Basic Priniciples Flashcards
What is Pharmacokinetcis?
What the BODY does to the DRUG
(ADME=absorption, distribution, metabolism, elimination)
*remember BD (body-drug)-like BD syringes.
What is Pharmacodynamics?
What the DRUG does to the BODY
What is Absorption?
Translocation of drugs from the site of administration into the circulation
In Utero exposure to Medications does what?
Increases risk of adverse effects
What adverse reaction can Sulfonamides and Ceftriaxone cause?
Kernicterus
What adverse reaction can Chloramphenicol cause?
Chloramphenicaol is a wide-spectrum antimicrobial bacteriostatic agent
Grey baby syndrome
What additive used in many medications can cause gasping syndrome?
Give an example of a med w/this additive
Benzyl Alcohol
Ativan
Neonates have complex sources of Pharmacokinetic & Pharmacodynamic variability including?
Age
Size
Growth
Organ Function
Which is studied more in neonates, Pharmacokinetics or Pharmacodynamics?
Pharmacokinetics
Pharmacodynamic is not studied as much, harder to predict
What are the Routes of Absorption?
IV (IV) GI (PO, PT) Rectal (PR) Intramuscular (IM) Percutaneous Intraosseous (IO) Intrapulmonary/Inhaled
What is Bioavailability?
How much drug enters the Systemic Circulation
For IV medications, if F=1, what does this mean?
It is 100% bioavailable
When is it important to consider the Bioavailability of a drug? (2 times)
- For ANY non-IV medication
2. When converting IV to PO (not all is absorbed, goes trhough many layers of metabolism 1st)
What 2 things affect Absorption?
- Physiochemical Factors
2. Patient Factors
Name 4 Physiochemical Factors that affect Absorption.
- Formulation of the Med
- Molecular Wt
- pKa (stability of the drug at different pH levels)
- Lipid Solubility
Name the 7 Patient Factors that affect Absorption.
- 1st Pass Metabolism
- Gastric Emptying Time
- Gastric pH
- Surface Area
- Size of Bile Salt Pool
- Bacterial Colonization
- Underlying Dz’s
Name the 7 Patient Factors that affect Absorption.
- 1st Pass Metabolism
- Gastric Emptying Time
- Gastric pH
- Surface Area
- Size of Bile Salt Pool
- Bacterial Colonization
- Underlying Dz’s
Name the 3 routes of Oral Administration
- PO
- Feeding tube (GT/NG/OG)
- Sublingual
What is important to know for Oral Admin. when a medication is given through a feeding tube?
Why?
Where the tube is located
- Site may affect absorption (stomach vs. trans-pyloric)
- Small-bore tubes & difficulty delivering some suspensions (crushed meds mixed-can get clogged)
- Med may be incompatible w/tubing
What Oral Admin route is difficult in pediatric pts?
Sublingual :-)
Gastric emptying time is _________ in infants.
Erratic
Gastric emptying time is delayed/erratic until ___-___ months of life.
It is Faster/Slower in older infants/children.
It Increases/Decreases to adult timing around 3 y/o.
6-8 months
Faster
Decreases
Gastric emptying contributes to what symptom?
Reflux
Most drugs absorbed in the Small intestine rely on _____ _______ rate for absorption
Gastric Emptying rate
What are the 2 things that affect Gastric Motility?
- Gastric Emptying time (erratic/delayed)
2. Intestinal Motor activity Matures over time
Immature intestinal motor activity leads to?
Uncoordinated Peristalsis
Longer Transit Times (8-96 hrs Infant vs. 4-12 hrs Adult)
When is Intestinal Motor Activity Mature?
4 Months
When is Intestinal Motor Activity Mature?
4 Months
The Gastric pH in infants is ________.
Meaning Increased/Decreased Acid production.
Increased
Decreased
What is the Gastric pH of a Full Term infant?
Drops to ____ at 24 hrs.
pH 6-8 at birth
pH 2-3 at 24 hrs
Is the Gastric pH of a Preterm infant increased/decreased vs Term?
Due to what?
Increased (elevated)
Immature Acid Secretion
The pH of a Preterm infant takes Longer/Shorter to normalize vs. term?
Longer.
No specific age, is case by case.
Gastric acid production reaches Adult levels at ____ age.
2 y/o
Are H2 blockers effective in Preemies?
Why or why not?
No.
They have increased pH (which is the MOA of an H2 blocker-so doesn’t help much)
What are 3 reasons Gastric pH matters?
- Affects stability and degree of drug ionization.
- Increased absorption of acid-labile drugs.
- Decreased absorption of weak acids.
What are 3 reasons Gastric pH matters?
- Affects stability and degree of drug ionization.
- Increased absorption of acid-labile drugs.
- Decreased absorption of weak acids.
Enzymes and Efflux pumps, Oral Absorption is dependent on what?
Pancreatic and Biliary FunctionThe rate of enzyme synte
The rate of Enzyme synthesis and activity is Increased/Reduced?
Reduced
Enzymes and Efflux pumps, Oral Absorption is dependent on what?
Pancreatic and Biliary Function
What 2 enzymes important for PO absorption are 20% of adult levels?
Leading to what?
Amylase and Lypase
Leading to Delayed Pancreatic Function
Reduced Bile Acid Pool results in what?
- Decreased rate of synthesis and pool size
2. Decreased absorption of lipophilic drugs-(don’t have the bile salts to absorb them)
Absorption is dependent on _ ________ in the intestinal wall.
It takes ____ to develop after birth
p-glycoproteins
Time
P-glycoproteins do what?
Increase drug Distribution across membranes.
What 4 things affect Immature Gut Flora?
- Age
- Vaginal Delivery and Br. Fdg (increase gut flora)
- Feeding type
- Drug Therapy (i.e. acid suppression therapy)
Name an example of a medication dependent on gut flora for absorption.
Digoxin
What medication/s affect gut flora–>increased risk of NEC?
H2 Blockers/PPI’s
What medication/s affect gut flora–>increased risk of NEC?
H2 Blockers/PPI’s
Describe First Pass Metabolism
Drugs are absorbed through the Gut–>Hepatic Vein–>Liver
All before distribution to the rest of the Body.
First pass metabolism is Increased/Decreased in Infants vs. Adults?
Why?
Decreased
Due to Hepatic Immaturity
T/F: Some meds become Activated by the Liver and some become Inactivated by the liver?
True, so you need to know type of drug and how it is metabolized
Rectal Absorption is Increased/Decreased in neonates/young infants?
Increased (enhanced)
Where does Rectal Absorption take place?
Is absorption static?
Hemorrhoidal veins
No, may be erratic
True/False: Rectal absorption bypasses 1st-pass metabolism?
True (of the lower rectum)
Lower rectum: absorbed directly into circulatory system
Does Upper rectal absorption by-pass 1st pass metabolism?
No, it is absorbed into the portal vein (has 1st pass)
When is Rectal route an option?
When PO is not a good option and IV access is not available.
*emesis, seizures, aspiration, NPO
What are 2 problems with Rectal route?
- High risk of expulsion of the med before absorption :-)
2. Doseage forms not commercially available for infants and small children (cut suppositories may not be accurate)
IM absorption is dependent on what?
Blood flow to injection site
Muscle Mass
Muscle Activity
Why is IM Absorption unpredictable in neonates/infants?
Less in neonates d/t:
Poor Muscle Perfusion
Decreased Muscle mass
Insufficient Muscle Contractions
Is IM route recommended if an IV route is available?
No. IV is preferred
*exceptions: Immunizations and Vit K (Phytonadione)
Why is Absorption substantially increased in NB’s?
Skin Hydration-(Increased perfusion and Hydration of Epidermis)
Thickness-(Thinner Stratum Corneum)
Total Surface Area-(Ratio of Total BSA: Body Mass is much higher than Adults)
Infants have Increased/Decreased exposure to topical medications?
Increased
Can topical medications lead to toxicity?
Yes
Give an example of a topical med that can lead to toxicity.
Steroids.
NO occlusive dressings.
What are the 2 methods of Intrapulmonary Absorption?
- Inhalation
2. Nasal delivery
Intrapulmonary medications have predominantly what effect?
Local
Can systemic exposure occur w/Intrapulonary absorption?
Yes
i.e. Tobramycin nebs (TOBI), Inhaled Corticosteroids
Intrapulmonary Absorption is a Difficult/Easy delivery mechanism in small children?
Difficult–inhaled meds can adhere to tubing.
True/False: Developmental changes and altered lung capacity alters the pattern of drug deposition?
True
What is IO admin?
Administration of drugs/fluids into the bone marrow
IO is an alternative to what?
IM/IV route
Up to 5 y/o, the bone marrow is still very _______.
Vascular
When is IO done?
Occasionally NICU, usually transport setting
Distribution is determined by what 4 things?
- Body composition
- Hydrophylicity & Lipophylicity of meds
- Protein Binding
- Pathological Conditions
What is meant by Body Composition?
Volume of Distribution
Total Body Water
What is Volume of Distribution?
The volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration.
Volume of Distribution depends on what?
The baby’s Fat vs. H2O content
What is the Vd formula?
Vd= Xo (total drug in body)/Co (concentration in plasma)
*expressed as a unit of Volume
What is the approximate % total body water in a preterm infant?
80% water
The TBW to Fat ratio is Increased or Decreased?
Increased
more TBW to Fat
The Body Composition of an infant leads to Increased volume of distribution for Hydorphilic OR Lipophilic drugs?
Why?
Hydrophilic
It takes larger loading doses to “Fill the Tank” to reach steady state
Name 3 drugs discussed in lecture that are hydrophilic and need larger loads.
Gentamicin, Linezolid, Phenobarbital
Adipose tissue in an infant has Higher/Lesser Water content (than other age groups)?
Higher water content in their Adipose tissue
What happens to Lipophilic drugs in babies?
They don’t stay in the body-get excreted.
They have lower levels of lipophilic drugs.
What is the Fat % of Preterm (<2kg)?
Full term (3.5kg)?
& 1 yr (10kg)?
6%
- 4%
- 4%
What is the Water % of Preterm (<2kg)?
Full term (3.5kg)?
& 1 yr (10kg)?
80%
70%
61.2%
As a baby develops, the dose will need to ______ with the Volume of Distribution change
Change.
What does Protein binding affect?
Volume of Distribution
Half-Life
Clearance of Medications
Neonates and young children have _______ quantities of plasma proteins and _______ affinity for binding medications
Decreased plasma proteins
Reduced affinity
Name 2 main proteins in the body that carry drugs?
Alpha-1 acid glycoprotein
Albumin
If a drug binds to a protein, it IS or IS NOT available to the body
Is Not
What do we worry about in regards to protein binding?
The Free-Circulating amount of drug
Monitor “free” levels
When the proteins bind with a drug, how are they released?
What is the unbound drug called?
A little at a time.
Free Fraction–free to distribute into tissues–>Increasing Vd
T/F: Some drugs displace bilirubin from binding sites on Albumin?
True
Sulfonamides (Bactrium) & Ceftriaxone (can use after 42 wks CGA-liver more developed)
If drugs displace bilirubin from binding sites on Albumin, what can result?
Kernicterus
Infants have More/Less Protein binding than Adults.
Thus, they have More/Less of the Active form of the drug.
Less Binding
More Active form
What Pathological Conditions can alter drug Distribution?
Cardiac Output and Regional Blood Flow
shunting of blood from different organ systems
What 2 conditions cause Decreased Vd?
- Cardiac Conditions
2. Malnutrition
What can cause Increased Vd?
Surgery
i.e. they need increased fluids and meds
Most drugs are metabolized by the?
Liver
Drugs are metabolized by the Liver into what 3 things?
- Inactive drug
- Active metabolites (weaker form)
- Pro-drug to active drug
What are the Phase 1 Reactions of Metabolism?
Oxidation
Hydrolysis
Hydroxylation
Reduction
What are the Phase 2 Reactions of Metabolism?
Conjugation
Glucuronidation
Sulfation
In Phase 1 Metabolism, the CYP450 System has _______ that metabolize drugs in the liver.
Enzymes
In Phase 1 Metabolism in Neonates, the _______ _____ of enzymes is decreased.
Absolute Mass
T/F: In Neonates, different enzymes mature at different rates.
True
T/F: Drugs are metabolized by different enzymes.
True
Glucuronidation doesn’t mature until ___ y/o.
3
Reduced glucuronidation =
Reduced conversion to metabolites
T/F: Infants have Sulfation at adult levels at birth?
True (it’s one of the main pathways of metabolism used by infants)
T/F: Infants are more susceptible to toxicity from overdose?
Why?
False-they are less susceptible
D/T reduced glucuronidation–>reduced ability to make the toxic metabolite NAPQI
What Phase 2 reaction is present in Infants but NOT adults?
Give a med example.
Methylation
Theophylline–>Methylation–>Caffeine
Elimination of drugs is done mostly by the _____.
Kidneys
The kidneys are _________ in structure and function at birth.
Immature
Renal blood flow Increases/Decreases over the 1st year of life.
Increases
As GFR increase, drug clearance _______.
Increases
What is the best indicator of renal function?
GFR
What 2 equations (names) can be used to indicate GFR/renal function?
Schwartz
Bedside Schwartz
GFR increases from birth w/age but is dependent on what 2 things?
- Blood Flow
2. Protein Binding
Serum Cr is a reflection of _______ _____ in the first few days of life?
Maternal Creatinine
What value can change Renal elimination?
Cardiac Output
(Increased Cardiac blood flow = Increased Renal blood flow = increased filtration)
*also works in the opposite direction.
Why do we need an increased dose with increased interval with a Neonate vs. Older child?
They need increased dosing to reach Therapeutic concentration, But need increased interval for Renal Clearance
How does Cooling affect metabolism and clearance?
Slows metabolism and clearance (slowing renal elimination)
A PDA will Increase/Decrease the Vd?
Increase Vd
A PDA results in Increased/Decreased blood flow to the kidneys?
PDA can/cannot be Tx’d w/ NSAID’S
Decreased
Can
What do indomethacin/Ibuprofen do?
Decrease Prostaglandins = Decreased Vasodilatin = Decreased Renal Blood Flow
With Indo/Ibuprofen use, infant’s will have short-lived increase in what due to decrease in what?
Serum Cr due to decreased GFR
Tubular secretion is about ____% of adult at birth.
It matures by _____ age.
20%
1 year
Neonates have _____ nephron function
Immature
Furosemide has a potential _______ Diuretic effect due to _________ of secretion into the intraluminal space (can’t get to the site of action).
Increased/Decreased doses/Kg needed.
Increased/Decreased Interval spacing needed.
Why?
Blunted effect
Immaturity
Increased
Increased
d/t decreased clearance or increased 1/2L
Secretion and Reabsorption mature within ____ wks Postnatal Age
30 wks PNA
Name 4 prinicples of Pharmacodynamics
- Relationship between the drug and the body
- Reflected in receptor binding and post binding affects
- Difference can alter drug efficacy and safety
- Data has not been elucidated for neonates.
Give a drug example with varying Pharmacodynamics
Milrinone. See different effects in different babies. It’s receptor-based but we don’t know/can’t predict it yet.
