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Pharmacologic Implications for Special Patient Populations:

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1 Pharmacologic Implications for Special Patient Populations:
Pregnant Elderly Pediatric Judith A. Kaufmann, Dr PH, FNP-C Associate Professor of Nursing Robert Morris University

2 Vulnerable Populations: At Most Risk for Adverse Drug Effects and Reactions

3 Reasons: The 5 “toos” Too few patients represented in studies to detect rare events 30,000 people in each category would need to receive the medication to detect 1 adverse reaction in a drug that affects 1:10,000 Too simple: patients with multiple conditions excluded from trials Too median-aged: studies exclude patients at each end of the spectrum

4 2 More “Toos” Too narrow: indications for newly approved drugs are based on pre marketing clinical trials for ONE very specific condition Once marketed, the drug may be used for untested indications Too brief: most clinical trials are short Some adverse effects take years to manifest clinically

5 Drugs in Pregnancy Treatment Goals
Utilize appropriate resources to determine teratogenic risk and excretion in breast milk Assess the risk: benefit ratio of pharmacotherapy Utilize drug regimen that is safe, effective and minimizes risk to fetus or infant Minimize drug exposure to neonate/infant during lactation

6 Epidemiology ~35% of women take some medications during pregnancy
Range/pregnancy = 1-15 medications (M=2.9) OTC medications not included WHO study showed that non-white, unmarried, less educated women less likely to use medications Today ~60% of women breastfeed Over 1,000 drugs per year are evaluated for teratogenic potential ~10% of children have abnormal physical or mental development Only 2-3% of these are associated with medications

7 Resources for Information
Data on drugs in pregnancy and lactation are almost always POST marketing Constantly being updated-need for immediate access to drug updates 1979-FDA categories for Drug Use in Pregnancy FDA’s Adverse Drug Reaction reporting system underused MEDWATCH Program initiated in 1993

8 Lessons from the Past Thalidomide first appeared in Germany on 1st October 1957 marketed as a sedative with few side effects Considered safe, used for morning sickness Drug testing procedures were less rigorous limited testing failed to reveal tetragenic side effects Pre-marketing tests conducted on rodents which metabolize the drug in a different way to humans Subsequent tests on rabbits and monkeys produced similar SEs as in humans. Late 1950’s: post marketing reports Pharcomelia: babies born with flipper-like limbs AKA: 'Thalidomide Babies’

9 Pharcomelia

10 FDA Categories for Drug Use in Pregnancy
Category A: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities Category B: Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.

11 FDA Categories Category C:
Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women Category D: Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

12 FDA Categories Category X: Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the drug is contraindicated in women who are or may become pregnant.

13 Excellent Website Ob.Gyn. News - Editorial

14 X-Rated Drugs Accutane Estrogen Isotrentinoin Vaccines: MMR, Varicella
CDC Advisory Committee on immunization Practices Vaccinate all pregnant women with INACTIVATED influenza vaccine in the fall or throughout influenza season

15 Addressing Patients’ Concerns for Vaccine Safety
The US FDA approved Fluarix, an inactivated influenza vaccine for adults in 2005 Fear of mercury and thimerosal Spurred by media IOM (2004) released results of analysis of potential link between thimerosal and neurobehavioral conditions and found no evidence of association BUT… urged “full consideration …to removing thimerosal from any product given to infants, children or pregnant women”

16 Current Vaccines Available
Thimerosal-free or Thimerosal-reduced May be added at the end of manufacturing process to prevent bacterial or fungal growth Results in minute traces in final product Institute for Vaccine Safety - Thimerosal Table

17 Thompson, et al, (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 Years. NEJM. 357 (13) N= 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes Findings: The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure associated with better performance on one measure of language and poorer performance on one measure of attention and functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination

18 Pregnancy alters the Pharmacokinetics of Most Drugs
Increase in total body water (~8L) Increase in total body fat Increase in GFR Decrease in gastrointestinal motility and changes in absorption and gastric acidity Increase in CO, blood volume and plasma proteins Decrease in plasma albumin concentration Changes in serum albumin effect the bioavailability of protein-binding

19 Pregnancy and Pharmacokinetics
Pregnancy often accompanied by nausea and vomiting, which may prevent absorption of the medication, but… Increased plasma volume, fetal growth, and increased interstitial tissue result in a wider distribution of medications

20 Bottom Line Every woman requires thorough history of pregnancy complaints prior to pharmacologic treatment Dosages may need to be considered based on the stage of pregnancy Prescribing in pregnant patient requires more than just attention to FDA drug categories

21 In Translation… Absorption affected by decreased GI tone
Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption of drugs Distribution affected by increased plasma volume causing prolonged half lives Fat soluble drugs stay longer in the body Drugs with high protein binding and lower lipid solubility (such as anticonvulsants) have longer half lives Hormones (strongly protein bound) compete for available binding sites-resulting in wide distribution of free, unbound drug in the body

22 Pregnancy and Pharmacokinetics
Metabolism of drugs in liver relatively unchanged Drugs cleared through liver eliminated similar to non pregnant women Excretion-increased rates of clearance Renal blood flow increases by 25-50% GFR increases by 50% Serum level of drug must fall to allow diffusion of drug from the fetus’s circulation

23 Placental Transfer Simple diffusion: molecular size may/not permit transfer Active transport: where concentration of substances are higher in fetus and transported back to the mother Pinocytosis: where soluble molecules (such as viruses) cross membrane in small vesicles and are released Facilitated diffusion: glucose is rapidly transferred to fetus Leakage: fetal cells enter mother’s circulation through small membrane breaks

24 Properties of Medications that easily cross the placenta
Small molecular size and weight ( d) Most drugs have weights < 600d Non-protein bound Non-ionized Lipophilic

25 Selecting a Drug for a Pregnant or Nursing Mother
Principles of teratology: Timing of exposure in fetal development Based on fetal developmental stage when insult is applied can help predict the possible defect Exposure at time of conception and implantation may kill the fetus (all or nothing effect) If exposure occurs in first 14 days after conception when the cells can assume another cell’s function (totipotential), the fetus may not be damaged Most sensitive period: time from implantation to the end of organogenesis (days ) Damage to developing organs heart is most sensitive during the 3rd and 4th weeks of gestation, external genitalia are most sensitive during the 8th and 9th weeks brain and skeleton are sensitive from the beginning of the 3rd week to the end of pregnancy and into the neonatal period.

26 Factors that Influence Teratogenicity of a drug
Genotypes of the mother and fetus Embryonic stage at exposure Drug dose Duration of exposure Nature of the agent and mechanism by which it causes a defect Simultaneous exposure to other drugs and environmental agents that potentiate a drug Maternal and fetal metabolism of the drug Extent to which the drug crosses the placenta

27 The safest pregnancy-related pharmacy is as little pharmacy as possible
However, women with a history of psychiatric, seizure-related, or hematologic illnesses frequently require medication throughout pregnancy. In such patients, care must to be taken to select the safest drug from the necessary class of medication. Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist Misri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. Can J Psychiatry. Aug 2007

28 The Male Partner… Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy Certain exposures may alter the size, shape, performance, and production of sperm suggests that drug exposure in the male may put the fetus at risk Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop unlike teratogenic agents affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development  Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure. Austin, 1994; Chatenoud, 1998

29 For example: Colchicine Pregnancy category - D
Trimester of risk - Unknown Associated defects and complications - potential chromosome aberrations Studies: Colchicine has been shown to cause birth defects in animals. The drug can lower sperm counts and cause sperm defects, resulting in birth defects.

30 Current EB Recommendations
In humans, no evidence of birth defects after paternal exposures, but to minimize any possible risk, counseling in men exposed to radio and chemotherapy should delay conception ~ 3 months after the end of therapy. Male patients treated with drugs with maternal teratogenic potential should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy. Reproductive Toxicology, 2008

31 Drug Exposure Options for Pregnant and Lactating women
Withhold the drug (e.g., headache medications) E.g., Ergotamine: Pregnancy category - X Trimesters of risk - all Associated defects and complications: LBW, and preterm birth, ergotamine-induced vasoconstriction in the placenta of pregnant women. The effect of ergotamine most obvious in male newborn infants, particularly after treatment in the third trimester. Delay drug therapy (if woman is close to end of lactation)

32 Options Choose drugs that pass poorly into placenta or breast milk- (e.g., some variations even within same class of drug) e.g., Benzodiazepines-Pregnancy category - D or X Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam (dalmane), temazepam (restoril), and triazolam (Halcion) (category X). Avoid alprazolam (Xanax-cat D) during pregnancy Chlordiazepoxide(Librium) appears to be safest choice during pregnancy.

33 Options Choose alternate routes of administration when possible
Avoid long acting/medications with long half lives Advise lactating women to time their medications before the infant’s longest sleep period Temporarily withhold breast feeding Can safely resume after 1-2 half lives (50%-75% elimination) For drugs with high toxicity, must delay 4-5 half lives Discontinue nursing if medication is for life threatening condition (e.g., chemotherapy)

34 Treatment of Select Conditions during Pregnancy
Asthma: Asthma complicates approximately 4% of pregnancies In some cases, asthma improves during pregnancy Those with poorly controlled asthma are at risk for: Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor

35 IMPLICATIONS of Pregnancy on Asthma
Pregnancy has a significant effect on the respiratory physiology of a woman Respiratory rate and vital capacity do not change in pregnancy, but there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual capacity and residual volume of air due to elevation of the diaphragm  Airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of progesterone 

36 Improved Outcomes associated with controlled asthma
Current EVIDENCE Supports Treatment Almost all anti-asthma drugs are safe to use in pregnancy and during breastfeeding.  Under-treating is a frequent occurrence for the pregnant patient because patients are worried about the medication effects on the fetus With a few exceptions, the medications used to treat asthma during pregnancy are similar to the medications used to treat asthma at other times during a person's life.

37 Choice of Asthma Medications
The type and dose of asthma medications will depend upon many factors. inhaled drugs are recommended because there are limited body-wide effects in the mother and the baby. It may be necessary to adjust the type or dose of drugs during pregnancy to compensate for changes in the woman's metabolism and changes in the severity of asthma.

38 Common Asthma medications
Inhaled B2 Agonists Albuterol-Category C Mild, infrequent episodic May cause maternal hyperglycemia, tachycardia, hypotension or neonatal hypoglycemia Briggs, et al., 2002: study of 1090 infants exposed to albuterol in 1st trimester-possible association with polydactyly No congential defects link in 2nd, 3rd trimester No adverse effects during lactation Possible B2Choice-Brethine (category B)

39 Theophylline (Cat C) Can be used along with inhalation therapy
Preferred treatment for patients requiring long term therapy Must monitor levels throughout pregnancy to avoid toxicity Especially important in 3rd trimester d/t decrease in theophylline clearance and increase in volume of distribution Keep maternal plasma concentrations as low as therapeutically possible Crosses placenta in equal concentrations to mother Not associated with congenital defects but can cause jitteriness, cardiac arrythmias, hypoglycemia, feeding difficulties in infants Neonates more likely affected

40 Corticosteroids (Cat C)
Systemic corticosteroids are reserved for patients who require more urgent treatment. Conversely, cromolyn and nedocromil (Cat B) inhibit antigen- and exercise-induced asthma. They can be indicated as the first-line anti-inflammatory medication for the treatment of asthma Does not have systemic absorption ?crossing of placenta

41 Corticosteroids (cat C)
Can be given IV, PO, or inhaled 2 reports congenital cataracts in infants exposed to prednisone throughout gestation No association found in other studies Spontaneous abortion, prematurity, cardiac abnormalities reported in one study ( Greenberger,1983) Prednisone <20mg/day safe in lactation In larger doses, delay nsg 3-4hours after dose

42 Epilepsy > 1 million women of childbearing age have epiliepsy
<1% of pregnancies are complicated by seizures 25% of women will have an increase in seizures during pregnancy Women with epilepsy (with or without medication) have a higher incidence of delivering an infant with congenital malformations and mental retardation Rates of major malformations affecting the heart, skeletal or nervous system in children born to women on anticonvulsants are at least double the rate in the general population Occurrence: 4–6 per hundred births vs the 2-3 per hundred births risk that all pregnant women face Benefits v risk are overwhelmingly important to consider

43 Epilepsy in Pregnancy AAP recommends that a patient who is seizure free for 2 years undergo trial medication withdrawal before becoming pregnant Suggested waiting period of 6 months after d/cing medication Anticonvulsant pharmacokinetics change during pregnancy: Lower serum concentrations due to increased renal and hepatic clearance Decreased protein-binding capacity Increased volume distribution despite lower serum concentrations, seizures may not increase due to increased free drug concentrations Must monitor concentrations of anticonvulsants closely

44 Newborns exposed to anticonvulsants
Hemorrhagic disease in newborns in first 24 hours can be fatal Due to deficiency in Vit K clotting factors as a result of anticonvulsant exposure All infants should be treated with Vit K at birth Some physicians recommend Vit K for mother in last 2-4 weeks of pregnancy Anticonvulsants also causes folate deficiencies Prophylactic folic acid during gestation recommended to prevent megaloblastic anemia and/or neural tube defects

45 Fetal Anticonvulsant Syndrome
Can occur with all antiepileptic drugs Phenytoin (cat D) can cause fetal hydratoin syndrome School, learning and developmental problems, craniofacial abnormalities, growth retardation, limb defects, cardiac lesions, hernias, distal digital and nail hyoplasia 10% risk for all of above (FHS) 30% risk of partial expression of syndrome

46 Phenobarbital (cat D) Less teratogenic that phenytoin but can cause heart defects and cleft palate Can also cause coagulopathies and folate deficiencies Also has potential to cause neonatal addiction Found in breast milk-causes newborn drowsiness, feeding difficulties, and infantile spasms after weaning

47 Carbazamine and Valproate (Cat D)
At first, thought to be less harmful to fetus Associated with the same congenital abnormalities plus spina bifida (1%) Can be used with caution in lactation

48 Lamotrigine (Lamictal), Gabapentin (Neurontin) and Oxcarbazine (Trileptal)= Cat C
Recent results encouraging Appear to be less teratogenic or associated with fetal loss in 1st trimester Caution: more data needed

49 So…the jury is still out…
Although there appears to be a predisposition for congenital malformations in the offspring of women treated for epilepsy, it is hard to establish a causal effect with the medication It may be a complex interaction of the medication, the nature of their disease, and genetics rather than just the medication alone Samuels, 2002 The three most common malformations noted in children of women treated for epilepsy are cardiac malformations, facial clefts, and genital/renal malformations.

50 The Teratogenicity of Anticonvulsant Drugs
Holmes, et al: NEJM 2001- Methods: screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size.

51 Results The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants

52 Conclusions A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself

53 Coagulation Disorders
Pregnancy is a hypercoagulable state Incidence for DVT is still low: % Current recommendations for prophylaxis based on risk factors: Hereditary factors (protein C deficiencies/leiden factors) Hx of DVT/PE Age >35 Multiple miscarriages

54 Heparin: anticoagulant of choice (Cat C)
Does not cross placenta Not associated with congenital defects Late pregnancy may be associated with increased heparin doses Perinatal mortality rates significantly improved for patients on heparin v. coumadin (3.6% v. 26.1% mortality) LMWH (Lovenox) safe and effective Less bleeding potential and less risk of osteoporosis Does not cross fetal circulation Not excreted in breast milk

55 Coumadin (cat D) Exposure during 6-8th weeks can cause fetal warfarin syndrome Defects in CNS and skeletal system Exposure throughout pregnancy can cause: Stillbirths, spontaneous abortion, facial abnormalities Compatible with breast feeding

56 Treating Common Problems in Pregnancy
Common Cold Nausea/Vomiting Constipation Heartburn Hemorrhoids

57 Over the Counter Drug of Choice
Drug Class During Pregnancy During Lactation analgesics acetominophen antacids Calcium carbonate antihistamine chlorpheniramine Hemorrhoidal agents Preparation H ointment decongestant Oxymetazoline nasal spray none laxative Psyllium or docusate

58 The Common Cold No value in treating with medications
If using medication, avoid combination products Limit duration of treatment Antihistamine of choice: chorpheniramine (cat B) or Loratidine (cat B) Avoid brompheniramine (Dimetapp-Bromfed) Antihistamines excreted in breast milk Nasal cromolyn, beclomethasone useful alternative Clubfoot and inguinal hernias associated with first trimester use of decongestants (e.g., Sudafed) Anti-tussives and expectorants all category C No epidemiologic studies demonstrate fetal harm

59 Nausea and Vomiting 80% of women experience n/v during 1st trimester
Hyperemesis gravidarum-intractable, causes lyte imbalances, weight loss, possible end organ damage Occurs in 1:1000 births Requires hospitalization Cause unknown-tx focused on sx Non pharmacologic measures not supported by evidence OTC phosphorated carbohydrate (EMETROL) safe Meclizine (cat B) drug of choice

60 Constipation Etiology: increased pressure on colon, decreased peristalsis, increased progesterone, decreased motilin, increased colonic absorption of water Bulk-forming laxatives (Metamucil) safe in pregnancy and lactation Increase fluids to prevent intestinal obstruction Surfactants/Stool softeners (docusate), mineral oil Cat c

61 Heartburn Affects 72% women in 3rd trimester
d/t relaxation of LES and uterine displacement + hormonal changes in gut motility Magnesium, calcium carbonate, and/or aluminum hydroxides considered safe Avoid H2 blockers If necessary-ranitidine preferred over cimetidine (has anti-androngenic effects) Metoclopromide (Reglan) cat B

62 Hemorrhoids OTC external preparations preferred
Avoid suppositories d/t potential for systemic absorption across rectal mucosa

63 General Principles

64 Limitations of Drug Therapy in Children
75% of FDA approved medications lack indications in children Pediatric practitioners actually prescibe “off label” FDA indications for dosing regimens are lacking Safety is based on post marketing reports of adverse events

65 Post Marketing Adverse Drug Reports
MED WATCH FDA https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm

66 Important Legislation
1994: first FDA regulations regarding drug product labeling of known use and dosing Resulted in FDA approval of limited number of drugs in children 1997: Pediatric Exclusivity Provision of FDA Modernization Act passed Incentive for manufacturers to implement studies of their products on children 1999: Pediatric Rule developed Mandated that manufacturers perform trials and provide safety and efficacy data 2003- Pediatric Research Equity Act-outlined FDA authority to enforce Pediatric Rule

67 Despite interest in pediatric drug therapy research, conducting clinical trials poses unique challenges Consider: Recent reports of suicide with SSRI Treatment/ over treatment of ADHD Treatment of GERD

68 For Release: November 5, 2007, ANTIREFLUX MEDICATION MAY BE OVERPRESCRIBED IN INFANTS A majority of infants taking anti-reflux drugs did not meet the diagnostic criteria for gastroesophageal reflux disease (GERD), according to a new study, "Are We Overprescribing Antireflux Medications for Infants With Regurgitation?" Researchers conducted esophageal pH monitoring (measuring the reflux or regurgitation of acid from the stomach into the esophagus) of 44 infants in a New Orleans medical center. Each of the children had persistent regurgitation and was referred to a specialty service for further management. The study showed that while only eight of the infants had abnormal pH levels indicating GERD, 42 of 44 infants were on antireflux medication. When medication was withdrawn from the infants who did not meet GERD criteria, reflux symptoms did not worsen. The study authors concluded that antireflux medications were unnecessary in the majority of infants who were prescribed such medication.

69 Developmental Pharmacology
Pharmacokinetic differences in children vary with age Drugs considered safe in one group of pediatric patients may be ineffective or toxic in another group Hepatic enzymes and metabolic pathways mature at different rates E.g., maturation of each pathway is asynchronous When a drug’s primary route of metabolism is immature, it may be shunted through an alternate pathway Drug dosing dilemmas can be avoided by using only those drugs with scientifically supported dosing

70 Key Points In infants, metabolism of most drugs is reduced
GFR is 20-40% of adult capacity at birth and increases after the 1st week of life-reaches maximal level by 12 months In general, children over 10 years have organ development and metabolism similar to adults May require dosing adjustments based on body surface area

71 Key Points (con’t) GI tract acidity, enzymatic activity, and motility differences in infants and young children alter absorption of PO drugs Drugs that are weak bases increase drug absorption Drugs that are weak acids reduce drug absorption Reduced gastric transit in infants delays absorption and peak plasma concentration time-but NOT the amount of drug absorbed

72 Key Points Absorption from transcutaneous route is enhanced in infants-increased risk of adverse effects Caution with use of topicals in infants The volume of drug distribution in infants and young children is increased due to increased body water Results in need for increased drug doses for water-soluble drugs (e.g., aminoglycosides) Drugs that are lipophilic (e.g., diazepam) may exhibit lower volume of distribution

73 Key Points Alterations in protein binding and tissue penetration of drugs may lead to reduced OR exaggerated response

74 Practical Tips for Pediatric Prescription Writing
Always obtain a weight at every pediatric visit As a rule, start with smallest dose in neonates and infants “round up” the dose if it falls between the given choices UNLESS it is a toxic drug or has narrow therapeutic window With acetominophen, calculate dosage using weight, not age Always specify preferred formulation (e.g., chewable tabs, suspension, etc) Stay current with literature!!!

75 Geriatric Pharmacology
Baby Boomers and Beyond…

76 Medication Use Statistics
People >65 consume 30% of prescription and 40% non-prescription drugs (Cohen, 2000) By 2030, the population >65 will double-with largest increases in 85-older Adverse drug reactions rank in the top 5 causes of mortality and morbidity in elderly 28% of elderly hospital admissions are due to adverse drug reactions

77 Adverse Drug Reactions
About 15% of hospitalizations in the elderly are related to adverse drug reactions The more medications a person is on, the higher the risk of drug-drug interactions or adverse drug reactions The more medications a person is on, the higher the risk of non-adherence

78 Costs of Drugs Average prescription drug cost for an older person is $500/year, but highly variable Nonprescription drugs and herbals can be quite expensive and dangerous when mixed with prescription drugs Many Medicare Managed Care Plans have dropped or severely limited drug coverage Drugs cost more in US than any other country Many elderly patients look toward “bootlegged” drugs” New drugs cost more-not covered

79 Non-prescription Drugs
Surveys indicate that elders take average of 2-4 nonprescription drugs daily Laxatives used in about 1/3-1/2 of elders - many who are not constipated Non-steroidal anti-inflammatory medicines, sedating antihistamines, sedatives, and H2 blockers are all available without a prescription, and all may cause major side effects

80 Prescription Drugs Elderly account for 1/3 of prescription drug use, while only 13% of the population Ambulatory elderly fill between 9-13 prescriptions a year (new and refills) One survey: Average of 5.7 prescription medicines per patient Average nursing home patient on 7 medicines

81 Pharmacokinetics Decrease in total body water (due to decrease in muscle mass) and increase in total body fat affects volume of distribution Water soluble drugs: lithium, aminoglycosides, alcohol, digoxin Serum levels may go up due to decreased volume of distribution Fat soluble: diazepam, thiopental, trazadone Half life increased with increase in body fat

82 Pharmacokinetics Absorption: Not highly impacted by aging
Variable changes in first pass metabolism due to variable decline in hepatic blood flow (elders may have less first pass effect than younger people, but extremely difficult to predict)

83 Pharmacokinetics and the Liver
Oxidative metabolism through cytochrome P450 system decreases with aging, resulting in a decreased clearance of drugs Hepatic blood flow extremely variable

84 Drugs with Cytochrome P450 Effects (partial)
Inhibitors Inducers Allopurinol Metronidazole Barbiturates Amiodorone Quinolones Carbamazepine Azole antifungals Phenytoin Cimetidine Rifampin INH Tobacco SSRIs Tacrine

85 Pharmacokinetics: Excretion and Elimination
GFR generally declines with aging, but is extremely variable 30% have little change 30% have moderate decrease 30% have severe decrease Serum creatinine is an unreliable marker If accuracy needed, do Cr Cl

86 The Cockroft and Gault Equation
Cr Cl = 140-age(yrs) X wt (kg) X .85 for women Cr (mg/100ml)X72 May overestimate Cr Cl, especially in frail elders Useful equation, but must be aware of its limitations

87 Pharmacodynamics: What the Drug does to the Body
Some effects are increased Alcohol causes increase is drowsiness and lateral sway in older people than younger people at same serum levels Fentanyl, diazepam, morphine, theophylline Some effects are decreased Diminished HR response to beta -blockers

88 Undertreatment CAD Anticoagulation in AF HTN, especially systolic HTN
Beta blockers ASA Anticoagulation in AF HTN, especially systolic HTN Pain Particular fear of narcotics in the elderly

89 Drug-Drug Interactions
Common cause of ADEs in elderly Almost countless – good role for pharmacist and computer or on-line programs Some common examples Statins and erythromycin and other antibiotics TCAs and clonidine or type 1Anti-arrythmics Warfarin and multiple drugs ACE inhibitors increase hypoglycemic effect of sulfonylureas

90 Drug-disease Interactions
Patient with PD have increased risk of drug induced confusion NSAIDs (and COX-2’s) s can exacerbate CHF Urinary retention in BPH patients on decongestants or anticholinergics Constipation worsened by calcium, anticholinergics, calcium channel blockers Neuroleptics and quinolones lower seizure thresholds

91 The “Prescribing Cascade”
Common cause of polypharmacy in elderly Some common examples NSAID ->HTN->antihypertensive therapy Metoclopromide ->Parkinsonism ->Sinemet Dihydropyridine -> edema ->furosemide NSAID ->H2 blocker ->delirium ->haldol HCTZ ->gout->NSAID ->2nd antihypertensive Sudafed ->urinary retention ->alpha blocker Antipsychotic ->akithesia ->more meds

92 NSAIDs Acetaminophen as effective as NSAIDs in mild OA
NSAIDs side effects GI hemorrhage (less with COX-2) Decline in GFR (COX-2 as well) Decreased effectiveness of diuretics, anti-hypertensive agents Indication should justify the increased toxicity of NSAIDs

93 Drugs and Cognitive Impairment
Common cause of potentially reversible cognitive impairment Demented patients are particularly prone to delirium from drugs Anticholinergic drugs are common offenders (TCAs, benadryl and other antihistamines, many others) Other offenders cimetidine, steroids, NSAIDs Medical Letter Drug Safety Drugs and Aging 1999

94 Drugs and Falls Biggest risk drugs are long acting benzodiazepines and other sedative-hypnotics Both SSRIs and TCAs associated with increased risk of falling Beta blockers NOT associated with increased risk of falling in published literature Mild increase in fall risk from diuretics, anti-arrythmics, and digoxin Leipzig, 2008

95 Drug-Food Interactions
Interactions between drugs and food warfarin and Vitamin K containing foods (remember green tea, as well) Phenytoin & vitamin D metabolism Methotrexate and folate metabolism Drug impact on appetite Digoxin may cause anorexia ACE inhibitors may alter taste

96 Drugs And Dosages to Avoid in Most Instances
Meperidine Diphenhydramine The most anticholinergic tricyclics: amitryptiline, doxepin, imipramine Long acting benzodiazepines such as diazepam Long acting NSAIDs such as piroxicam High dose thiazides (>25mg) Iron: 325 mg once daily is enough

97 Anticipate SE’s Narcotics Steroids Levothyroxine
Begin lactulose or sorbitol and a stimulant laxative Colace is NOT sufficient in most instances Steroids Think about osteoporosis prevention Remember steroid induced diabetes Levothyroxine Calcium interferes with absorption of levothyroxine ?Biphosphonates and ? Atrial fibrillation (NEJM, 2009) Calcium and MI ??(BMJ, 2010)

98 High Risk Situations Patient seeing multiple providers
Patient on multiple drugs Patient lives alone and/or has cognitive impairment Discharge from hospital or any change in venue

99 Hospitalization: A High Risk Time
At hospitalization: 40% of admission medications stopped 45% of discharge medications were started Serious prescribing problems in 22% Other prescribing problems in 66% Beers JAGS 1989, Lipton Medical Care 1992

100 Non-adherence Lack of understanding of how to take Unable to take
High risk times: Hospital discharge, new meds added, complex regimens Unable to take Conscious nonadherence Side effects Lack of understanding of benefits of drug Financial

101 Complementary Therapies
Very commonly used in the elderly Some common herbs and alternative therapies: “Anti-aging” DHEA, growth hormone Dementia Gingko biloba BPH Saw palmetto, PC-SPES OA Chondroiton sulfate, glucosamine Depression St. John’s wort, SAMe

102 “Do No Harm?” California Department of Health Services, Food and Drug Branch screened 250 Asian herbal products collected from herbal stores in California assayed products using gas chromatography, mass spectrometry, and atomic-absorption techniques Ko, NEJM 1998; 339; 847 32% contained unlabeled medications, 14% mercury, 14% arsenic, 10% lead

103 Herbals and Supplements: Regulation
Demonstration of safety is NOT required prior to marketing Manufacturing standards are not required Can have health claims, but not claims about treating, preventing, or curing For glucosamine/chondroitin, 1/3 of combinations did not contain listed ingredient has drug information

104 Herbals and Supplements:Potential interactions with Rx Drugs
SAMe may increase homocysteine levels St. John’s wort and Oral contraceptives Ginkgo may increase anticoagulant effects of ASA, warfarin, NSAIAs, ticlopidine, and may interact with MAOIs Bottom line: Try to know what your patient is taking, and ask in a nonjudgmental way

105 Mr. W. is a 86 year old man with pulmonary HTN, COPD, CRI (creatinine of 2.2), CHF with an ejection fraction of 20%, mild dementia, depression, and severe anemia. He is frequently admitted to the hospital because of severe disease and poor adherence with his medical regimen. His discharge medications on last admission one month ago were aspirin 325mg, enalapril 20mg QD, furosemide 80mg BID, combivent, and sertraline 50mg. The inpatient team decided that he was undertreated, and added metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID, and 3 inhalers. He was readmitted within a week. How might you approach his regimen? This man has already shown that he is not adherent, and adding medications to his regimen has probably made his adherence worse. Asking him about adherence can be revealing. In this case, he admits that he is “just taking too many medications” and so randomly stopped a few. He also is complaining about urinating all day, so almost always skips his PM furosemide. Although beta blockers improve outcomes in severe CHF, in this man is who marginal with his medications, had lung disease, and limited insight, it may not be worth it. Keeping the regimen simple is more likely to result in success. Likewise, his iron, if he needs it at all, would be adequate at a once daily dose. Probably combivent would be a better choice to improve adherence. RCTs have demonstrated decreased mortality with both beta blockers and aldactone in CHF. However, applying those results to this man with multiple severe diseases, mild dementia and decreased adherence may not be wise. So, in short we recommend: Changing furosemide to 120mg once daily D/c feSo4 or decrease it to once daily Drop metoprolol and aldactone Change inhaler back to combivent

106 Principles for Managing Drugs
Complete drug history, including herbs and nonprescription drugs Avoid medications if benefit is marginal or if non-pharmacologic alternatives exist Consider the cost Start low, go slow, but get there! Keep regimen as simple as possible Write instructions out clearly Have patient bring in medications at each visit

107 Principles (continued)
Consider medication box or “mediset” If things don’t make sense, consider a home visit Discontinue drugs when possible if benefit unclear or side effects could be due to drug Be cautious with newer drugs Consider if the benefit of the 7th or 8th drug is sufficient to justify the cost, increase in complexity of regimen, and risk of side effects

108 Newer drugs What is unique about this compound?
What clinical data is available? How does it compare with traditional therapy? How expensive is it? With third party payers cover this product? Does the potential advantage of this new drug justify the risk of using a new drug?

109 Summary The elderly take more medications than any other age group
Pharmacokinetics and pharmacodynamics are altered Adverse drug reactions are common Risks go up with the number of drugs used Nonprescription and herbal therapies are common With care and common sense, we can probably do a better job


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