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THE NOTION BEHIND THE NOTION BEHIND NEONATE DOSINGNEONATE DOSING
Eric Okazaki, Pharm.D.
PGY-1 Pharmacy Resident
St. Alphonsus Regional Medical Center
ISHP Fall Conference 2014
Introduction:
Why do we do the things we do?
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http://eocpr.com/wp-content/uploads/2012/04/Red-Cross-CPR-Certification-6.jpg
http://www.advantagecpr.org/
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Introduction
• Standard concentrations
• Separate medications
• Label medications
• Double Checks
Images from:
http://blog.cdhcpa.com/wp-content/uploads/2013/12/why3.jpg
http://www.123rf.com/photo_16603415_abstract-word-cloud-for-patient-safety-with-related-tags-and-terms.html
Goal
• Provide information that will enhance the thought process
(generate questions) for each action.
Event• Medication ordered
Guidelines
• ISMP, JACHO, Polices and Procedures act as guides
Action
• Carry out the action according to guidelines
Result• Patient Safety
Image from:
http://dievinti.blogas.lt/
Puppet Puppet = React= React
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Goal
• Provide information that will enhance the thought process
(generate questions) for each action.
Event• Medication ordered
Guidelines
• ISMP, JACHO, Polices and Procedures to provide direction
Thought
• Understand the WHY behind the directions
Action
• Carry out the action understanding the guidelines
Result• Enhanced Patient Safety
Image from:
http://messingwiththemind.blogspot.com/2010_10_22_archive.html
Act = PuppetAct = Puppet--MasterMaster
Objectives
• CONCEPT:Explain the basics principles that describe how the body handles medication when it enters the body (ADME properties).
• CONCEPT: Point out the differences between neonate and adult physiology.
• APPLY:Use these concepts to review medications used in the Neonatal Intensive Care Unit.
• DISCUSS:Review how these concepts will allow us to question/think about our actions—improve results (patient safety)
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Objectives
Concept:
• ADME properties
Concept:
• Differences in Neonate and Adult Physiology.
Apply:
• Use both concepts to review common medications used in the ICU.
Discuss:
Review how this
understanding will
enhance our actions.
Concept: ADME
Pharmacokinetics: The timeline of events that represents the manner in which the body deals with medications.
Explained in 4 steps: ADME properties
(A): Absorption—Getting the drug into the body
(D): Distribution—Getting the drug to its action site
(M): Metabolism—Breaking down the drug into metabolites
(E): Excretion—Removing the drug and its metabolites
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Concept: ADME
Absorption: The process by which the drug gets into the
body and into circulation.
Image from:
http://www1.genesishealth.com/services/bariatric_surgery/digestive_diagram.aspx
Oral Route = Mouth, Stomach,
Intestine
Topical Route = layers of the
skin
Rectal Route = lower 2/3 of
rectum
IV Route = immediate
Concept: ADME
Distribution: The process by which
the drug gets to its sites of activity in
the body.
• Properties of the drug determine
where it can and cannot “spread”
- Hydrophilic, lipophilic, protein bound,
molecule size, charge, etc.
- Vd = Volume drug distributes in body
• Drug properties stay constant, our
bodies are different
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http://www.paradoja7.com/human-circulatory-system-pictures/human-circulatory-system-pictures/
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Concept: ADME
Metabolism: The process by which the drug is broken down
in the body.
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http://www.8ball.co.uk/retro-asteroid-mens-t-shirt
• Phase I and II enzymes break down drugs in preparation for excretion from the body.
• Original form of the drug is altered into a metabolite which may or may not be active.
• Not all drugs are metabolized in the body.
(P-450
Enzymes)
(Metabolites)
(Parent Drug)
Concept: ADME
Excretion: The
process by which the
body removes the drug.
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http://classes.midlandstech.edu/carterp/Courses/bio211/chap25/chap25.htm
• The drug and the metabolites are
removed from the body usually as
urine or feces.
• Not everything is completely
removed
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Neonates are not small adults, they are not small children,
their bodies are different: Human growth is not a linear
process!
• Physiological changes occur dynamically
- Hours: cardiopulmonary physiology
- Weeks: renal/hepatic function
- Months: gastric function
- Years: musculoskeletal development
These changes impact ADME properties!These changes impact ADME properties!
Concept: Physiology
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http://threeboysandanoldlady.blogspot.com/2013/10/green-giant-raise-giant-25-gift-card.html
http://brucebradley.com/food/gerber-a-broken-promise/
Concept: Physiology + ADME
Absorption: Getting the drug into the body
GI tract • Reduced acid production, less acidic• GI emptying is irregular• Gastro-esophageal reflux• Splanchnic blood flow decreased• Longer GI absorption times in neonates• Increased rectal absorption (hepatic/contractions)
Topical• Greater hydration, greater perfusion of the skin• Greater surface area: mass ratio
Intramuscular• Less skeletal muscle blood flow
Intravenous• Vein size, irritability, concentrations, location
Image from:
http://www1.genesishealth.com/services/bariatric_surgery/digestive_diagram.aspx
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Concept: Physiology + ADME
Distribution: Getting the drug into the body
• Neonates have greater extracellular and total body water
spaces
• Greater body water composition
• Limited volume requirements
• Less plasma proteins (i.e. albumin)
• Increased endogenous substances (i.e. bilirubin)
• Greater BSA: Mass ratio
• Less lean mass
Image from:
http://www.paradoja7.com/human-circulatory-system-pictures/human-circulatory-system-pictures/
Concept: Physiology + ADME
Metabolism: Breaking down the drug into metabolites
• Phase I and II enzymes are rapidly changing:- CYP3A7 enzyme predominant in fetal liver
- CYP2E1 surges hours after birth
- CYP2C9 and CYP2C19 appear at 1 week
- CYP1A2 is a late bloomer at 1-3 months
- Glucuronidation is decreased
…and many more
* Hepatic metabolism is increased in ages < 10 years compared to adults
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Concept: Physiology + ADME
Excretion: Removing the drug and its metabolites
• Nephrogenesis occurs between 9 – 36 weeks
• Filtration: Low renal blood flow (5-6%, adult 15-25%)
• Tubular reabsorption: Less in neonates
• Tubular secretion: Greater in neonates
Image from:
http://classes.midlandstech.edu/carterp/Courses/bio211/chap25/chap25.htm
Concept: Physiology + ADME
• Gastric Function
• Integument
• Body Composition
• Metabolic Function
• Renal Function
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Examples: Absorption
Lidocaine/Prilocaine (EMLA)
(Topical Absorption)
Caution: EMLA dosing is restricted by age (<37 weeks)
and weight, system toxicity
Reason: * Neonates (preterm) absorption is improved
* BSA to weight ratio
* Metabolism (CYP3A4)
Image from:
http://www.rxzone.us/product.cfm/rx/Emla-Cream-30-GM-234377.html
Examples: Distribution/Metabolism
Ceftriaxone
(Vd and Metabolism)
Caution: Hyperbilirubinemia, risk of kernicterus, andcalcium interaction
Reason: * Increased bilirubin levels
* Decreased plasma proteins
* Displacement of bilirubin
* Decreased UGT metabolism
Images from:
http://www.acesurgical.com/rocephin-1gm-vial.html
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Examples: Metabolism
Caffeine Citrate
(Metabolism)
Caution: Used in apnea of prematurity, delayed onset
of side effects
Reason: * Metabolism by CYP1A2
* Longer half-life, renal excretion
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http://www.fresenius-kabi.us/preservative-free/product-175.html
Examples: Metabolism
Benzyl Alcohol
(Metabolism)
Caution: “Gasping Syndrome”
Reason: * Multiple items may contain benzyl alcohol
* Glycine-conjugation
* 99 mg/kg
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http://www.naturesriches.co.in/product/benzyl_alcohol
http://advancedgraphics.com/product/wreck-it-ralph-slam-disneys-wreck-it-ralph/
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Examples: Excretion
Gentamicin
(Excretion)
Caution: Dosing needs to be adjusted per changes in
renal function
Reason: * Body water distribution
* Improving renal function
Image from
https://www.uichildrens.org/uploadedFiles/UIChildrens/Health_Professionals/Iowa_Neonatology_Handbook/Pharmacology/Antimicrobial.pdf
ADME “CASE”
Lasix (furosemide) is a diuretic used in the neonate
population. Tertiary medication resources caution its use in
neonates <32 weeks due to accumulation and variable
availability in the body. What is actually happening?
* ECW 44.5% in neonates, 18.7% in 10-15 yo
* ECW at (Day 1): 1,473 mL, (Day 2): 516 mL
* Binding to albumin
* Metabolized into inactive metabolites
* GFR 2-4 ml/min in neonate, 120 ml/min in adults
* Renal tubule function
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How does this Apply?
• What does this mean in the community setting?
• What does this mean in the hospital setting?
• What does it impact?
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• Drug delivery
• Pulling of stock
• Medication preparation
• Product labeling
• Double check
Recap:
• The body's ability to absorb, distribute, metabolize, and
excrete a drug is based on the patient’s physiology
• Most drugs are prepared and studied for use based on
adult physiology
• Dosing for neonates is not based on a straight linear
percent reduction of the adult dose
• Knowing the differences in physiology can help us utilize
ADME principles to deliver appropriate neonate dosages
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Recap:
• Not all doses are going to be smaller than adults
• Notice the route
• Notice the formulations
• Notice the volumes
• Notice the concentrations
• Notice the decimals
• ASK QUESTIONS!
Remember…
Understand why, ask questions…
…Become a Puppet-master!
What questions do you have?
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http://www.mmm-online.com/ddr-on-dtc-abilify/article/242294/
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References:• DiPiro, J. T. Pharmacotherapy: A pathophysiologic approach. 6th ed. New York, New York: McGraw-Hill Medical, 2005.
• Takemoto, C.K., Hodding, J.H., Kraus, D.M. Pediatric & neonatal dosage handbook: a comprehensive resource for all clinicians treating pediatric and neonatal patients. 19th ed. Hudson, OH: Lexi-comp, 2012.
• Trissel, L.A. Handbook on Injectable Drugs. 15th ed. Bethesda, MD: American Society of Health System Pharmacists, 2011.
• Thomson Reuters. NeoFax: 2011. 24th ed. Montvale, NJ: Physicians Desk Reference Inc., 2011.
• Phelps, S.J., et al. Pediatric injectable drugs: the teddy bear book. 9th ed. Bethesda, MD: American Society of Health-System Pharmacists, 2010.
• Ginsberg G, et al. (2002). Evaluation of child/Adult Pharmacokinetic Differences from a database Derived from the TherapeuticDrug Literature. Toxicological Science 66:185-200.
• Kearns, G. et al. (2003). Developmental Pharmacology—Drug Disposition, Action, and Therapy in Infants and Children. The New England Journal of Medicine 349(12): 1157-1167.
• Fernandez, E. et al. (2011). Factors and Mechanisms for Pharmacokinetic Differences between Pediatric Population and Adults. Pharmaceutics 3:53-72.
• Pacifici, GM. (2013). Clinical Pharmacology of Furosemide in Neonates: A Review. Pharmaceuticals 6(9):1094-1129.
• Usher, R., Shepherd, M., Lind, J. (1963). The Blood Volume of the Newborn Infant and Placental Transfusion. Acta Paediatrica 52(5):497-512.
