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pharm midterm > basic principles of neonatal pharm > Flashcards

basic principles of neonatal pharm Flashcards

1
Q

neonates are at inc risk for what?

A

experience adverse drug reactions and exposure via intrauterine environment

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2
Q

what can sulfonamies and ceftriaxone lead to in this population?

A

kernicterus

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3
Q

what can chloamphenicol lead to in this population?

A

grey baby syndrome; unable to metabolism the abx

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4
Q

what can benzyl alcohol lead to in this population?

A

gasping syndrome

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5
Q

what is pharmocokinetics?

A

what your BODY does to the DRUG

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6
Q

What is ADME?

A

Absorption (bioavailability)
Distribution (vol of distribution)
Metabolism
Excretion (clearance, half life and rate constant)

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7
Q

ADME are all processes that can be classified as what?

A

mechanisms of pharmacokinetics

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8
Q

What is half life?

A

T 1/2; in the process of elimination it is the time needed for the drug concentration to be decrease by 1/2.

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9
Q

What are routes of absorption?

A

intravenous, gastrointestinal, rectal, intramuscular, percutaneous, intraosseous, intrapulmonary/ inhaled

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10
Q

What is bioavailability?

A

F; it characterizes the extent of drug absorption and is the amount of drug that enters systemic circulation

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11
Q

What does F=1 indicate?

A

100% drug available for absorption; meaning all the drug was administered; more likely in IV route than PO (F<1)- r/t first pass metabolism

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12
Q

What is the rate of absorption?

A

not the same as bioavailability; the rate of absorption dictates the onset of effect and determines the duration of effect

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13
Q

How do oral drugs undergo metabolism prior to reaching systemic circulation?

A

blood from the intestinal tract that contains the absorbed drug is carried to the liver by the portal win where it can be metabolized before reaching the general systemic circulation (first pass metabolism)

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14
Q

What is one example of first pass metabolism and its implications for absorption and bioavailability?

A

morphine; it has excellent absorption but because of first pass metabolism, has low bioavailability as a PO medication

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15
Q

What routes are vulnerable to limited bioavailability?

A

PO, IM, subQ, rectal and inhaled

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16
Q

how does the rate of absorption differ in neonates as compared to adults?

A

oral liquids have a faster absorption

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17
Q

What are the factors affecting physicochemical absorption?

A

formulation of med (disintegration, dissolution, sustained-release), molecular weight, pKa, stability of gastric pH, lipid solubility

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18
Q

What are the patient factors affecting medication absorption?

A

first pass metabolism, co-admin with food, erratic gastric contents and/or emptying time, GIT pH, surface area, size of bile salt pool, bacterial colonization and underlying disease state (ex: short gut)

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19
Q

In general how is first pass metabolism affected in the neonatal patient?

A

it is lessened r/t hepatic immaturity

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20
Q

What is first pass metabolism?

A

it is gut metabolism + liver metabolism; drugs are absorbed through the gut, then enter the liver via the hepatic vein

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21
Q

What are the unique nutritional obstacles to medication administration in this specific population?

A

frequent feeding: Q3 or continuous; consistent buffer in the stomach; very difficult to achieve a true fasting state

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22
Q

What are the unique gastric emptying obstacles to medication administration in this specific population?

A

gastric emptying is erratic in infants, slower than adults (reaches adult levels by 6-8 mo), contributes to reflux, affects time drug reaches small intestine (major absorption site) and affected by caloric density of feeds

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23
Q

What are the unique gastric motility obstacles to medication administration in this specific population?

A

gastric motility is irregular in infants, uncoordinated peristalsis, longer transit time (8-96 hours in infants/ 4-12 in adults)

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24
Q

What are the unique gastric pH obstacles to medication administration in this specific population?

A

less acid production (inc pH)- term infant at birth pH 6-8, drops to 1-3 by dol 1; preterm infant takes longer to normalize (~3 wk)- immature acid production; acid production correlates with PNA, not corrected age

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25
Q

Why is gastric pH important in pharmacokinetics?

A

it affects the stability and degree of ionization of a drug; if molecules carry a charge, the stomach does not readily absorbed charged substances; inc absorption of acid labile Rx (penicillin, amp, nafcillin) and dec absorption of weak acid Rx (dilantin, phenobarb)

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26
Q

What are the unique GIT surface area obstacles to medication administration in this specific population?

A

small gut surface area decreased in infants as compared to adults

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27
Q

What are the unique pancreatic obstacles to medication administration in this specific population?

A

pancreatic fx is impaired; dec rate of synthesis, pool size and intestinal transport

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28
Q

Rx absorption can also be affected by gut flora. What affects the presence/ colonization of gut flora in infants?

A

age of infant, delivery method, feeding type and current Rx therapy (ex: acid suppressant)

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29
Q

What is an example of a Rx affected by immature gut flora in neonates?

A

digoxin, the rate of metabolism is reduced in an uncolonized tract

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30
Q

How does GIT permeability differ in the neonate?

A

increased permeability

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31
Q

How does reflux affect absorption?

A

unpredictable loss of drug

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32
Q

How does short bowel syndrome affect absorption?

A

decreases surface area of absorption

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33
Q

How do cardiac defects affect absorption?

A

shunting blood away from the GIT decreases the rate of absorption

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34
Q

How does hypo-/hyperthyroidism affect absorption?

A

can inc or dec GI transit time

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35
Q

What are the advantages to renal administration?

A

less first pass metabolism (absorbed directly into hemorrhidal veins- lower rectum absorbed into system; upper rectum absorbed into portal vein), alternative to PO if there is no PIV access (seizures, aspiration risk, NPO, emesis)

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36
Q

What are the disadvantages to renal administration?

A

erratic absorption, infant specific doseage is not readily available, may be expelled before fully absorbed

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37
Q

What factors can determine IM absorption?

A

blood flow to the injection site (pt with impaired peripheral perfusion should not be given IM meds), muscle mass and muscle activity

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38
Q

How is IM absorption altered in neonates as compared to adults?

A

less muscle mass, poor perfusion to various muscles, peripheral vasomotor instability and insufficient muscle contractions

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39
Q

What are examples of IM medications given to neonates?

A

amp, gent, vit K, ceftriaxone

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40
Q

What is the state of percutaneous absorption in neonates?

A

it is enhanced in infants

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41
Q

Why is percutaneous absorption enhanced?

A

thinner stratum corneum (> with lower GA), inc blood flow to the skin, in total body surface area, can result in systemic exposure of topical meds (steroids, antiseptics)

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42
Q

How does aquaphor affect neonatal skin?

A

in skin integrity and decreases losses

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43
Q

Why is IO a chosen route of administration?

A

bone marrow is highly vascularized (up to 5 yr old), alt to IV/IM, occasionally done in transport situations

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44
Q

What is the goal of intrapulmonary drug administration?

A

to concentrate med to a localized area that is the target of the intervention although systemic absorption can occur

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45
Q

what are examples of meds administered via intrapulmonary route?

A

dexamethasone, budesonide and tobramycin

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46
Q

What are the obstacles to intrapulmonary medication absorption?

A

developmental changes alters the capacity of lungs and patterns of drug deposition

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47
Q

what determines drug distribution in the neonate?

A

the binding affinity of drugs for proteins, if the med is hydrophillic/lipophilic, body composition (% of extracellular fluid and total body water), molecular weight, degree of ionization at body pH and hemodynamic factors (cardiac output)

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48
Q

What are three examples of classically hard to treat infections in the NI?

A

osteomyelitis, meningitis (difficult rx access r/t BBB) and endocarditis

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49
Q

what is volume of distribution?

A

the theoretical volume that the total amount of drug administered would have to occupy (if distributed evenly) to provide the same concentration as is currently in the blood plasma Vd= A/Cp

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50
Q

Why is the binding of drugs to protein carriers dec in the neonate (specifically albumin)?

A

dec amount of plasma proteins, lower binding capacity, decreased affinity for proteins and competition for binding sites (if Rx dominates, albumin it leaves more unconjugated bili> kernicertus

51
Q

what is the result of less protein binding?

A

more “free” active drug leaving drug to distribute out of the plasma into tissues inc the Vd; ex: dilantin- monitor free levels

52
Q

How is distribution affected by total body water?

A

newborns have a higher proportion of extracellular fluid (interstitial + plasma) and total body water (50% of baby; <20% adults)

53
Q

What is the effect of an increase in extracellular fluid typical of newborns?

A

increase in ECF= increase Vd; drugs that are hydrophillic will have a very large Vd (amino glycosides- gent, tobra, amikacin)

54
Q

What are the special considerations for aminoglycosides in neonates?

A

increased mg/kg dosing needed (r/t inc Vd); ex gent dosing in the NI= 4-5mg/kg (in adult it’s 1mg/kg

55
Q

What are the special considerations when dosing premature infants with regards to adipose tissue?

A

less body fat; drugs that are lipophillic will have a smaller Vd

56
Q

What are the special considerations for a neonate on ECMO?

A

the ECMO circuit doubles the blood vol of the baby

57
Q

the clearance of most drugs is dependent upon what?

A

the initial hepatic metabolism and following excretion of parent drug/metabolites by the liver or kidney

58
Q

What organs are responsible for metabolism medications?

A

primarily the liver, but also: kidneys, skin, lungs and intestine

59
Q

What are the special considerations with regard to hepatic metabolism in neonates?

A

various hepatic pathways responsible for drug metabolism mature at different times; infants have delayed maturation of drug metabolizing enzymes

60
Q

What is the function of Phase I (CYP enzymes)?

A

oxidation, hydrolysis, hydroxylation and reduction

61
Q

What is the function of Phase II (synthetic metabolism)?

A

conjugation, glucuronidation and sulfation

62
Q

How does hepatic metabolism biotransform medications?

A

it turns non-polar, lipid soluble Rx into polar, water soluble, transforms inactive parent drug (prodrug) into the active drug and changes medications into active metabolites

63
Q

What occurs in Phase I metabolism via the CYP450 system?

A

the absolute mass of enzymes is decreased; measured by the absolute weight as a percent of the liver

64
Q

What is an example of phase I metabolism immaturity in the neonate?

A

diazepam; hydroxylation function is deficient in newborns resulting in a longer half life

65
Q

What is an example of phase II metabolism immaturity in the neonate?

A

methylation is present in newborns but not adults; ex: theophylline infants methylate theo into caff; at 4-6 mo oxidative pathways mature thereby inc CL of caff (shortening T1/2)

66
Q

What is an example of phase I metabolism that is not different from adults?

A

sulfation reaches adult levels at birth; ex: acetaminophen; thereby infants are less susceptible to toxicity, infants conjugate with sulfate

67
Q

What occurs in glucuronidation in phase II metabolism?

A

not mature until 3yrs, resulting in slower CL requiring sm doses; ex: chloramphenicol accumulates if allowances are not made for this difference can result in grey baby syndrome

68
Q

what are symptoms of grey baby syndrome?

A

abd distension, vasomotor collapse and may ultimately lead to death

69
Q

When does alcohol dehydrogenase mature?

A

5 yrs old

70
Q

What is clearance?

A

a measurement of drug elimination; vol of blood/plasms from which drug is completely removed per unit of time

71
Q

What organs are responsible for the most drug elimination?

A

liver and kidney

72
Q

what is first order elimination?

A

clearance remains constant over the range of concentrations; ‘linear PK”; increase in dose will result with proportional increase in drug concentration; ex: gent

73
Q

what is zero order elimination?

A

clearance is NOT independent of drug concentration; “non linear or Michaelis-Menten” elimination; capacity limited/ saturable drug elimination; sm inc in dose can = lg inc in concentration; ex: phenytoin (have given more Rx than a pathway can handle, CL is overwhelmed)

74
Q

what is the primary site of drug metabolism?

A

hepatic clearance; also responsible for ultimate drug clearance

75
Q

what factors impact hepatic CL?

A

a Rx affinity for certain hepatic enzymes, hepatic blood flow, protein binding, liver disease and cardiac fx

76
Q

what comprises total renal clearance?

A

GFR+ tubular secretion- tubular reabsorption

77
Q

what is secretion with regards to renal elimination?

A

active transport

78
Q

what is reabsorption with regards to renal elimination?

A

lipid soluble or non-ionized Rx able to diffuse through membrane

79
Q

how are water soluble meds usually secreted through the kidneys?

A

excreted intact with no change to drug

80
Q

What characterizes GFR in the newborn?

A

totally dependent on blood flow and protein binding, physiologically dec, preemies 2-4 fold dec v term; inc rapidly by yr 1; inc in CO + ∆ in renal vascular resistance = inc renal perfusion

81
Q

why is UOP something to be monitored when giving indomethacin/ibuprofen for PDA tx?

A

dec prostaglandins= dec vasodilation = dec renal perfusion

82
Q

What factors affect GFR in the neonate?

A

GA; accelerated increase postnatally (even in ELBW); recommended to ∆ dose regimen during the first 4 weeks of life

83
Q

How should neonates by dosed with gent as it r/t renal elimination?

A

4-5mg/kg Q 24-48h; children 2.5mg/kg Q 8-12h

84
Q

What is the gold standard of GFR?

A

creatinine clearance

85
Q

What is creatinine?

A

100% filtered at the level of the glomerulus; only slightly secreted by tubular cells; not reabsorbed by the tubules; CrCl will NOT factor in secretion of reabsorption of drugs

86
Q

When will maternal cr levels become less significant?

A

> 48h postnatally

87
Q

What is typical of levels of SCr in ELBW infants?

A

very high levels

88
Q

How can GFR be estimated in neonates?

A

there are age-specific equations although not as precise as adults; generally less SCr and with transplacental SCr

89
Q

What is the equation for estimating GFR?

A

the schwartz equation
eGFR=(k x height in cm)/ Cr mg/dL
k= constant of proportionality that is age specific; <1yo term= 0.45

90
Q

With regard to nephrons, which function matures first: tubular secretion of glomerular maturity?

A

glomerular maturity (by 1 yo age tubular secretion is fully fx); tubular secretion is an active process b/c it goes against the concentration gradient by utilizing transporter proteins

91
Q

what is an example of tubular secretion immaturity?

A

lasix potential has a blunted effect due to immaturity of secretion into intraluminal space (cannot get to the site of action)

92
Q

how do drug-drug interactions occur and what is their cumulative affect?

A

d-d interactions can occur if both are eliminated through the same tubular secretion protein leading to dec secretion, increased drug levels and increased side effects

93
Q

what are examples of d-d interactions with tubular secretion?

A

probenecid competes with PCN for secretion resulting in inc PCN levels; Ampho B can cause renal tubular toxicity and ∆ secretion of other meds

94
Q

what is renal P-Glycoprotein?

A

it is a transporter involved in tubular secretion; d-d interactions possible via inhibitors or inducers; ex: digoxin (substrate) + erythromycin (inhibitor) = inc dig levels

95
Q

What is the effect of a PDA on Vd?

A

a PDA can inc Vd; it also dec renal perfusion

96
Q

With NSAID administration for tx of PDA, what medications should be closely monitored?

A

renally eliminated meds including gent and vanc

97
Q

What is the net effect of dopamine on GFR?

A

used frequently in the NI for hypotension and oliguria; can result in inc renal perfusion thus inc GFR; beginning dopamine can potentially result in subtherapeutic levels of renal excreted meds

98
Q

What is the net effect of lasix on GFR?

A

lasix is a loop diuretic; must be excreted into the luminal side of the renal tubule in order to inhibit chloride reabsorption (effectiveness depends on renal fx), inc renal perfusion through prostaglandin activation (vasodilation)- PGE may blunt response to PDA tx with indomethacin

99
Q

Why is elimination rate constant (K) important?

A

can be used to predict concentration at any time

K= 0.693/ T 1/2

100
Q

After 3.3-5 half lives what remains in the body?

A

at the same dose concentration is at 90-97% of final stead state concentration

101
Q

What is pharmacodynamics?

A

what the DRUG does to the BODY; ex: opioid receptors develop earlier in the respiratory and cardiac centers of the brain

102
Q

Why is therapeutic drug monitoring important?

A

drug actions are directly r/t drug conc at site of action

103
Q

why order TDM with cefotaxime?

A

for conc of med in CNS to treat meningitis

104
Q

why order TDM with vancomycin?

A

concentration of med in blood to treat coagulase negative staphylococci

105
Q

Why is TDM important with regard to toxicity?

A

for Rx with narrow therapeutic range (digoxin & theophylline), monitor for known toxicity at certain concentration thresholds (gent)

106
Q

Why is TDM important with regard to efficacy?

A

monitor time above minimum inhibitory concentration (MIC) and for time dependent medications (vanc)

107
Q

Why is TDM important with regard to individualized dosing regimens?

A

premature v term infants, inadequate response, d-d interactions, organ dysfx and MIC info

108
Q

What is therapeutic range?

A

the range of concentration where there is high efficacy and low risk of toxicity in the MAJORITY of patients; may need to individualize (ex: vanc trough- 10mcg/mL is therapeutic for BSI, subtherapeutic for osteomyelitis)

109
Q

What is the distribution phase?

A

ex: gent; 30 min infusion time allows for distribution within the tissue compartment as rapidly as the dose is administered; results in dec s/e and toxicity

110
Q

When should peak levels be drawn and why?

A

30 min after 30 min infusion time to allow for distribution

111
Q

Why do NI pts need a higher mg/kg dosage and then an extended time interval of aminoglycosides?

A 
increased Vd (higher dosage); decreased CL, decreased GFR (lengthened time interval)
AG are excreted un∆ by kidneys; longer T 1/2
TROUGH levels should be used to estimate overall renal fx
112
Q

What is the s/e profile of aminoglycosides?

A

ototoxicity- irreversible and nephrotoxicity- may be reversible

113
Q

What is the concentration-dependent killing effect?

A

optimal effect at certain concentration; goal in NI is to achieve concentrations with 4-5mg/kg dose, then allow the concentration to fall throughout the long 24-28 hour dosing interval

114
Q

What is total drug concentration?

A

protein bound + unbound “free” drug; in a choice, draw for free levels

115
Q

What are common antiepileptic drugs used in the NI requiring TDM?

A

Phenobarb (linear PK), phenytoin (non-linear PK, highly protein-bound- check free levels), oxcarbazepine and levetiracetam

116
Q

In the sympathetic nervous system, what are the neurotransmitters?

A

norepinephrine, epinephrine and dopamine

117
Q

What is the effect of SNS neurotransmitters/ catecholamines?

A

stimulate different adrenergic receptors depending on the structure; fight or flight

118
Q

What is the effect of adrenergic alpha 1 receptor activation?

A

present in vascular beds and skeletal muscle; vasoconstriction of arteries and veins, inc cardiac contractility

119
Q

What is the effect of adrenergic alpha 2 receptor activation?

A

present on presynaptic nerve endings; INHIBITS presynaptic release of norepinephrine through feedback mechanism and DECREASES sympathetic outflow

120
Q

What is the effect of adrenergic beta 1 receptor activation?

A

present in cardiac muscle; INCREASE HR and INCREASE cardiac contractility

121
Q

What is the effect of adrenergic beta 2 receptor activation?

A

present in bronchial muscle and peripheral vasculature; broncodilation in the lungs and vasodilation in the peripheral vasculature

122
Q

What is the effect of dopaminergic receptor activation?

A

present in kidneys and viscera; dilates arterioles in renal and splanchnic circulation

123
Q

What is the effect of dopaminergic V 1 receptor activation?

A

vasoCONSTRICTION in smooth muscle, liver and other tissues

124
Q

What is the effect of dopaminergic V 2 receptor activation?

A

increases water permeability and resporption in the collecting tubules

pharm midterm (5 decks)

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