UNIT 3: Ch 8, 9, and 10

Pharmacokinetics: Neonates and Infants

Because organ systems that regulate drug levels are not completely developed, at risk for drug effects that are both intense and prolonged. By accounting for pharmacokinetics, we can increase probability that drug therapy will be effective and safe

Teratogens: neurobehavioral and metabolic anomalies

Benzos taken late in pregnancy may cause hypoglycemia and respiratory complications alone with a hypotonic state called floppy infant syndrome. Streptomycin can cause congenital deafness

Percentage of (geriatric) patients fail to take their medication as prescribed:

Between 26-52%

Pharmacokinetics: Children 1 Year and older

By 1 year, most pharmacokinetics in children are similar to adults Drug sensitivity in kids >1yr is more similar to adults than the very young Although pharmacokinetically similar to adults, they still metabolize drugs faster Drug metabolizing capacity markedly elevated until age 2, then gradually declines. Further sharp decline happens at puberty Because of increased metabolism, an increase in dosage or reduction in interval may be needed

Drug Therapy During Breastfeeding:

Drugs taken by lactating patients can be excreted in breast milk. Factors that determine entry into breast milk are the same factors as those that determine passage of drugs across membranes. Lipid-soluble drugs enter breast milk readily Ionized, highly polar, protein bound drugs tend to be excluded

Promoting Adherence

Effective education is critical; issues to address Written instructions should reinforce verbal With young children, spills and spitting out are common causes of inaccurate dosing When more than one person is helping medicate a child, all participants should be warned against multiple dosing With some disorders- esp. Infections- symptoms may resolve before course of treatment has concluded

Placental Drug Transfer

Factors that determine passage across the placental membrane are the same as other membranes Drugs that are lipid-soluble cross the placenta easily Ionized, highly polar, or protein-bound drugs have difficulty crossing the membrane Assume that any drug taken in pregnancy will cross the placental membrane

Teratogen exposure, week 3-8:

If exposure occurred during organogenesis (week 3-8), reference about FDA approved prescribing information should be consulted to determine the type of malformation expected Then 2 ultrasounds to assess extent of injury If severe, termination should be considered

Pharmacokinetics: Neonates and Infants

Pharmacokinetic factors determine the concentration of a drug at its site of action and hence determine the intensity and duration of response. If drug levels are elevated, responses more intense If drug elimination is delayed, responses will be prolonged

Teratogens: behavioral changes

Teratogens that affect behavior may be nearly impossible to identify Behavioral changes often delayed, so may not be apparent until school Difficult to develop a correlation between maternal drug use

Pharmacokinetics: Neonates and Infants, hepatic metabolism:

The drug-metabolizing capacity for newborns is low. Neonates are especially sensitive to drugs that are eliminated primarily by hepatic metabolism Reduce dosages of these Capacity of liver to metabolize many drugs increases rapidly about 1mo after birth and reaches adult level months later, fully developed at 1yr

A teratogen that can cause malformation in single dose

thalidomide

Drugs that are contraindicated during breastfeeding: anticancer agents/immunosuppresants

cyclophosphamide, cyclosporine, doxirubicin, methotrexate

BEERS List

BEERS list identifies drugs with a high likelihood of causing ADR in older adults Drugs on this list should generally be avoided in older adults except when the benefits outweighs the risks

Minimizing Drug Risk During Pregnancy

A first step to decrease drug risk is to develop comprehensive list of drugs used Include prescriptions, OTC meds, supplements, recreational drugs Vit A can cause craniofacial abnormalities if taken in excess If pregnancy status is unknown, and high-risk drug prescribed, pregnancy test should be done before taking medication

Pharmacodynamic Changes in Older Adults: Adverse Drug Reactions and Drug Interactions

ADRs are 7 times more common in older adults, accounting or 16% of hospital admissions Most often dose related, not idiosyncratic; Symptoms in the older adults are often nonspecific (dizziness, cognitive impairment), making identifying ADRs harder

Pharmacokinetics: Children 1 Year and older, ADRs:

Adverse Drug Reactions Pediatric patients are subject to ADRs when drug levels rise too high Vulnerable to unique ADRs related to organ system immaturity and to ongoing growth and development

Why do geriatric patients experience more ADRs and more drug-drug interactions

Altered pharmacokinetics (secondary to organ system degeneration) Multiple and severe illnesses Multidrug therapy Poor adherence To help ensure drug therapy is as safe as possible, individualization of treatment is essential; each patient must be monitored for desired and ADRs, and the regimen adjusted accordingly

Pharmacokinetics: Children 1 Year and older, ADRs:

Among these age related effects are: growth suppression (glucocorticoids), discoloration of teeth (tetracyclines), and kernicterus (sulfonamides)

Drug Therapy in Geriatric Patients

As a rule, older patients are more sensitive to drugs and show wider individual variation. Experience more ADRs and more drug-drug interactions

Teratogens: preimplantation/presomite period (conception-wk 2)

Drugs given during the preimplantation/presomite period, teratogens act in an all-or-nothing fashion If drug dose is sufficiently high, result is death of conceptus If dose is sublethal, full recovery possible

Physiologic Changes that can affect pharmacotherapeutics in Older Adults: metabolism

Decreased hepatic blood flow: Half-life of certain drugs may be increased, prolonging responses Response to oral drugs that ordinarily undergo extensive first-pass metabolism may be enhanced because fewer drugs are inactivated before entering system circulation Decreased hepatic mass Decreased activity of hepatic enzymes

Drug Therapy During Pregnancy: Basic Considerations

Despite the impossible challenge of balancing risk/benefits, drug therapy shouldn't be avoided Health of fetus depends on health of mother, so mother's conditions need to be controlled Uncontrolled maternal asthma is more dangerous to the fetus than the meds to treat it

The increased sensitivity of infants is due largely to immature state of 5 processes:

Drug absorption Protein binding of drug Exclusion of drugs from the central nervous system by blood brain barrier Hepatic drug metabolism Renal drug excretion

Pharmacokinetics: Neonates and Infants, IM administration, absorption:

Drug absorption in the neonate is slow and erratic. Delayed absorption due to low blood flow throughout muscle in the first days of life By early infancy, absorption of IM drugs becomes more rapid than neonates AND adults

Pharmacokinetics: Neonates and Infants, transdermal administration, absorption:

Drug absorption through skin is more rapid and complete in infants than in older children and adults. The Stratum corneum of the infant skin is thin, and blood flow is greater. Because of this, infants are at increased risk for toxicity from topical drugs.

Factors that predispose older patients to ADRs:

Drug accumulation secondary to reduce Polypharmacy Greater severity of illness Presence of comorbidities Use of drugs that have a low therapeutic index (digoxin) Increased individual variation secondary to altered pharmacokinetics Inadequate supervision of long-term therapy Poor patient adherence

Drug Therapy During Pregnancy: Basic Considerations

Drug use during pregnancy is common: ⅔ take meds; some for pregnancy-related conditions (nausea, pre-eclampsia), while others treat chronic conditions (HTN, DM).

Teratogenesis and Stage of Development:

Fetal sensitivity to teratogens changes during development; thus effect is dependent on when the drug is given: preimplantation/presomite period (conception through week 2) Embryonic period (week 3-8) Fetal period (week 9 through term)

Identification of teratogens:

For the following reasons, teratogens are hard to identify: Incidence of congenital abnormalities is relatively low Animal tests may not be applicable to humans Prolonged drug exposure may be required Teratogenic effects may be delayed Behavioral effects are difficult to document Controlled experiments cannot be done in humans

Physiologic Changes that can affect pharmacotherapeutics in Older Adults: distribution

Four major things alter distribution: Increased body fat Decreased lean body mass Decreased total body water Decreased serum albumin + Decreased cardiac output

Pharmacokinetic Changes in Older Adults

From early adulthood on, there is a gradual, progressive decline in organ function. As a rule, these changes increase drug sensitivity (largely d/t reduced hepatic and renal drug elimination) Changes may be minimal is adults who've remained fit Note that age related changes are not only a source of increased sensitivity to drugs but potential source of increased variability

Pharmacokinetics: Neonates and Infants, oral administration, absorption:

GI physiology in the infant is very different from adults Gastric emptying time is both prolonged and irregular in early infancy, then reaches adult values by 6-8 months In drugs that are absorbed primarily from the stomach, delayed gastric emptying enhances absorption, but for those absorbed by intestines, absorption is delayed Because gastric emptying times are irregular, absorption effects are unpredictable Gastric acidity is very low 24 hours after birth and doesn't reach adult values until 2 years; because of this, absorption of acid-labile drugs is increased

Teratogens: embryonic period (wk 3-8)

Gross malformations are produced by teratogenic exposures during the embryonic period This is when the basic shape of organs is being established. Fetus are especially vulnerable during this time; extreme caution

Pharmacodynamic Changes in Older Adults: Alterations in receptor properties

In support of the possibility of altered pharmacodynamics is the observation that beta-adrenergic blocking agents (drugs used primarily for cardiac disorders) are less effective in older adult, even when given in same concentrations Possible explanations: A reduction of the number of beta receptors Reducing in the affinity of beta receptors for beta-receptor blocking agents Other drugs (warfarin, central nervous system depressants) produce more intense effects in older adults→ increased receptor # or receptor affinity

Teratogenasis: Incidence and Causes of Congenital Abnormalities

Incidence of major abnormalities (life-threatening or require surgery) - 1-3% Incidence of minor or functional abnormalities is unknown Congenital anomalies have several causes: Genetics account for 25% of anomalies <1% caused by drugs Most causes are unknown

PLLR: Females and males of reproductive potential

Included to address need for pregnancy testing or contraception and adverse effects associated with preimplantation loss or effects on fertility Pregnancy testing Contraception Infertility

PLLR: Lactation

Lactation Risk Summary Presence of drug in human milk Effects of drug on breastfed child Effects of drug on milk production/excretion Clinical Considerations Minimizing exposure Monitoring for ADRs

Factors that increase risk for poor adherence in older adults

Multiple chronic disorders Multiple Prescription Medications Multiple Doses per day for each medication Drug packaging that is difficult to open Multiple Prescribers Changes in the regimen (addition of drugs, changes in dosage size or timing) Cognitive or physical impairment (reduction in memory, hearing, visual acuity, color discrimination, or manual dexterity) Living Alone Recent discharge from hospital Low literacy Inability to pay for drugs Personal conviction that a drug is unnecessary or dosage too high Presence of side effects

Physiologic Changes that can affect pharmacotherapeutics in Older Adults: absorption

Not a major factor; the percentage of an oral does that becomes absorbed doesn't usually change with age, however the rate of absorption may be slowed Gastric acidity is reduced, therefore absorption of drugs requiring highly acidic environments to dissolve may be reduced Increased Gastric pH Decreased absorptive area Decreased splanchnic blood flow Decreased GI motility Delayed Gastric Emptying

Pharmacokinetics: Neonates and Infants, distribution, blood-brain-barrier:

Not fully developed at birth; drugs and other chemicals have easy access to CNS Makes infants especially sensitive to drugs affecting CNS function All drugs employed for CNS effects (morphine, phenobarbital) should be given in reduced dosages Also reduced for drugs used for action outside the CNS, if they're able to produce CNS toxicity as a side effect

Adverse Reactions during Pregnancy

Not only are pregnant patients susceptible to traditional ADRs, may have some that are unique to pregnancy only, as well. When heparin is taken by a pregnant woman, can cause osteoporosis, causing compression fractures in the spine. Prostaglandins (misoprostol) stimulates uterine contractions and can cause abortions Aspirin taken near term can suppress contractions and increase the risk for serious bleeding.

Drugs considered hazardous during breastfeeding:

Opioids, marijuana, anticancer drugs, atenolol, bromocriptine, ergotamine, lithium, nicotine, and more

Pediatric dosage determination:

Pediatric doses have been established for some drugs, but not most For those that don't have doses, can be extrapolated from adult doses, based on Body Surface Area (BSA): Child's BSA x adult dosage / 1.73m^2 = pediatric dosage /\ Adjust subsequent doses on clinical outcome and plasma concentration

Pediatric ages:

Pediatrics covers all patients up to age 16: Premature infants (less than 36 weeks gestational age) Full-term Infants (36-40 weeks gestational age) Neonates (first 4 postnatal weeks) Infants (postnatal weeks 5 to 52) Children (age 1 to 12) Adolescents (age 12 to 16)

PLLR: Pregnancy

Pregnancy Exposure Registry If it exist, statement is "There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to *name of drug* during pregnancy" Risk Summary Summarize outcomes for the following content: Drug dosage, length of time taken, and weeks of gestation when drug was taken, and pharmacological mechanism of action Human and animal data Clinical Considerations disease- associated maternal and/or embryo/fetal risk Maternal and embryo/fetal adverse reactions Labor or delivery Data Human Data Animal Data

Physiologic Changes During Pregnancy

Pregnancy causes physiological changes for drug disposition Compensatory dosing may be needed By 3rd trimester, renal blood flow is doubled, causing an increase in GFR Accelerated clearance of drugs eliminated by kidneys Example: lithium excretion is increased 100%, so increase the dosage Tone and motility of bowel decreases in pregnancy, increasing time in intestines Increases intestinal absorption, decrease doses of meds absorbed intestinally

Drug Therapy During Pregnancy: Basic Considerations

Presents a dilemma; benefits MUST outweigh risks Most drugs haven't been tested during pregnancy When drugs given during pregnancy, there are risks for the fetus

Considerations for End of Life Care

Priority treatment varies as goals shift from disease prevention and management to provision of comfort measures. Drugs that were once considered important in care (drugs for cholesterol management) may no longer be important and may be discontinued Drugs that were considered inappropriate due to age (sedatives) may become predominant in their care

Pharmacokinetics: Neonates and Infants, distribution, protein binding:

Protein Binding Binding of drugs to albumin and other plasma proteins is limited in infants because: Amount of serum albumin is relatively low Endogenous compounds (fatty acids, bilirubin) compete with drugs for available binding sites Drugs that ordinarily undergo extensive protein binding in adults undergo much less in infants Concentration of free levels of such drugs is relatively high in infant, intensifying the effects To ensure effects aren't too intense, dosages in infants should be reduced; protein binding capabilities reaches adult value within 10-12mo

Regular use of dependence-producing drugs and pregnancy

Regular use of dependence-producing drugs (heroin, barbituates, alcohol) can result in birth of a drug-dependent infant If newborn dependence isn't supported by drugs, withdrawal syndrome ensues. Symptoms: shrill crying, vomiting, and excessive irritability Neonate should be weaned; give progressively smaller doses Certain pain relievers given during pregnancy can depress respirations Monitor newborn until respirations normalized

Teratogens: fetal period (wk 9- term)

Teratogen exposure in fetal period (2nd and 3rd trimesters) usually disrupts function rather than gross anomalies. Disruptions in brain development can cause learning deficits and behavioral abnormalities.

Physiologic Changes that can affect pharmacotherapeutics in Older Adults: excretion

Renal function undergoes progressive decline beginning in early adulthood: Drug accumulation secondary to reduced renal excretion is most important cause of ADRs in older adults Decreased renal blood flow: When patients are taking drugs excreted by kidneys, renal function should be assessed In older adults, proper index is creatinine clearance, not serum creatinine levels Decreased glomerular filtration rate Decreased tubular secretion Decreased number of nephrons

US FDA Pregnancy and Lactation Labeling Rule

Requires three sections: Pregnancy, lactation, and females and males of reproductive potential

STOPP

STOPP stands for Screening Tool of Older People's potentially inappropriate Prescription Has an advantage of also considering economic costs of drug therapy When combined with START (Screening tool to Alert doctors to Right Treatment), set can be used to promote selection of appropriate treatment in addition to avoidance of inappropriate treatment

Pharmacokinetics: Neonates and Infants, renal Excretion:

Significantly reduced at birth; renal blood flow, GFR, and active tubular secretion are all low during infancy Drugs that are eliminated primarily by renal excretion must have lower dosages Adult levels of renal function reached by 1year

Teratogens, to note:

To note: lack of proof of teratogenicity does not mean a drug is safe to use. Conversely, proof of teratogenicity does not mean every exposure will result in congenital abnormalities. With most, risk of abnormalities is less than 10%

3 criteria to be met to prove a drug is a teratogen:

To prove a drug is a teratogen, 3 criteria must be met Must cause a characteristic set of malformations Must act only during a specific window of vulnerability Incidence of malformation must increase with increasing dosages and number of exposures

Responding to Teratogen Exposure

When a pregnant patient has been exposed to a known teratogen, first step is to determine exactly when drug was taken and when pregnancy began

Pharmacokinetics: Neonates and Infants IV dosing

When given IV, levels decline more slowly in infants than adults Drug levels remain above the MEC for longer than adults

Pharmacokinetics: Neonates and Infants SQ dosing

When given SQ, not only do levels in the infant remain above the MEC, longer than the adult, but levels rise higher, they are more intense and prolonged

Hazardous drugs and breastfeeding:

When hazardous drugs must be used, steps should be taken to minimize risk: Dosing immediately after breastfeeding (lowers concentration at next feeding) Avoiding drugs with long half-life Avoiding sustained-release formulations Choosing drugs that tend to be excluded from milk Choosing drugs least likely to affect infant Avoiding known hazardous drugs Abandoning plans to breastfeed if a necessary drug is known to be harmful to the child. Fortunately, most drugs detected in milk are in concentrations too low to cause harm

Drug Therapy in Pediatric Patients

Young patients respond differently to drugs than the rest of the population. Most differences are quantitative- they're more sensitive to drugs than adults and show greater variations. Drug sensitivity is largely from organ system immaturity Higher sensitivity→ greater risk for ADRs

Drugs that are contraindicated during breastfeeding: controlled substances

amphetamine, cocaine, heroin, marijuana, phencyclidine

Drugs that are contraindicated during breastfeeding: others

atenolol, bromocriptine, ergotamine, lithium, nicotine, radioactive compounds (temporary cessation)