Peds & Geri Flashcards
Young children are not simply small adults; they have unique physiology that changes remarkably with age; especially in what?
The first year
Neonates and infants have a high percentage of body water. This means what?
Drugs distributed in water have a high volume of distribution
In infants, cardiac output is dependent on:
Heart rate!
Due to infants/neonates having a high body water percentage what may be enhanced for this population?
Drug toxicity
Anesthetic drugs that cause a reduction in heart rate may ________ depress blood pressure and blood flow to tissues.
Disproportionately
Name the three common age groups of the pediatric population:
- ) Neonates - less than 4weeks after birth
- ) Infants - between 4 wks and 1 yr
- ) children - greater than 1 yr of age
Neonates often have two subdivisions. What are they?
- Prematurely (before 37 wks gestation)
2. Term (greater than or equal to 37 weeks)
The understanding, assessment and management of acute pain in pediatrics has lagged behind that of adults. Pediatric pts often receive….
Less analgesia postoperatively than adults
What was the established view of neonates regarding pain?
Neonates were neither capable of perceiving pain NOR able to remember painful stimuli
The primary indication for anesthesia once was the prevention of…
Movement during surgery! :(
Achieved with little more than Controlled ventilation and NMB’s
The behavioral response to standard noxious stimulus in the neonate may be:
Unpredictable
The stress response associated with noxious stimuli in the neonate is:
Impressive and CONSISTENT
Infants undergoing surgery w/o adequate anesthesia suffer significant ________ and ________ response which adversely affects post op recovery.
Hormonal and metabolic
Important developmental changes in the determinants of pharmacoKINETICS occurs during:
Infancy
Infantry changes in pharmacokinetics include:
- drug absorption
- distribution
- Binding
- entry into the brain across BBB
- Metabolism
The principal site of absorption for drugs given ORALLY is:
The small intestine
The rate at which a drug leaves the stomach is the determinant of speed of:
Drug Absorption
Oral Drug absorption is determined by:
The rate at which a drug leaves the stomach
The rate at which most drugs are absorbed when given orally is SLOWER in neonates and infants than in older children because:
Gastric emptying is delayed
Delayed Gastric emptying is more prevalent in what pediatric populations?
Neonates and infants (vs older children)
In neonates, the time (Tmax) at which maximum concentration (Cmax) is achieved is ______.
Prolonged
Gastric emptying and intestinal motor motility rates reach normal adult rates at what age?
6-8 months
In neonates, the gastric pH is:
Elevated.
Greater than 4
The increased gastric pH in neonates increases the bioavailability of ___________. And decreases the bioavailability of _______ ______ when given orally.
Increases: acid-labile compounds (PCN G)
Decreases: weak acids (Phenobarbital)
Compared to the older child, The infant gut is more permeable to:
Large molecules (proteins, high molecular-weight drugs)
Absorption of _______ drugs is increased in neonates due to what 3 reasons?
Topically applied drugs (corticosteroids, LA Creams, antiseptics)
Due to:
- ) Larger relative skin surface area
- ) increased cutaneous perfusion
- ) thinner stratum corneum
Neonates have a tendency to form methgb b/c they have reduced levels of :
Methemoglobin reductase
B/c fetal hemoglobin is more readily oxidized than adult hgb, and neonates have a reduced level of methgb reductase what tends to happen?
Methemoglobin
The reluctance to use EMLA cream in neonates results because of what reasons:
- ) increased epidermis absorption
2. ) reduced methemoglobin reductase
EMLA has been shown to be safe in neonates when applied as a
One time dose.
Shown to be efficacious for circumcision pain
B/c of neonatal reduced muscle bulk, skeletal muscle blood flow, and muscular contractions, it might be expected that IM absorption would be decreased in neonates.
Why is this not necessarily true?
Neonates have high density of skeletal muscle capillaries
Compared to adults, Pulmonary absorption ion infants and children is generally :
More rapid
A more rapid “wash in” of inhalational Anesthetics in neonates and infants is caused by what 2 factors:
- Greater fraction of CO going to vessel rich tissue group (LUNGS)
- Lower tissue/blood solubility of inhaled Anesthetics
When delivered at a constant rate, an inhalation drug with a greater volume of distribution will take longer to reach:
Steady state concentration
What ratio is achieved more rapidly in infants than in adults?
Fe / Fi Ratio (equilibration)
Because the Fe/Fi ratio (equilibration) is achieved more rapidity in infants, the increase of what may occur quickly?
toxicity of inhaled anesthetics
Bradycardia, cardiac depression d/t halothane
Why do you not want bradycardia in infants/neonates?
CO is dependent on HR1
Age has little effect on the solubility of the less soluble drugs, N2O, and Sevo.
True or False?
True
In neonates, induction of anesthesia will be
Slowed
Right to left shunting of blood in the neonate will do what to the rate of induction?
Speed up.
Right to left shunting may be caused by: (what was in ppt)
Pulm Atresia
Hypoplastic left heart syndrome
Intrapulmonary condition: atelectasis, Congenital vascular malformations
Total body water = in the preterm neonate
85%
Total body water.= in the term neonate
75%
Total body water decreases at about 5 months and remains relatively constant afterwards at approximately this %:
60%
At birth ECF = %?
At 1 yr ECF = %?
45% at birth
26% at 1 yr
ECF continues to reduce during childhood until the normal adult level is reached.
Adult ECF % is?
18%
Examples of polar drugs:
Aminoglycosides
NMBDs
Polar drugs distribute _______ into the ECF but enter cells more ______.
Rapidly into ECF
Enter cells more slowly
Initial dose fo polar drugs is usually higher or lower in the neonate/infant compared to older children?
Higher
Why is initial dosing of polar drugs (NMBDs, AMG’s) higher in neonate/infant vs children and adults?
Larger ECF volume
Approx Intubation doses of Succinylcholine in infant, Children, and adolescent/adults:
Infant: 3-4mg/kg
child: 2mg/kg
Adolescent/adult: 1mg/kg
What is the percentage of body wt /fat in a 1.5kg premie vs term neonate?
3% in 1.5 kg premie
12% in term
This proportion doubles by 4-5months of age
Baby fat is lost when infants start walking and protein mass increases by 20% in a term neonate
What % in adult?
50%
Acidic drugs tend to bind to
Mainly to albumin
Basic drugs bind to
Globulins
Lipoproteins
Glycoproteins
Examples of acidic drugs:
Barbiturates
Example of basic drugs:
Diazepam
Amide LA’s
In the newborn, relative to adults, plasma protein binding of many drugs is:
Decreased
Reduced protein binding in neonates is important for drugs with more :
- more than 95% pr-binding
- high extraction ratio
- narrow therapeutic index (lidocaine)
Binding to albumin is increased in neonates vs infants/children/adults.
True or false?
False.
Albumin binding is reduced in neonates
Plasma albumin concentrations are lowest in
Premature infants
And other fetal proteins such as x-fetoprotein, have a reduced affinity for drugs.
In neonates, what is competing with acidic drugs for albumin binding sites?
Increased concentrations of free fatty acids and unconjugated bilirubin
Alteration in neonate ionization and binding properties of plasma proteins due to the neonatal (metabolic) tendency:
To manifest a metabolic acidosis
Approx what age are serum albumin concentrations about that of an adult?
5 months
*binding capacity approaches adult values by 1 yr of age
Most drugs cross physiologic membranes as a result of
Passive diffusion
ionization
Maturational changes in tissue binding also affect drug:
Distribution
Tissue binding also increases the
Volume of distribution
Myocardial digoxin concentrations in infants:adults is ?
6 times higher in infants than adults
Despite similar serum concentrations
Name several factors that influence the process of tissue and protein binding:
- molecular size
- ionization
- tissue binding
- lipophilicity
- P-glycoprotein (member of ATP transporter family is capable of producing a biological barrier to membrane passage
Maturational changes in tissue binding also affect drug
Distribution
Tissue binding increases the
Volume of distribution
How do Myocardial digoxin concentrations in infants compare to those in adults? (Similar serum concentrations)
Infants are 6 times HIGHER than adults
What is a lipid membrane interface b/w the endothelial cells of the brain blood vessels and the ECF of the brain?
The BBB
Brain uptake of drugs is dependent on what two elements?
- Lipid solubility
- Blood flow
Example: uptake is enhanced by high lipid solubility and cerebral blood flow.
it’s postulated that the BBB permeability to water soluble drugs (like morphine) changes with
Maturation
Fentanyl is water or lipid soluble?
Lipid
How does fentanyl effect the respiratory depression of infants in comparison to adults (with comparable plasma concentrations)?
It is similar in infants and adults
The increased neonatal respiratory depression observed in morphine could be due to ________ rather than ____ age related changes.
- pharmacoKINETICS
- BBB
In term neonates, how is the vol of distribution and plasma concentrations of morphine impacted?
Term neonates vol distribution = reduced
Initial plasma concentrations = may be higher in neonates than adults
Respiratory depression is the same in children from what ages at the same morphine plasma concentration?
2-570 days (about 1.5 yrs old)
The majority of drug metabolism (clearance) occurs in the
Liver
Majority of drug metabolism (clearance) occurs in the liver where lipid soluble compounds are converted to more
Water soluble compounds
Water soluble compounds are generally excreted in the
Bile or urine
Water soluble drugs may be excreted unchanged in the kidneys by these two functions:
- Glomerular filtration
And/or - Renal tubular secretions
Many renal and liver processes are immature int he neonate and mature within the first year of life. During this time, what systems appear to evolve and approximate adult rates?
Enzyme systems
Drugs are metabolized in the live by
Phase I and II reactions
Phase 1 metabolic processes involve what?
Commonly catalyzed by the….
Oxidative, reductive, or hydrologic reactions.
- catalyzed by the mixed function oxidase system
Phase II pathways involve
Conjugation
What phase reactions are generally lost in the elderly?
Phase II (conjugation)
The major enzyme system for oxidation of drugs is:
Cytochrome P450 (CYP)
When does CYP appear to be “switched on”?
At birth
CYP2E1 activity does what after birth?
Increases
CYP2D6 becomes detectable when?
After CYP2E1 activity which increases after birth
CYP3A4 and CYP2C family of enzymes appear at what age?
During the first week
The last CYP enzyme to appear is?
CYP1A2
Name the CYP enzymes in order (5);
- CYP2E1 (increases after birth)
- CYP2D6 (detectable soon after)
- CYP3A4 and
- CYP2C family appear during first week
- CYP1A2 (last to appear)
EDAC-1A
“Eliminate drugs and call 1A”
Immaturity of the CYP systems in neonates may have important effects on the risk of
Drug toxicity
neonates are dependent on what CYP systems for levobupivacaine and ropivacaine clearance?
Levobupivacaine = CYP3A4
Ropivacaine = CYP1A2
What factor(s) dictate the reduced epidural infusion rates in neonates?
The dependence on immature CYP systems — CYP3A4 for levobupivacaine and CYP1A2 for ropivacaine clearance
What is the toxic metabolite of paracetamol (acetaminophen)?
N-acetyl-p-benzoquinone imine (NAPQI)
n-acetyl-p-benzoquinone imine (NAPQI) is formed by
CYP2E1, 1A2, and 3A4
NAPQI metabolite binds to intracellular hepatic macromolecules to produce cell….
Necrosis and death
kill the liver…. slow death
Fentanyl is metabolized by ______ into _____.
Fentanyl is metabolized by oxidative N-dealklation (CYP3A4)
Into; NORfentanyl
NORfentanyl is then….
Hydroxylated
All metabolites of fentanyl are in/active?
INACTIVE
Fentanyl clearance in term neonates is what percentage of adult values?
When is clearance that of an adult?
70-80% of adult values
Reaches adult values within the first TWO weeks of life.
Where is most of fentanyl metabolized?
Liver.
Small amt by kidney
High dose therapy with fentanyl results in prolonged effects in the neonate d/t reduced clearance.
When intraabdominal pressures are increased, how is clearance effected?
Fentanyl clearance is reduced.
Increase IAP (omphalocele) decreases hepatic BF and decreases hepatic extraction
What two processes are drugs and their metabolites excreted by the kidneys :
- Glomerular filtration
2. Tubular secretion
GFR is approx %? Of adults at birth in a term neonate?
At 1 year?
GFR is about 30% of adult at birth
~ 90% at 1 year
What pathway is responsible for the elimination of PCN?
Para-amino hippurate pathway
Para-amino hippurate pathway, immature in neonates, results in an increased _________ for PCN and related compounds.
Elimination half life
Why is the elimination half life of PCN and related compounds increased in neonates?
Immature para-amino hippurate pathway
At birth, slightly acidic urine results in:
Decreased elimination of weak acids
What is the approx pH of urine at birth?
6-6.5
The immaturity of renal clearance pathways for caffeine results in prolonged effect of what prodrug used to treat/prevent post-op apnea in preterm neonates?
Theophylline
N-methylation of theophylline produces what?
Caffeine
oxidative demehtylation by CYP1A2 is responsible for the metabolism of _____.
Caffeine
In neonates, caffeine metabolism is
Deficient
Theophylline is effective for post-op apnea in premies b/c of what reason?
Caffeine is cleared slowly by the immature kidneys
Remifentanil, and to a lesser extent, atracurium are rapidly broken down by
Nonspecific esterases (in tissue and erythrocytes)
Remifentanil clearance in all age groups is approx ?
150 L / Hr (70kg)
Clearance is greater in what pt population?
Term neonates than infants/adults
Clearance is expressed
Per kilogram of body weight
The constant rate of hydrolysis by plasma esterase of propacetamol to paracetamol is age or size related?
SIZE related
Not age related
Ester LA’s are metabolized by
Plasma pseudocholinesterase
Plasma pseudocholinesterase concentrations are greater or less in neonates?
Less/reduced
Opioid receptors are not fully developed in
Newborn rats
And mature into adulthood
Neonatal sensitivity to morphine is attributed to ….
PharacoKINETIC rather than pharmacoDYNAMIC differences
Neonates have an increased sensitivity to the effects of what drug class?
Why?
NMBD’s
Reason is unknown, observation that there is a threefold reduction int he release of ACh from infant (rat) phrenic nerve
The NT at most inhibitory synapses in the human CNS
GABA
GABAa Receptor is the site of action for:
- Benzodiazepines
- Barbiturates
- Numerous anesthetic drugs
At birth, the cerebellum contains 1/3 the number of GABAa receptors found in the adult. These receptors also have reduced binding affinity for
Benzodiazepines
GABAa Receptor complex becomes more prevalent from birth to ____.
The values then decrease to ___% of peak values by ___ yrs.
Birth to 2 yrs.
Decrease to 50% of peak values by 17 years
GABA receptor complex changes are consistent with age related MAC changes of inhalational anesthetics and possible contribute to why we …
Give higher doses of Midazolam are required in young children for sedation
The amount of drug going to the brain (and subsequent anesthetic effect) may also be affected by changes in
Regional blood flow
Bronchodilators have a REDUCED effect in infants b/c of
Immaturity of bronchial smooth muscle in at this age
Cardiac calcium stores in the endoplasmic reticuluma re reduced in the neonatal heart b/c of
Immaturity
Exogenous calcium has greater impact on contractility in neonates than in
Older children or adults
The development and discovery of new drugs based on genome information is called
Pharmacogenomics
Pharamacogenetics may influence either
Pharmacokinetics OR pharmacodynamics
Pharmacogenetics is the genetically determined variability in
Drug metabolism
A well known example of genetic variability influence is:
Plasma cholinesterase activity and succinylcholine metabolism
Polymorphism of CYP2D6 is inherited as an autosomal recessive trait.
HomoZygous individuals are deficient int eh metabolism of what groups of drugs:
- Antidepressants
- Beta adrenoceptor blocking drugs
- Neuroleptic drugs
- Opioids
The growth in body weight and length and changes in physiology during infancy and childhood impact drug:
- absorption
- distribution
- metabolism
Neonatal - concomitant changes affect protein binding and receptor physiology and alter the ______ of drugs
Efficacy
What year of life is the most critical period during which the majority of these maturational changes take place?
The first year
In neonates and young infants, Orally administered drugs are often absorbed more ….
Due to?
Slowly
Due to delayed gastric emptying
What element of neonates affects the bioavailability of orally administer acid-labeled compounds and weak acids?
Higher gastric pH 6-6.5
Inhalational anesthetics are generally absorbed more rapidly in infants and children than in adults; however, induction of anesthesia is slower in the presence of
Right to left shunting of blood
From cyanosis CHD or intrapulmonary conditions
Processes involved in metabolism and clearance of drugs mature during
The first year of life?
