic acid which is not used because it doesn’t achieve systemic antibacterial levels. The name is partially derived from the fact that these drugs have a fluorine group on them. Inhibits protein synthesis by binding to DNA gyrase (topoisomerase II) and topoisomerase IV. This inhibits the relaxation of the supercoiled DNA thereby promoting breakage of DNA strands.

General Uses:– CAP, Nosocomial pneumonia, acute maxillary sinusitis, complicated and

uncomplicated UTI, prostatitis, some soft tissue infections, Crohn’s Disease.

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FluoroquinolonesDrug Dosage


Ciprofloxacin(Cipro)

PO/IV

Adults: PO: 500 mg bid; IV: 400 mg bidPeds: PO: 20-30mg/kg bid; IV: 6-10mg/kg bid (CF patients)

Not good for Strep. Pneumonia. CYP1A2 inhibitor; F=0.7; SE: GI upset, QT prolongation, glucose changes, tendon rupture, seizure risk; renal dose CrCl < 50 ml/min;

Norfloxacin(Noroxin) PO

Adults: PO: 400 mg bidPeds: Not approved < 18y

Same SE’s as above: CrCl < 30 ml/min: adjust dose to once daily

Ofloxacin(Floxin) PO

Adults: PO: 200-400 mg bidPeds: Not approved < 18y

Same SE’s: CrCL 20-50 ml/min daily; if < 20 ml/min 50% of dose

Levofloxacin (Levaquin)

PO/IVAdults: 250-750 mg qd; dose for CAP is now 750 mg qdPeds: Not approved < 18y

F=0.95; L-isomer of ofloxacin; Same SE’s above; has P. aeruginosaindication; resistance concern; adjust CrCl < 50 ml/min;

Moxifloxacin(Avelox)

PO/IVAdults: 400 mg qdPeds: Not approved < 18y

F = >0.85; No renal adjustment; may cause most QT prolongation; NOT for UTI’s

Gemifloxacin(Factive)

POAdults: 320-640 mg qd Peds: 5-10 mg/kg/d generally not recommend

F= 0.71; Renal adjust dose CrCl < 40 ml/min; QT prolongation; NOT for UTIs

All of the fluoroquinolones are Pregnancy category: C and Lactation Risk Category: L3 for oral and IV.Avoid use of any di & tri valent cations (Al, Ca, Fe, Mg) within 2 hrs of taking FQ’s. This also includes sucralfate (which has Al)

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Fluoroquinolones: OticDrug Usual Dose Misc.

Ciprofloxacin otic solution (0.2%), (Cetraxal)

> 1 yr for Acute Otitis Media Externa: 1 single use container into affected ear bid x 7 days

Due to Pseudomonas aeruginosa or staphylococcus aureus. Comes in refilled, single use containers. Let dose penetrate for 1 min before moving head.

Ciprofloxacin 0.3% and dexamethasone 0.1% suspension(Ciprodex Otic)

>6 months: Acute otitis media in peds with tympanostomy tubes or acute otitis externa in children & adults: 4 gtt in affected bid x 7d

Note: Dose is same for all indications; avoid with viral infectionsComes in 7.5 mL

Ciprofloxacin 0.2% and hydrocortisone 1% suspension (Cipro HC Otic)

>1 yr: Otitis externa: 3 gtt in affected ear bid x 7 d

Note: Only one NOT sterile and therefore should NOT be used if tympanic membrane is ruptured. Avoid with viral infectionsComes in 10 mL bottle

Ofloxacin 0.3% solution(Floxin Otic)

Otitis externa = 6 months – 13 yrs: 5 gtt qd x 7d. If > 13 yrs then 10 gttqd x 7dAcute Otitis Media = 1-12 yrs: 5 gttbid x 10 dChronic Supprative Otitis Media = > 12 yrs: 10 gtt in affected ear bid x 14 d

Comes in 5, 10 mL

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Top 10 Drugs in Pediatrics Comparative Pathophysiology

Asthma:– Eosinophils– Airway hyperreactivity– Bronchodilator response– Inhaled corticosteroid response

COPD:– Neutrophils– No airway hyperreactivity– Limited bronchodilator response

– Limited inhaled corticosteroid response

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Levels of Asthma Control

CharacteristicControlled(All of the following)

Partly Controlled(Any present inpast week)

Uncontrolled

Daytime symptoms <2 times per week

>2 times per week >3 features of partly controlled asthma in any weekLimitations of

activitiesNone Any

Nocturnal symptoms/ awakening

None Any

Need for reliever/ rescue treatment

<2 times per week

>2 times per week

Lung function(PEF or FEV1)

Normal <80% predicted or personal best

Exacerbations None Any within 1 year Any within 1 week

Note: applies also children 5 and younger.50

Pharmacotherapy of Asthma

2 agonists (Bronchodilators) Corticosteroids Mast cell stabilizers Leukotriene modifiers Theophylline Anti‐IgE Antibodies

Step 1 Step 2 Step 3 Step 4 Step 5

Asthma education and environmental controlIf step up therapy needed, assess inhaler technique and confirm symptoms are from asthma and not something else first.

Rapid acting inhaled β2‐agonist PRN (Alternatives treatment includes: inhaled anticholinergic, short‐acting oral β2‐agonist or short‐acting theophylline)

Controller options

Select one Select one To Step 3 treatment, select one or more

To step 4 treatment add either

Low‐dose inhaled ICS

Low dose ICS (+) long‐acting β2‐agonist

Medium‐or high‐dose ICS (+) long‐acting β2‐agonist

Oral corticosteroid(lowest dose)

Leukotriene modifier

Medium or high‐dose inhaled ICS

Low dose ICS (+) leukotrienemodifier

Leukotriene modifier

Sustained release theophylline

Anti‐IgE treatment(omalizumab)

Low‐dose ICS (+) SR theophylline

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Treatment Steps NAEPP‐3Age

Severity Birth to 4 yrs 5 to 11 yrs > 12 yrsStep 6: Persistent Asthma

HD inhaled steroid +LBA OR Singulair

+ oral steroid

HD inhaled steroid +LBA + oral steroid

HD inhaled steroid +LBA + oral steroid

Step 5: Persistent Asthma

HD inhaled steroid +LBA OR Singulair

HD inhaled steroid +LBA

HD inhaled steroid +LBA


MD inhaled steroid +LBA OR Singulair

MD inhaled steroid +LBA

MD inhaled steroid +LBA + oral steroid


MD inhaled steroid

LD inhaled steroid +LBA OR Singulair OR Theo

ORMD Inhaled steroid alone

LD inhaled steroid +LBA OR

MD Inhaled Steroid (alone)


LD inhaled steroid LD Inhaled steroid LD Inhaled steroid

Step 1: Intermittent Asthma

none none none

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Mechanism of Action: Beta‐2 Agonists

ATP

cAMPAMP

Protein Kinase

Cytosolic Ca2+

Bronchodilation &Mast cell stabilization

Adenylate cyclasePhosphodiesterase

(PDE‐4)

R‐albuterol

(+)

Actin & Myosin Interaction

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Short Acting Inhaled 2 –AgonistsDrug Indication(s) Age

(yrs) Dose Onset (min)

Duration (hrs)

Albuterol HFA MDI(Proventil & Ventolin, ProAir HFA)

• Prevention, relief & treatment of reversible bronchospasm

• Prevention of exercise induced asthma

≥ 4;

ProAIR HFA ≥ 12

Adults: 2 puffs q4-6hr prn; Exercise induced asthma: 2 puffs 15 min prior to exercise

Peds: 1 puff q4-6hr prn

5-8 3-6

Albuterol inhalation soln(AccuNeb)

• Relief of reversible bronchospasmNote: no prevention or treatment; no EIA; but younger age

≥ 2Adults: 2.5 mg q6-8hr prn

Peds: 1 puff q4-6hr prn2-5 3-6

Levalbuterol HFA MDI(Xopenex HFA)

• Prevention & treatment of reversible bronchospasm

≥ 4Adults: 2 puffs q4-6hr prn

Peds: 2 puffs q4-6hr prn5-10 3-6

Levalbuterol Inhalation soln(Xopenex)


≥ 6Adults: 0.63-1.25 mg tid

Peds: 0.31-0.63 mg tid10-17 5-6 (up to

8 in some)

Pirbuterol MDI(Maxair Autohaler)


≥ 12Adults: 1-2 puffs q4-6hr prn

Peds: None≤ 5 5

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ORAL: Short Acting 2 –AgonistsDrug Indication(s) Age (yrs) Dose Onset

(min)Duration

(hrs)

Albuterol syrup• Relief of reversible

bronchospasm≥ 2

Adults: 2-4 mg q6-8hr

Peds: 0.1-0.2 mg/kg q8hr30 4-8

Albuterol tabs(VoSpire; extended release tabs)

• Relief of reversible bronchospasm

≥ 2 (for IR)≥ 6 (for ER)

Adults: 2-4 mg q6-8hr

Peds: 2 mg q6-8hr30 4-8

Metaproterenol syrup

• Prevention & treatment of reversible bronchospasm in asthma or COPD

≥ 6Adults: 20 mg tid - qid

Peds: 10 mg tid - qid30 ≥ 4

Metaproterenol tabs

• Prevention & treatment of reversible bronchospasm in asthma or COPD

≥ 6Adults: 20 mg tid to qid

Peds: 10 mg tid to qid30 ≥ 4

Terbutaline tabs

• Relief of reversible bronchospasm

• Tocolytic for premature labor (acute; short-term use)

≥ 6Adults: 2.5-5 mg tid

Peds: 2.5 mg tid30 4-8

5556

Dosing: short vs. long‐acting– Positive response in asthma is a 200 ml or 12% in FEV1

compared to baseline; (not the case for COPD)– Onset and duration of action in comparison short‐acting

anticholinergics– Inhaler techniques vary with MDI vs. DPI’s– Inhaler vs. nebulizer delivery– Use with exercise

Side Effects:– Tremor– Heart palpitations– Hypokalemia (Clinically insignificant – unless PO)– Reduction in O2 Sat (those not on O2 supplementation)

2 Agonists

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Levalbuterol (Xopenex): – Unlike racemic albuterol, levalbuterol is only the R‐albuterol isomer (active drug).

– Dose is half of racemic albuterol– Overall, no differences in side effect profile and increases heart rate as racemic albuterol.

– 3 x the cost of racemic albuterol

2 Agonists

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2 Agonists

Albuterol Levalbuterol


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Inhaled Corticosteroids: Mechanisms of Action

Direct action:– Inhibit cytokine‐induced production of pro‐inflammatory proteins

Indirect actions:– Alter production of m‐RNA

• Suppresses inflammatory system• Production of anti‐inflammatory mediators• Increase production of 2‐receptors • Decrease broncho‐hyperreactivity• Decrease mucus production/hyper‐secretion

Inhaled Corticosteroids

Drug Indication(s) Age (yrs) Dose Onset Max

Benefit

Beclomethasone MDI(QVAR)

• Maintenance of treatment of asthma as prophylaxis

• Asthmatics requiring systemic steroids that need to be reduced or stopped

≥ 5Adults: 40-320 mcg bid

Peds: 40-80 mcg bid

1-2 wks 3-4 wks

Budesonide inhlnpowder (Pulmicort Flexhaler; Pulmicort Turbuhaler) **PregCategory B**

≥ 6

Adults: Flexhaler=360-720 mcg bid; Turbuhaler=200-800 mcg bid. ** Once-daily dosing for mild asthmaPeds: Flexhaler=180-360 bid; Turbuhaler=200-400 mcg bid

24 hrs 1-2 wks

Budesonide inhlnsuspension(Pulmicort Respules)


≥ 6

Adults: none

Peds: 250-500 mcg bid or 250-1000 mcg daily

2-8 days 4-6 wks

Ciclesonide (Alvesco)*(pro-drug)

• Maintenance of treatment of asthma inpatients >12 yrs of age

≥ 12

Adults: 80-320 mcg bid; **Once-daily dosing for mild asthmaPeds >12 yrs: same as adult

1-4 wks 1-2 wks

Note: No COPD indications. 61

Inhaled CorticosteroidsDrug Indication(s) Age

(yrs) Dose Onset Max Benefit

Flunisolide MDI (AeroBid; AeroBid-M; Aerospan HFA –built in spacer)




Peds: 500 mcg bid

1-4 wks -

Fluticasone HFA(Flovent Diskus; Flovent HFA)




Peds: 88 mcg bid24 hrs 1-2 wks

Triamcinolone (Azmacort) *(built in spacer)


Peds: 200-600 mcg bid1 wk 2+ wks

Mometasone furoate inhalation powder(Asmanex)


≥ 4;≥ 12

Adults: 220-440 mcg bid (*440 mcg bid if on oral steroids); **Once-daily dosing for mild asthmaPeds: none

1-2.5 hrs 1-2 wks

Note: No COPD indications. 62

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Corticosteroids

Dosing Consideration During Exacerbation:– Step Down approach– Once controlled, decrease dose by 25% every 2 for at least 8 weeks

– Remember, late phase can take several weeks to resolve

– In patients with mild asthma, once‐a‐day dosing options exist for:

• Budesonide• Ciclesonide• Mometasone furoate

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Corticosteroids Oral or IV therapy:

– Burst therapy (10‐14 day course)– Tapering generally not necessary if less than 14 days of use

Side Effects:– If by inhalation: risk of thrush (rinse mouth)– Effects on bone growth– Adrenal suppression– Osteoporosis– Cataracts– Worsen glucose control (mainly in diabetics)– Avascular necrosis of the femoral head/neck– Elevation in WBC– Decreased thyroid function (decreases TSH secretion from

the pituitary)

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Corticosteroids Counseling:

– Inhaler technique based on the device– Use in the right order if on short acting bronchodilator

– Importance of daily use and not for acute exacerbations

– Rinse mouth with water after inhaler use to prevent oral thrush

• Candidiasis


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Top 10 Drugs in Pediatrics Seasonal (“hay‐fever”) vs. Perenneal (yr round) Nose normal function:

– Heat, warm, & clean air coming in Immune Response:

– Early: IgE Ab bind to allergen ‐> mast cells; release of pro‐inflammatory mediators within min and causes vasodilation (swelling & congestion)

– Late: Influx of WBCs, activation of lymphocytes Risk Factors:

– Family history, atopic dermatitis, asthma– Social & Environmental: active/passive smoking, pollen, mold, dust mites, animals, strong odors

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Background

Treatment Nonpharmacological:

– Allergen Avoidance

Pharmacotherapy– Antihistamines (oral, nasal sprays, ocular)– Intranasal Steroids– Leukotriene Modifiers

Immunotherapy– Allergy shots

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General Approach to Treatment

First‐line is typically to control symptoms in acute setting:– Antihistamines (oral, intranasal, or ocular)– Decongestants (both PO & topical)– Intranasal Steroids (Mod‐Severe Disease)

Maintenance Treatment:– Antihistamines (oral, intranasal, ocular)– Nasal Steroids (excellent for & is usually first line in perennial rhinitis)

– Addition of a leukotriene modifier (mainly montelukast)– Immunotherapy for resistant or specific cases

Ann Allergy Asthma Immunol 1998;81:478-518. 70

Medication Therapy

Medication Congestion Itching Runny Nose Sneezing

Anticholinergics - - +++ -

Antihistamines + +++ ++ +++

Cromolyn Sodium + + + +

Decongestants +++ - - -

Leukotriene Receptor Blockers + + + -

Intranasal Steroids ++ +++ +++ +++

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Antihistamines Competitively inhibit H1 receptors preventing binding by

histamine. They are more effective at preventing the actions of histamine than reversing it. – H1 activation in the central nervous system (CNS) is needed for

wakefulness; if antagonized can cause sedation and appetite and cognitive & psychomotor performance and neurotransmission in the CNS

– Very little H2 receptor antagonism– (1st generation antihistamines mainly): Have cross antagonist

reactivity/inhibition of muscarinic receptors in the CNS which can result in anticholinergic side effects (causing dry mouth, urinary retention, constipation, increase pulse).

• The older, first generation can also interact with alpha receptors, 5‐HT receptors, and human ether‐a‐go‐go (hERG) K+ ion channels (why older agents contributed to cardiac toxicity).

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1st Generation (“Sedating”): AntihistaminesDrug Dosage Form Adult Dose Ped Dose Misc

Brompheniramine (Dimetane)

4mg, 8 mg LA, 12 mg SR, 2mg/5cc

4 mg q4-6h(max 24 mg/d)

Age <6: 1mg q4-6Age 6-12: 2-4 mg q4-6h; max 12mg/d

Often 1-2nd choice, less sedation (30%) compared to others

Carbinoxamine(Arbinoxa; Palgic)

4 mg scored tab; oral solution = 4 mg/5 cc 4-8 mg q6-8 hrs

Age 2-5: 0.2-0.4 mg/kg/d in 3-4 divided doses

Take on empty stomach. Avoid in ages < 2 & elderly

Chlorpheniramine (Chlor-Trimeton)

4mg, 8 mg LA, 12 mg SR, 2 mg/5cc

4 mg q4-6h(max 24 mg/d)

Age <6: 1mg q4-6Age 6-12: 2-4 mg q4-6h; max 12mg/d

Often 1-2nd choice, less sedation (30%) compared to others

Clemastine(Tavist)

1.34, 2.68 mg, 0.5mg/5cc

1.34-2.68 mg BID(max 8.04 mg/d)

Age 6-12: 1-2 tsp BID

Children may experience sedation or paradoxical effect

Cyproheptadine(Periactin)

4 mg tablet; syrup = 2 mg/5 cc (473 mL, 480 mL bottles)

4-20 mg/d in 3 divided doses

2-6 yrs: 2 mg q8-12 hrs7-14 yrs: 4 mg q8-12 hrs

Other uses: Spasticity in SCI, Migraine prophylaxis in peds, appetite stimulant.

Diphenhydramine(Benadryl)

25, 50, 12.5 mg/5cc25-50 mg q4-6 h(max 300 mg QD)

Age 2-6: 6.25 mg q4-6h (max 37.5 mg)Age 6-12: 12.5-25 mg q4-6 (max150)

> 30% incidence of sedation, confusion, dizziness, etc..

Hydroxyzine(Atarax; Vistaril)

10, 25, 50, 100 mg, 10mg/5cc, 25 mg/5cc 25-50 mg TID-QID

Age 2-6: 50 mg in 3-4 divided dosesAge 6-12: 50-100 in 3-4 divided doses 73

2nd Generation (“Non‐Sedating”): Antihistamines

Drug Dosage Form Adult Dose Ped Dose MiscOral Drugs

Cetirizine(Zyrtec)

5, 10 mg, 5mg/5cc 10 mg qd

Age 6-11 month: 2.5 mg qdAge 12-23 month: 2.5-5 mg QD

10-15% of pts sedation compared to others (due to being an acid metabolite of hydroxyzine (Atarax), long-acting; give qhs; now OTC

Levocetirizine (Xyzal)

5 mg tabs 5 mg qd Ages 6-11: 2.5 mg qd

Is active (S) enantiomer of cetirizine; potency (30-fold) & H1 receptor dissociation

Loratadine(Claritin)

10 mg, 10 mg Reditab,5mg/5cc 10 mg qd

Age 2-5: 5 mg qdAge >6: 10 mg qd

Metabolized by 2D6, 3A4 to desloratadine. Available OTC

Desloratadine(Clarinex)

5 mg tab, 5 mg Reditab 5 mg qd 12: 5 mg qd

Metabolite of loratadine; more potent H1 blocker and longer half-life.

Fexofenadine(Allegra)

60 mg cap, 30, 60, 180 mg tab

60 mg BID or 180 mg qd

6-11: 30 mg bid12: 60 mg bid or 180 qd

Metabolite of terfenadine (off market due to QT prolongation). Caution with hepatic dysfunction; about 10% of pts get sedation

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Side Effect Profiles First Generation Antihistamines:

– Cross the BBB and has cross antagonist reactivity with muscarinic receptors in addition to histamine receptors, thus resulting in anticholinergic effects

– Anticholinergic side effects – confusion, dizziness, urinary retention, xerostomia (dryness), diplopia, glaucoma (intraocular pressure)

Second Generation Antihistamines:– Do not readily cross the BBB and thus do not inhibit H1 receptors that cause the sedation

– With the exception of cetirizine (Zyrtec), most are considered “non‐sedating” and less anticholinergic side effects. Since cetirizine is the metabolite of hydroxyzine and thus shares structural similarities it is can act centrally to a small degree = sedation

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Side Effect Profiles Cardiac Safety Issues:

– Due to terfenadine and astemizole (affected the hERG K+ ion channels thereby contributing to QT prolongation and torsades de pointes); now taken off market. The metabolite of terfenadine (i.e., fexofenadine) not a concern. Both were also CYP3A4 substrates and interactions worsened risk.

– Current 2nd generation antihistamines don’t have this toxicity

Overdoses (mainly concerned with 1st generation):– Hyperthermia– Excessive dryness – Flushed skin– Dilation of pupils +/‐ blurred vision– Altered mental status– Need to rule out other causes: e.g., encephalitis, metabolic and electrolyte abnormalities.

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Mechanism of Action: Intranasal Steroids

Arachidonic Acid

Leukotrienes (LT)‐LTB4 (chemotaxis & activation neutrophil

adhesion)‐LTC4, D4, E4 (vasoconstriction, vascular

permeability, bronchoconstriction)

Prostaglandin (PG)H2

PGE‐ PGE2 (vasodilation, pain, fever)‐ PGI2 (vasodilation, inhibit platelet

aggregation)

TXA2‐Vasoconstriction‐Plt aggregation

Thromboxane SynthetaseProstaglandin Synthetase

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Phospholipase A2

5‐Lipoxygenase Cyclooxygenase (COX)

Aspirin

Steroids(‐)

(‐)

NSAIDsCOX‐2’sSteroids

(‐)

Zileuton

(‐)

MontelukastZafirlukast

(‐)

Misoprostol(PGE1 analogue)

(+)

Cell Membrane


78


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Leukotriene Modifiers

Leukotriene Receptor Antagonists:– Montelukast (Singulair)– Zafirlukast (Accolate)

5‐Lipoxygenase Inhibitor:– Zileuton (Zyflo; Zyflo CR) – taken off the market and now back on by another company

Mechanism of Action: Leukotriene Modifiers

Arachidonic Acid

Leukotrienes (LT)‐LTB4 (chemotaxis & activation neutrophil

adhesion)‐LTC4, D4, E4 (vasoconstriction, vascular

permeability, bronchoconstriction)

Prostaglandin (PG)H2

PGE‐ PGE2 (vasodilation, pain, fever)‐ PGI2 (vasodilation, inhibit platelet

aggregation)

TXA2‐Vasoconstriction‐Plt aggregation


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Phospholipase A2


Aspirin

Steroids(‐)

(‐)

NSAIDsCOX‐2’sSteroids

(‐)

Zileuton

(‐)

MontelukastZafirlukast

(‐)

Misoprostol(PGE1 analogue)

(+)

Cell Membrane

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Leukotriene ModifiersDrug Dosing Age

(yrs) Notes

Leukotriene Receptor Antagonist

Montelukast (Singulair)

5-10 mg daily in the evening (if

used for asthma) 2

FDA approved for asthma, allergic rhinitis, & EIA. Preg B; CYP2C9, 3A4 substrate; CYP2C8 inhibitor; no interactions with theophylline, digoxin, fexofenadine. If taking for allergies time of day for administration does not matter.

Zafirlukast (Accolate)

20 mg bid on empty stomach

(1-hr before or 2-hrs after a meal)

5

FDA approved for asthma. Preg B; CYP2C9 major substrate; Inhibitor of 1A2, 2C9, 2D6, 3A4. Interacts with warfarin. Taking with food decreases bioavailability 40%.Cases of hepatotoxicity, eosinophilia, vasculitis. Monitor AST/ALT. Avoid with breastfeeding due to tumorigenicity seen with animal studies.

5-Lipoxygenase Inhibitors

Zileuton (Zyflo; Zyflo CR)

Zyflo: 600 mg qid with food

Zyflo CR: 600 mg bid within 1

hour of food

12

Preg C; CYP1A2, 2C9, 3A4 minor substrate; Inhibitor of 1A2; interactions with theophylline, warfarin, propranolol. Common SE: HA (> 10%) Cases of hepatotoxicity (mainly in older females). Monitor AST/ALT baseline, then monthly x 3, then q2-3months thereafter. Avoid with ETOH due to risk of liver toxicity.


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Nonopioid Adjuvant(s)

Weak Opioid Adjuvant(s)

Strong Opioid Adjuvant(s)

Adjuvant(s) Strong Opioid

Adjuvant(s)Weak Opioid

Adjuvant(s) Nonopioid

World Health Organization (WHO)Treatment Ladder

MildPain

ModeratePain

SeverePain

Predominantly Nociceptive Pain Predominantly Neuropathic Pain

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Ceiling effect Route of administration Pill burden Tolerance Physical Dependence Patient specific factors:

– Side effects from other medications– Liver function (specifically synthetic function)– Whether opioid requires activation– Dosage form– Don’t forget about treating depression!

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Drug Therapy Considerations

Non‐Opioid Agents– Acetaminophen, NSAIDs– Formulations: Transdermal/Topical, Oral, Parenteral

Opioids– Agonists/antagonists, Weak Opioids, Strong Opioids– Formulations: Transdermal/Topical, Oral, Parenteral

Adjuvants– Antidepressants– Anticonvulsants

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Drug Categories Mechanism of Action: NSAID

Arachidonic Acid

Leukotrienes (LT) Prostaglandin (PG)H2

PGD2PGE2PGF2

TXA2


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Phospholipase A2 (PLA2)


Cell Membrane Phospholipid

TXB2

PGE

PlateletAggregation

ThrombusFigure. Mechanism of action of aspirin and NSAIDsCopyright. Pharmacology Weekly, Inc.

(‐) (+)

Aspirin Ibuprofen

(‐) (‐)

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