Neonatal Pharmacology

application of drugs for the purpose of disease prevention and the treatment of suffering

a substance administered for the diagnosis, cure, treatment, relief of a symptom, or prevention of disease

what the drug does to body

the study of the movement of drugs and their metabolites through the body from absorption to excretion (basically, what the body does to the drug)

The amount of a drug that is availe to the site of action and the rate at which it is available.

Therapeutic range
Blood concentration of a drug that produces the desired effect without toxicity

Therapeutic drug monitoring
The process of measuring drug peak and trough levels to gauge the level of a patient’s drug exposure and allow adjustments of dosages with the joint goals of maximizing therapeutic effects and minimizing toxicity.

When is Therapeutic drug monitoring valuable?
when a good correlation between response and plasma concentration exists.
When you have wide variation in drug plasma level from a given dose.
When the medication has a narrow therapeutic range.
When the desired effects cannot be assessed by other simple means.

Steady state
The physiologic state in which the amount of drug removed via elimination is equal to the amount of drug absorbed with each dose.

Half-life of a medication
The time required for medication to fall to half its initial value.
A medications duration of action is often related to it’s half-life and may also indicate when another dose should be given.

It takes approximately 5 half-lives to reach steady state or 5 half-lives once a medication has been discontinued to be considered out of the system.

peak level
The maximum concentration of a drug in the body after administration, usually measured in a blood sample for therapeutic drug monitoring.
Usually drawn after adequate time has been allowed for the drug to distribute throughout the body

trough level
The lowest concentration of drug reached in the body after it falls from its peak level, usually measured in a blood sample for therapeutic drug monitoring.
Usually drawn just before the next dose is due.

random level
Blood test done to measure the level of medication in the blood; drawn without regard to the time of administration of the drug.
These drug levels are often used when patients have a changing renal function.

receptor concept
the principle that medications act by forming a complex with a specific macromolecule in a way that produces a given response

receptor effects
The medications affinity for binding to the receptor plays a large part in determining the dose of medication to achieve the desired effect.
The characteristics of the receptors are responsible for the selective nature of medication response.
This allows for an explanation for medication antagonists limiting of inhibiting the response to the original medication
Some medications do not act through receptors .

medication antagonists
medication that limit or inhibit the response to the original medication. Ex. Naloxone and morphine

Receptor/medication complex
Regulating Gene Expression
acts by mediating a response that ultimately involves gene expression or new protein synthesis
these medications generally do not have a rapid response
Epoetin alfa

Receptor/medication complex
cell membrane permeability
many clinically useful applications
have a short lag time between administration and administration response

Receptor/medication complex
increasing the intracellular concentration of a medication
increase the production of and activity of an enzyme system within a cell
stimulate a rapid response in changing cell characteristics

low sensitivity
having less than the expected response to the usual dose of a medication

Extreme sensitivity
having a greater than expected response to the usual dose of a medication

Unpredictable adverse reaction
a patient whose medication reaction is substantially different from what would be predicted

a diminished response to a medication when it is given long term

a rapidly diminished medication response without a dose change. Albuterol

Factors affecting individual medication response
alterations in concentration
variation in antagonist substances
alteration in the numbers or function of receptor molecules
changes in the concentration of molecules other than receptor molecules

desired effect
the expected response to a drug

sub-therapeutic effect
less than desired outcome for a medication

side effect
Any effect produced by a drug that is not the desired effect in addition to the desired effect.

All medications have some side-effects. minor to serious

toxic effect
Resulting from an excess amount of medication in a patient’s blood, these effects may be caused by the excessive use of medication, overdose, impaired excretion, or idiosyncratic reaction to the medication itself.

Principles of medication absorption
movement of the medication from the site of administration to the bloodstream
regardless of route, medications must cross the cell membrane
absorption of a medication is dependent on route

Common sites for drug administration
GI tract

What are considerations for using the GI tract medication administration?
Large surface area for absorption
Gastric emptying and intestinal transit times
GI tract acidity
GI enzyme activity
Bacterial flora
GI tract perfusion
Underlying disease states

How can gastric emptying and intestinal transit times effect medication administration?
preterm infants have prolonged and irregular times
reaches adult values at 6-8 months
motility in reduced by: prematurity, asphyxia, reflux, and RDS
administration of hypocaloric feeds, human milk, and metacloprrmide can increase transit times.
Prolonged transit and enterohepatic recirculation may increase bioavaliability
some medication concentrations mat decrease because of increased first-pass loss.

first pass
drugs absorbed in the small intestine are transported to the liver before circulation to the rest of the body. The liver may metabolize the medication before the drug enters the main circulation. If the liver metabolism inactivates the drug, higher drug doses may be required for the PO route. First pass effect does not happen with parenteral routes of medication administration.

How does GI tract acidity effect drug metabolism?
The GI tract is almost neutral at birth.
the stomach acidity gradually increase to adult levels by age 2
net effect is depend ant on the medication and preperation

How does GI enzyme activity effect drug metabolism?
neonates are deficient in pancreatic enzymes at birth
may inhibit absorption of some medications
one compensating mechanism neonates have is an increased Beta-gluronidase secretion.

enzyme deconjugates bilirubin in the gut, allowing it to be reabsorbed, (meaning frequent stools help jaundice).
also capable to metabolize some medications.
Up to 7 times higher concentrations than adults.

How does bacterial flora effect drug metabolism?
may effect motility and medication metabolism.
colonization is dependent on oral intake, antibiotic administration and disease states.
normal colonization take place in 4-6 days
intestinal flora are required to produce vitamin K

How do GI diseases alter medication metabolism?
diarrhea, emesis or NG suctioning may reduce time avaliable for medication absorption.
genetic diseases (CF) or circulatory (NEC) will alter pancreatic enzymes or intestinal mucosa, decreasing absorption.

What are some considerations for rectal administration of medications?
useful when IV route is not available.
serum levels may be as high as IV route
This route is discouraged because of volume and fragility of the rectum
retention time is the rate-limiting step

What are some considerations for inhalation medications?
medication response may be rapid due to large surface area.
when the site of action is the tracheobronchial tree this route is preferred. (albuterol, terbutaline)
fewer side-effects because the medication may not be absorbed systemically.
certain medications can be delivered during an emergency
may be ineffective in infants with PPHN or abnormal circulation

What are some considerations for topical medications?
utility is limited to medications who are absorbed through the skin

What are some considerations for IM/SQ medications
minimal SQ tissue and muscle mass limit the route
limited to medications that do not cause tissue damage.
response time is dependent on blood flow.

What are some considerations for IV medications
direct route to the bloodstream
bypasses all absorptive barriers
most reliable route of administration
serum concentrations achieved rapidly
adequate and equal levels are not guaranteed
rapidly reaching toxic levels may require that medications be delivered over prolonged periods.

medication distribution
movement of a medication to and through various body compartments.
determined by: size of the compartment, number and type of binding sited, amount of medication.
may be altered if the medication is highly protein bound or tissue bound.

Total water content of an adult

Total water content of a term ifant

Total water content of an preterm infant

volume of distribution
refers to the extent of drug distribution within the body and is expressed as the volume of fluid or tissue in which a drug is dissolved;
expressed in units of L or mL;
important indicator of drug distribution into body fluids and tissues
a large value indicates drug distributes extensively into body tissues and fluids

Effect water content has on distribution
water soluble medications have a higher volume of distribution
less mature infants may require a higher dose to achieve the same peak concentration
in the first days after birth infants will have a rapid change in volume of distribution for water soluble medications
diuretics and indomethacin may have a major impact on water loss.
changes in water loss may make gentamicin difficult to dose. frequent monitoring may be necessary

What effect does fat have on medications?
wide variability in neonates. 1% @28 weeks to 15% for term neonates
medications with more lipid solubility have a greater affinity for these tissues
reduced fat% causes lower volume of distribution.
Plasma concentration will be higher because less will be bound (morpheine and lorazepam)

What effect do erythrocytes have on medications?
in the neonate they contain 2.5 times more binding sites for digoxin compared to adults.
results in higher dose by wieght

What effect does plasma protein have on medications?
medications may bind to protein
amount bonded effects the available to achieved desired effect.
serum levels may be altered in the sick neonate, or ELBW

What medications are primarily bound to serum albumin?
phenytoin, indomethacin, lasix

What medications are primarily bound to lipoproteins, glyoproteins, and Beat-globulins?
lidocane, propranolol

What effect does unconjugated bilirubin have on medications?
Albumin has an increased affinity for bilirubin and decreased affinity for medications.
causes increased medication availability for action.

Some medications will displace UCbilirubin from albumin and increase risk for brain injury. (cefitriaxone, sulfonamides) and should be avoided with increased blilrubin or 2 months of age.

What effect does the blood brain barrier have on medication delivery?
it is incomplete in the newborn causing a greater permeability to some medications (phnytoin, benzodiazepine)
may be beneficial in treating meningitis

What effect does solubility have on medications?
low-lipid solubility medications do not distribute well through the membrane but may through the body water spaces.
high-lipid solubility medications are the opposite
relative solubility may make some medications inappropriate because they may not reach an organ that is “fatty”.

one or more biochemical reactions involving a parent drug. Biotransformation occurs mainly in the liver and produces a metabolite that is either inactive or active. Also known as metabolism.

Phase 1 metabolism
-oxidation, reduction, hydrolysis
-increase the polarity of drug molecule (making more ionized, more polar, more charged.) if you reveal a COOH, or OH it makes it more water soluble. this is purpose of metabolism
-hepatic microsomal enzyme drug metabolism:cytochrome P-450: smooth endoplasmic reticulum is where this is housed.
-purpose is to increase the water solubility of the drug
-cytochrome p-450 system can be inhibited and induced. this is a major reason why we get a lot of drug interactions

Phase 2 metabolism
production of metabolites with increased water solubility and increase molecular weight, enhancing elimination

requires conjugation reaction
facilitate elimination
glucuronidation: addition of glucouronic acid. catalyzed by UGTs (expressed in tissue dependant manner and are inducible. highest in GI)
neonates deficient in conjugating system making them vulnerable to drugs such as antibiotics with are inactivated by glucouronic acid

responsible for substrate uptake in the liver

Principles of medication ecretion
final elimination of a medication

How are medications excreted through sweat, salivary ans mammary glands?
Small amounts may be excreted
very limited sweat production makes this route insignificant

How are medications excreted through the lungs?
important route of excretion of gaseous anesthetics
less important for other medications

How are medications excreted through the GI tract?
large lipid-soluble surface area allows for diffusion of medications into the bloodstream. May make the reabsorption of medications or metabolites possible

How are medications excreted through the liver
most important site for metabolism and an important site for excretion. excretion of bile is an important component

How are medications excreted through the kidneys
This is the most important site for excretion
renal blood flow, GFR and tubular secretion iare important parts of this system

How does GFR influence medication excretion?
passive filtration
influenced by renal blood flow, glomerular membranes and water solubility of the medication
limited in neonates
related to gestational age
Important to: indomethacin, digoxin, aminoglycocides, and vancomycin

How does tubular secretion and absorption effect meidcations?
secretion is dependent on tubular function. (penicillin, morphine, thiazides are tubular dependant)

-may occur passive or actively
-reabsorption matures more slowly than GFR
-caffeine, glucose, phosphate and sodium are dependent

Antimicrobial medication
medications that inhibit the growth or kill bacteria, fungi, viruses, protozoa, and amoebae

bacteriostatic medications
Agent inhibiting the growth of bacteria
Ex. Clyndamycin, fluconazole

capable of killing bacteria. Antibiotics, antiseptics, and disinfectants can be bactericidal.
ainoglycocieds, penicillin, cephalosporin

minimal inhibitory concentration
the lowest antibiotic concentration that prevents visible bacterial growth

minimal bactericidal concentration
lowest concentration of antibiotic that results in a 99.9% decline in colony
-dose it takes to kill bacteria

How do microorganisms develop resistance?
enzyme action
decreased cellular penetration
altered taget proteins
efflux pump

efflux pump
Resistance mechanisms which pumps out antibiotics out of bacterial cells

How is the concentration of antibiotics determined?
limited side effects
readily achievable and maintainable

How is the choice of antibiotic made?
relative permeability of the target tissue (blood-brain barrier)
known MIC/MBC
patient characteristics

How does prematurity effect the absorption of medications?
-Changes in GI pH can increase or decrease medication absorption (Penn G is adsorbed better in infants than older infants and older children).
-Skin permeability in the extremely premature neonate may allow topical antibiotics to be adsorbed systemically.
-Blood flow changes may affect absorption or distribution. (Repeaed administration of aminoglycosides IM an SQ antibiotics may damage tissue)

Inotropic/Vasopressive medications
-Includes a broad range of medications that improve cardiac output by increasing the heart rate and force of contraction and increasing the vascular tone

medciation that influences the heart rate (can be positive or negative)

This category of meds increase myocardial contractility

-inhibits the sodium/potassium pump
-increases the intracellular calcium
-increases cardiac contractility
-decreases conduction through the AV and SA node to slow the ventricular rate

Sympathomimetic amines
Inotropic drugs that increase contractility.
epinephrine, ISO, DopAmine and dobutamine)

alpha 1 adrenergic
contraction of the vascular smooth muscle and constriction of blood vessles

alpha 2 adrenergic
activates receptors in the brain to suppress the sympathetic nervous system. decreased motility and tone of the intestine and stomach

beta 1 adrenergic
-Increased HR and myocardial contractility

Beta 2 adrenergic
-Relaxes bronchial smooth muscle
-stimulates mucociliary activity
-some inhibitory action on inflammatory mediator release(antihistamine)
-increased fluid, mucin(submucosal glands)

-used to normalize blood pressure.
-reduce vascular resistance
-decrease pulmonary vascular resistance
-captopril and propranolol

-used to treat arrhythmia
-digoxin, lidocane, esmolol

Special considerations with cardiac medications in the neonatal population
-shock may alter the distribution
-desired response in one organ may lead to undesired effect in another
-some medications are highly albumin bound and may lead to hyperbilirubinanemia

a medicine used to relieve pain

n. substance that removes sensation with or without loss of consciousness

sedative medication
provide mood alteration

-A drug that causes sedation
-one of several derivatives of barbituric acid

-chlorohydrate, lorazepam

Compulsive drug craving and use.

drug tolerance
the tendency for larger doses of a drug to be required over time to achieve the same effect

drug dependance
person taking the drug must continue to take the drug in order to avoid the onset of physical and/or psychological withdrawal symptoms
may need tapering of dose

Basic principles of CNS medication use
-mechanism of action not always clear
-assessment for need is ongoing and needs to be monitored carefully
-consideration for risk/benefit
-long term effects are not known
-other methods should be used first

Special considerations for CNS medications in the neonate
-limited knowledge of development should result in caution
-oral administration highly unpredictable (morphine)
-oral/rectal Tylenol may be enough
-as neonate body fat increases the dose will increase
-slower hepatic metabolism or disease may markedly increase half-life
-renal failure may cause toxic effects or nedications may hase a direct effect on renal function

Drugs that eliminate fluid by increasing urine output by the kidneys

Principles of diuretic use
-commonly cause loss of electrolytes
-effects is base on function of renal tissue
-any medication that increases GFR may have an indirect diuretic effect

special considerations for diuretics on the neonate
-renal tubular function is limited in the neonate and maturity
-larger dose may be required to achieve the same effect
-limited tubular function potentates electrolyte loss

What vaccinations should not be given in the hospital?
-MMR and varicella
-live vaccine

active immunization
-administration of all or part of a microbe or a modified product of to evoke a immune reaction
-some provide a complete protection, some partial, some must be readministerd

passive immunization
-the injection of specific antibodies to provide protection against a pathogen or toxin. The administered antibodies may derive from human blood donors, immunized animals or hybridoma cell lines.
-hep B immune globulin, varicella immune glogulin, palivizumab

Special considerations for immunizations in neonates
-usually give at 2 months because of limited immune response before that age
-the does should NOT be decreased in neonates
-when vacceine is given at birth this does will not be counted. Hep B would need 4 doses rather than 3
-antibody titers will be inadequate to determine response

Misconceptions about vaccine contraindications
-acute illness with low grade fever or mild diarrhea
-current antibiotics or convalescence from illness
-reaction to DPT with fever less than 105F
-pregnancy within the household
-allergies other than neomycin or streptomycin other than anaphalyxis
-family history of seizure with pertussis or measles vaccine
-duck allergies
-family Hx. SIDS

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