Basic Principles Flashcards
(132 cards)
1
Q
ADME stands for?
A
absorption, distribution, metabolism, excretion
2
Q
Neonates and infants are at increased risk for?
A
adverse drug reactions
3
Q
Sulfonamides and ceftriaxone cause…
A
kernicterus
4
Q
chloramphenicol causes…
A
gray baby syndrome. It is an antibx they can’t metabolize
5
Q
benzyl alcohol causes
A
gasping syndrome—they can’t metabolize it
6
Q
Pharmacokinetics is what?
A
What the body does to the drug
7
Q
Absorption is related to…
A
bioavailability (F)
8
Q
Time needed for drug concentration to decrease by 1/2 is?
A
Half life (T 1/2)
9
Q
If drug X has a T 1/2=6hr and starting conc is 40mg/ml, what is the remaining conc after 12 hours?
A
10mg/ml (or 25% of the original conc)
10
Q
Routes of absorption are…
A
IV, PO/PT, PR, IM, percutaneous, IO, intrapulm/inhaled
11
Q
Bioavailability (F) is…
A
how much drug enters systemic circulation
12
Q
What is the bioavailability (F) for IV meds?
A
F=1 (100% available)
13
Q
What is the bioavailability (F) for PO, PR, SC, etc meds?
A
F<1 (less than 100% available)
14
Q
Rate of absorption is not the same as…
A
bioavailability. Can differ from adults.
15
Q
Oral liquids have a faster/slower rate of absorption?
A
faster
16
Q
Compounded meds may have an alteration in…
A
stability
17
Q
Physicochemical factors that affect drug absorption
A
med formulation (disintegration, dissolution, sustained-release), molecular wt (bigger=decreased metabolism), pKa (stability in pH in stomach), lipid solubility
18
Q
Patient factors that affect drug absorption
A
1st pass metabolism (decreased in neonates), co-admin with food, gastric content & emptying time, GIT pH, surface area of the bowel, size of the bile salt pool, bacterial colonization, underlying disease states
19
Q
1st pass metabolism is:
A
gut metabolism + liver metabolism (drugs absorbed thru gut to hepatic vein to liver)
20
Q
Why is 1st pass metabolism decreased in infants v. adults?
A
hepatic immaturity
21
Q
What effects do frequent feeds (Q3hr, continuous) have on GI absorption?
A
consistent buffer in stomach
22
Q
Gastric emptying is…
A
Erratic in infants, slower than in an adult, contributes to reflux, affects time for drug to reach small intestine, affected by caloric density of foods
23
Q
What is a major absorption site?
A
small instestine
24
Q
When does the newborn’s gastric emptying time reach adult values?
A
6-8 months
25
Gastric motility in infants is...
irregular, uncoordinated, has longer transit time (8-96 hr in infant, 4-12 hr in adult)
26
Infants have more/less acid production than adults?
less=increased pH
27
Term infant stomach pH at birth is...
6-8 (neutral)
28
When does the term infant's stomach pH drop to 1-3?
within 24 hours of birth
29
When does the preterm infant's stomach pH normalize?
about 3 weeks due to immature gastric acid secretion
30
Acid production correlates with PNA or PCA
PNA (post natal age) not PCA (post corrected age)
31
Why does pH matter?
affects stability & degree of ionization of the drug
32
PO Phenobarb is a weak acid, so it is ionized at a higher pH (alkaline). Therefore there is decreased/increased absorption.
decreased
33
PO penicillin, ampicillin, nafcillin are _______ thus have increased/decreased absorption.
acid-labile, increased
34
GIT surface area is ____________ in infants.
decreased compared to adults
35
Pancreatic function in a neonate leads to...
decreased rate of synthesis, pool size, & intestinal transport
36
Immature gut flora in infants is affected by...
age of infant, delivery method, feeding type, drug therapy
37
Due to less tight junctions in the in the stomach and intestines, there is _____ permeability.
increased
38
Disease states affecting GI absorption
Reflux (unpredictable loss of drug), short bowel syndrome (decreased surface area), cardiac defects (shunting blood away from gut), hypo-hyperthyroidism (increase or decrease in GI transit time)
39
Advantages of rectal absorption
less 1st pass metabolism (absorbed by hemorrhoidal veins-lower rectum=absorbed directly into system, upper rectum=absorbed into portal vein), alternative to PO or if no IV access (emesis, seizures, aspiration, PO)
40
Disadvantages of rectal absorption
erratic absorption, infant dosing often not commercially available, dose often expelled before fully absorbed
41
IM absorption is determined by...
blood flow to the injection site, muscle mass, muscle activity
42
IM absorption is altered in premies due to...
less muscle mass, poor perfusion to various muscles, peripheral vasomotor instability, insufficient muscle contractions
43
Examples of IM meds
ampicillin, gentamicin, ceftriaxone, vit K
44
IV or IM route is preferred?
IV-IM absorption is unpredictable in infants
45
Why is percutaneous absorption enhanced in neonates/infants?
thinner stratum corneum, increased blood flow to skin, increased total body surface area: body mass ratio v. adults, can see systemic exposure of topically applied meds (steroids, antiseptics)
46
Aquaphor does what to the skin?
increases skin integrity, decreases losses
47
IO absorption is an alternative for what?
IV/IM
48
IO can be used up to what age?
5 years-marrow is very vascular
49
The goal of intrapulmonary absorption is...
local effect although systemic absorption can occur (i.e. dexamethasone, budesonide, tobramycin)
50
Things that alter patterns of drug deposition in the lungs
developmental changes & altered capacity of lungs
51
Drug distribution is determined by
binding affinity of drug proteins, hydrophilic v. hydrophobic, body composition (% of ECF and TBW), molecular wt, degree of ionization at body pH, hemodynamic factors (C.O.)
52
Difficult to treat neonatal infections
osteomyelitis, meningitis, endocarditis
53
Must consider what when choosing drug therapy & target concentrations?
distribution
54
Volume of distribution is...
the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood conc.
55
Vd=A/Cp
Volume of distribution. A=total amount of drug in the body, Cp=conc in plasma
56
Binding of drugs to proteins is ____ in infants due to...
decreased---decreased amounts of plasma proteins, lower binding capacity, decreased affinity of proteins, competition for binding sites, lower albumin levels
57
less protein binding =
more 'free' active drug
58
You should monitor 'free' drug levels due to..
unbound drug is free to distribute out of plasma into tissues thus increasing the volume of distribution for total drug
59
ECF compartment=
plasma + interstitial fluid
60
What % does the ECF compartment compose in premies, 4-6month olds, children, & adults?
premie=50% of body weight, 4-6 month=30-35%, children=20-25%, adults<20%
61
What type of drugs does an increased ECF compartment make a larger Vd for?
hydrophilic-i.e. Aminoglycosides (gent, tobra, amikacin)-increased mg/kg dosing needed
62
Less body fat in premies leads to an larger/smaller Vd?
smaller
63
ECMO does what to the baby's blood volume?
basically doubles it
64
Metabolism (CL) is dependent on..
initial hepatic metabolism followed by excretion of parent drug/metabolites by liver & kidney
65
Most metabolism (CL) occurs in...
liver
66
Other routes of metabolism (CL) include...
kidneys, intestine, lungs, skin
67
Why may there be issues with drug metabolism in the hepatic pathways in an infant?
Infants have a delayed maturation of drug metabolizing enzymes. The various hepatic pathways mature at different times.
68
Phase I metabolism
CYP enzymes-oxidation, hydrolysis, hydroxylation, reduction-absolute mass of enzymes is decreased in infants
69
Phase II metabolism
synthetic metabolism-conjugation, glucuronidation, sulfation
70
Biotransformation of drugs
non-polar, lipid soluble to polar, H2O soluble, active metabolites, inactive parent drug (prodrug) to active drug
71
Deficient hydroxylation (phase I) of diazepam in infants leads to a ______ T 1/2.
long
72
Due to the ability to methylate (phase II) (adults are not), infants are able to methylate theophylline to...
caffeine
73
When oxidative pathways mature around 4-6 months, then CL increases/decreases thus shortening/lengthening caffeine T 1/2.
increases, shortening
74
Sulfation (phase II) is the ability to conjugate meds with...
sulfate-this is why infants are less susceptible to acetaminophen toxicity from an overdose
75
Glucuronidation (phase II) does not mature until...
3 years of age
76
The immaturity of glucuronidation (phase II) leads to...
slower CL & need to use smaller doses
77
Lack of ______ is what causes Chloramphenicol to cause gray baby syndrome.
glucuronidation-accumulation occurred due to lack of adjustment of dose
78
Alcohol dehydrogenase (phase II) does not mature until...
5 years of age
79
Gasping syndrome in infants is caused by...
Accumulation of benzyl alcohol (preservative) due to immaturity of alcohol dehydrogenase (phase II)
80
Elimination is measured by...
clearance (CL), volume of blood/plasma from which drug is completely removed per unit of time
81
Most elimination is done by...
kidney & liver
82
Clearance (CL) is constant over the range of concentrations in...which shows a 'linear' PK.
1st order elimination
83
Clearance (CL) of gent is by...
1st order elimination
84
With 1st order elimination, an increase in dose results in a proportional ____ in drug conc.
increase
85
Zero order elimination is dependent/independent of drug concentration.
independent
86
Clearance (CL) of phenytoin is by...
zero order elimination
87
capacity limited/saturable drug elimination with a non-linear graph describes...
zero order elimination
88
The primary site of drug metabolism and ultimate drug CL
liver
89
Hepatic CL is influenced by...
drug's affinity for certain hepatic enzymes, hepatic blood flow, protein binding, liver disease, cardiac function
90
In renal elimination, total CL=
GFR+tubular secretion (active transport)-tubular absorption (only by lipid soluble or non-ionized drugs)
91
Is there a change in urine when H2O soluble drugs are excreted?
no
92
GFR is dependent on... and is _____ in newborns.
blood flow & protein binding, decreased
93
GFR is affected by...
increases in CO + changes in renal vasc resistance ->increased renal blood flow, GA, PNA (accelerated increase needs dose regimen change), Indomethacin for PDA (decrease PGE=decreased vasodilatation=decreased renal blood flow)
94
Gold standard for GFR assessment
CrCl
95
Creatinine is 100% filtered at...
the glomerulus-only slightly secreted by tubular cells and is not reabsorbed by the tubule
96
CrCl will/won't factor in secretion or reabsorption of drugs.
won't
97
Estimating GFR in infants is easier/harder than in adults? Why?
harder-less precise-less SCr and transplacental Cr-not considered reliable in infants <6months
98
Tubular secretion matures by _____ & is ahead/behind glomerular maturation.
1 year of age, behind
99
Tubular secretion is an active/passive process.
active, goes against conc gradient & requires transporter proteins
100
Why is there the potential for a blunted diuretic effect of furosemide in an infant?
immaturity of tubular secretion into intraluminal space (can't get to site of action)
101
Drug interactions can occur is both are eliminated by the same tubular secretion protein leading to...
decreased excretion, increased drug levels, increased side effects
102
Ampho B can cause what in the kidney?
renal tubule toxicity & alter tubular secretion of other meds
103
Renal P-Glycoprotein
transporter involved in tubular secretion of drugs
104
Digoxin (substrate) + erythromycin (inhibitor) can increase...
digoxin levels
105
PDA can cause
increased Vd, decreased blood flow to kidneys, when treating-closely monitor renally eliminated meds (gent, vanco)
106
Dopamine and GFR
can increase renal blood flow thus increasing GFR, potential for subtherapeutic levels of meds (gent, vanco), used frequently for hypotension & oliguria
107
Furosemide & GFR
loop diuretic, effectiveness is dependent on renal function, secreted into luminal side of renal tubule to inhibit chloride reabsorption, increases renal blood flow thru PGE activation (vasodilatation)
108
Elimination rate constant (K) can be used to predict...
conc at any time, K=0.693/T 1/2
109
Accumulation: after 3.3-5 half lives at the same dose, conc is at _____% of final steady state conc.
90-97%
110
Pharmacodynamics
what the drug does to the body-not much know in this area for neonates
111
Therapeutic Drug Monitoring
drug actions directly related to drug conc at site of action (i.e. conc of cefotaxime in CNS for meningitis or conc of vanco in blood for CONS bacteremia)
112
Why monitor drug concentrations?
toxicity (narrow therapeutic range, known toxicity at certain conc), efficacy (time above MIC), individualized dosing regimens (MIC info, drug interactions, organ dysfunction, inadequate response)
113
Therapeutic range
range of conc where there is high efficacy & low risk of toxicity in the majority of patients (i.e. vanco trough 10 mcg/ml=ok for blood stream infection but subtherapeutic for osteomyelitis)
114
Why is the rate of infusion 30 minutes for Gent?
Allows for distribution within the tissue compartment as rapidly as the dose is administered, decreased side effects & toxicity, draw peaks 30 minutes after 30 minute infusion
115
Take home points for drawing drug levels
draw at correct times, before changing regimen consider the timing of the dose leading up to the next level
116
Examples of Aminoglycosides
Gent, tobra, amikacin
117
Why do NICU patients need a higher mg/kg dose of aminoglycosides and then an 'extended' interval of 24-48 hours?
increased Vd, decreased CL, decreased GFR (AGs are excreted unchanged by the kidneys), longer T 1/2
118
Side effects of aminoglycosides
ototoxicity, nephrotoxicity
119
Conc-dependent killing effect is...
optimal effect at certain conc, want to achieve appropriate peak with 4-5mg/kg dose then allow dose to fall thru out 24-48 hour interval
120
Anti-epileptic Drugs used in the NICU
phenobarb (level increase 1 mg/L for each 1mg/kg given), phenytoin (non-liner PK, highly protein bound), oxcarbazepine, levetiracetam
121
Total drug conc=
protein bound + unbound (free)
122
neurotransmitters in the SNS
norepi, epi, dopa
123
Neurotransmitters in the SNS stimulate
adrenergic receptors-fight or flight
124
Alpha-1 adrenergic receptors
in vascular beds & skeletal muscle-vasoconstriction of arteries & veins, increase cardiac contract.
125
Alpha 2 adrenergic receptors
on presynaptic nerve endings-inhibit presynaptic release of norepi, decrease sympathetic outflow
126
Beta 1 adrenergic receptors
in cardiac muscle-increase HR and cardiac contract.
127
Beta 2 adrenergic receptors
in bronchial muscle & peripheral vasculature-bronchodilatation in lungs, vasodilation of peripheral vasculature
128
Other adrenergic receptors
Dopaminergic (in kidneys & viscera=dilates arterioles in renal & splanchnic circ), V1 (vasoconstr. in smooth muscle & liver), V2 (increase H2O permeability & resorption in collecting tubules)
129
Overall goal of pharmacology
to produce the desired effects with minimal adverse reactions
130
Therapeutic index
difference between the therapeutic and toxic dosages
131
New Drug development
takes about 12 years lab to market: pre-clinical testing, phase I-IV clinical trials, final approval
132
8 rights of drug admin
right patient, drug, dose, time, route, reason, documentation, equipment
