Pharmacology and Aging

Pharmacology and Aging Fred Farris, PhD Pediatric Pharmacology: Sulfanilamide Elixir • Sulfanilamide elixir made with ethylene glycol • Ingested by children • Caused almost 100 deaths from renal failure • Precipitated U.S. Food, Drug and Cosmetic Act of 1938 • Required that drugs and cosmetics be tested for toxicity before marketing Pediatric Pharmacology: Thalidomide • Introduced in 1956 as sedative/hypnotic • Used to ameliorate nausea and vomiting during pregnancy • Some peripheral neuritis in patients with long-term use • No known serious human toxicities or addictive properties at therapeutic levels University of Hamburg Pediatric Clinic: Reports of Phocomelia • 1949 to 1959 – No cases • 1959 – one case • 1960 – 30 cases • 1961 – 154 cases • Comparable increases observed in other parts of the world Thalidomide Teratogenicity • Amelia: Absence of limbs • Phocomelia: Preaxial reduction of long bones of limbs • Arms usually affected more than legs • Approval in US blocked by Dr. Frances Oldham Kelsey Pediatric Pharmacology: Chloramphenicol • Death of three newborn infants in 1960 • Followed administration of moderately large amounts of chloramphenicol • Recommended IM dose of microcrystalline suspension was 100 to 150 mg/kg/day for children of 15 kg or less • One death at dose of 220 mg/kg/day for 2.5 days • One death at dose of 23o mg//day for 3 days • Recommended oral dose of chloramphenicol palmitate suspension was 50 - 150 mg/kg/day for children of 15 kg or less • One death at dose o 50 mg/kg/day for 2.7 days and 10 hr after a single inadvertent dose of 400 mg Kefauver-Harris Amendment • Thalidomide: 10,000 deformities in 46 countries • Chloramphenicol: Children deaths • Initiated 1962 Amendment to US Food, Drug and Cosmetics Act • Before marketing firms must prove safety and effectiveness for proposed use, and disclose potential side effects Pediatric pharmacology: What’s unique? • Continuous development from embryo to adolescent • “Perpetual pharmacologic moving target” • Pharmacodynamics and pharmacokinetics change with time • The most profound differences occur in the first weeks through first year of life. • Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking • Children are not “miniature adults” • Dosing based on “rule” (Young’s, Clark’s) or scaling (by body weight or body surface area) not always predictable for a given drug. • Animal studies not always predictive. • Clinical studies in children fraught with ethical and financial hurdles. • Administration of drug can also be problematic. Pediatric pharmacology: Approved drugs • Children are “therapeutic orphans” • Only 20-30% of approved drugs have pediatric labeling • FDA has encouraged pediatric studies • Financial incentive to conduct studies • Orphan and off-patent drugs - no incentive to do studies • Increased studies resulted in new labeling for 40 drugs. • For approval of selective number of new drugs pediatric studies have been required. • Resources • Center for Drug Evaluation and Research at FDA - www.fda.gov/cder/pediatric/ • Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies. JAMA. 2003;290:905-911. The “Moving Target”: Developmental Changes • Body composition • Organ function • Drug metabolizing enzymes • Unique metabolic pathways • • • • Renal function Receptor response Unique disorders Extremely small margin of error for the most fragile patients • Errors can be devastating • Individual variance unpredictable Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents Kearns, G. L. et al. N Engl J Med 2003;349:1157-1167 Developmental Pharmacology: GI Absorption • During first years of life, changes in gastric pH related to density and function of parietal cells in stomach can occur • At term, only 20% of neonates possess proportion of parietal cells as adults • Highest gastric pHs occur in neonates and may be influenced by amniotic fluid in stomach • Oral bioavailability of acid labile drugs may be higher in neonates and decrease with maturity • Infant formula may increase gastric pH, to levels > 4 for up to 90 min after feeding • Human breast milk contains epidermal growth factor which can inhibit acid secretion • Gastric acid - approaches adult values ~ 3 mo in full-term infants Developmental Pharmacology: GI Absorption • Gastric emptying • Delayed and unpredictable in newborns - adult values ~ 6 mo. • GI motility • Slow in newborns; may be increased in children. • Usually affects the rate but not the fraction of drug absorbed. • The absorptive surface area/BSA is > infants and children vs. adults • The impact on absorption is usually minimal but is unpredictable • Activity equivalent to adults is typically achieved by 2 years of age Developmental Pharmacology: GI Absorption • Activity of Intestinal drug metabolizing enzymes • CYP3A4/5, CYP1A, N-acetyltransferase, xanthine oxide, glutathione-S-transferase And transporters • P-glycoprotein, organic anion, and cation transporters Reach adult levels between ages 6 and 12 months Developmental Pharmacology: Skin Absorption • Percutaneous absorption • Directly related to the degree of skin hydration. • Inversely related to the thickness of the stratum corneum. • Thinnest in premature neonate • Greater extent of cutaneous perfusion • Premature infant has a significantly less effective skin barrier to absorption of drugs and toxins • Ex. Hexachlorophene toxic to immature infants • Effect may be exacerbated by skin conditions like eczema – that disrupt integument • Newborn skin surface area : body weight is 3X > adult Other Routes of Drug Administration • Intramuscular • Lipid solubility favors distribution from site into circulation (rate) • Water soluble at physiologic pH to prevent precipitation • Highly susceptible to variance in absorption due to blood flow and relative muscle mass • Dispersion driven by muscle contraction (low in neonates and immobility) • Reduced skeletal-muscle blood flow in neonate • Can be extremely, cause hemorrhage, nerve damage, abscess, necrosis, fibrosis, and  CPK • Rectal • Absorption is excellent for some agents • Less first pass effect due to decreased hepatic clearance • Pulmonary for site specific agents • Unintentional • Breast milk • Transplacental Developmental Pharmacology: Absorption PK Pathway Premature Neonates Neonatal < 1 mo. Early infant Mid-Infant 3–5 mo. Late infanttoddler 6 – 24 mo. Older child ,  ,      Dermal       Lung       Absorption Oral Developmental Pharmacology: Distribution • Larger extracellular and total-body water spaces in neonate and young infants • Adipose stores also have higher ratio of water to lipid • RESULT: Lower plasma levels (relative to weight) for water soluble drugs. Effect on lipid soluble less • Plasma proteins • Low in preemies and neonates ( free fraction) • Most important in displacement of bilirubin from albumin resulting in toxicity (kernicterus) • Tissue transporters - P-glycoprotein ATP-binding cassette family of transporters • May limit cellular uptake of xenobiotic substrates [blood-brain barrier, hepatocytes, renal tubular cells and enterocytes] • Very limited data; premature infants probably most affected Developmental Pharmacology: Metabolism • Prior to birth the fetus is in a relatively protected environment • The xenobiotic clearing processes of the mother prevent exposure of the fetus. • The placenta also acts as a barrier. • Maturation of drug metabolizing enzymes occurs longitudinally • The very young have very low activity • Ex. Cardiovascular collapse in chloramphenicol associated “gray baby syndrome” • Cause for caution for drugs that have wider therapeutic index in adults • Ex. Methylxanthines, nafcillin, 3rd generation cephalosporins, captopril and morphine • Distinct patterns for each class and isoform of drug metabolizing enzymes. Embryonic Development of the Liver • Originates in 4th week of gestation as a duodenal diverticulum • By 6th week hepatic nodules are present • By 9th week of gestation liver represents 10% of fetal body weight • As architecture of liver develops, enzyme families develop in conjunction Development of Drug-Metabolizing Enzymes: Phases of Drug Metabolism • Phase I • Oxidation • Reduction • Hydrolysis • Phase II • Conjugation Phase I Enzymes: Cytochrome P450 1A Subfamily • CYPs responsible for biotransformation of endogenous and exogenous substrates • At birth, total hepatic CYP concentration is 30% that of an adult • Have variable rates of maturation • Hepatic CYP1A1 may be expressed during organogenesis and then decline to very low levels at birth • CYP1A2 activity is minimal during fetal period, begins to develop 8-28 days postnatal, and reaches adult activity by one year of age Phase I Enzymes: Cytochrome P450 3A Subfamily • CYP3A subfamily is most abundant of hepatic CYP450s and responsible for biotransformation of 50% of the therapeutic drugs administered to pediatric patients • Subfamily consists of four genes, CYP3A4, CYP3A5, CYP 3A7, and CYP3A43 • CYP3A7 is most abundant CYP3A isoform in fetal liver and continues as most dominant till 2 months of age • Dominance switches from CYP3A7 to CYP3A4 around birth • By 1 year of age CYP3A7 declines to 7% of fetal levels Phase I Enzymes: Cytochrome P450 2D Subfamily should know 5 • CYP2D6 is responsible for biotransformation of 12% of clinically relevant drugs used in pediatrics • CYP2D6 is low during fetal development and first few weeks of life • A steady increase in activity following birth with 30% of adult activity at 1 month and 70% of adult activity at 1-5. years of age Developmental Ontogeny of Phase I Enzymes Enzyme Known Developmental Pattern CYP2D6 1 week of age. Poor activity (i.e., 20% of adult) by 1 month. Adult competence by 3– 5 years of age SSRIs (fluoxetine, paroxetine, sertraline), risperidone, atomoxetine, promethazine, dextromethorphan, diphenhydramine, chlorpheniramine CYP2C19 Apparently absent in fetal liver. Low activity in first 2–4 weeks of life with adult activity reached by approximately 6 months. Activity may exceed adult levels during childhood and declines to adult levels after conclusion of puberty Proton pump inhibitors (omeprazole, pantoprazole, lansoprazole), propranolol CYP2C9 Detected at very low levels (1% of adult levels) in early gestation (earliest at 8 weeks). At term, activity increases to approximately 10% of that observed in adults and by 5 to 6 months of age, is approximately 25% of adult levels Warfarin, phenytoin, ibuprofen, indomethacin Enzyme Known Developmental Pattern1A2 CYP1A2 Not present in appreciable levels in human fetal liver. Adult levels reached by approximately 4 months and exceeded in children at 1–2 years of age. Adult activity reached after puberty Clozapine, clomipramine, caffeine, haloperidol, ondansetron, theophylline CYP3A7 Fetal form of CYP3A which is functionally active (and inducible) during gestation. Virtually disappears by 1 to 4 weeks of postnatal when CYP3A4 activity predominates, but remains present in approximately 5% of individuals Cyclosporine, erythromycin, lidocaine, midazolam, nifedipine, tacrolimus, verapamil, zolpidem CYP3A4 Extremely low activity at birth reaching approximately 30 to 40% of adult activity by 1 month and full adult activity by 6 months. May exceed adult activity between 1 and 4 years of age, Cyclosporine, erythromycin, lidocaine, midazolam, nifedipine, tacrolimus, verapamil, zolpidem Enzyme Known Developmental Pattern1A2 CYP2E1 Undetectable expression in the fetal liver. In newborn livers levels are 10% of adults. Steady increase of expression with age. Adult levels are reached in children between 1 and 10 years of age. There is a strong association between protein levels and activity along the developmental spectrum Anesthetics (halothane, isoflurane, enflurane), acetaminophen CYP2B6 Variable detection in fetal liver and at low levels relative to adults (median levels approximately 15% of adult). There is an approximate 2-fold increase in median expression after the neonatal period (birth to 30 days postnatal) with considerable variability. Expression is less variable in infants and children with median levels reported at approximately 40% of adults Development of Phase I Enzymes Half-Lives of CYP1A2 Substrates Half-Lives of CYP3A Substrates PEDIATRICS Vol. 113 No. 4 April 2004, pp. 973-983 Developmental Pharmacology: Phase I Metabolism Premature Neonates Neonatal < 1 mo. Early infant Mid-Infant 3–5 mo. Late infanttoddler 6 – 24 mo. Older child CYP1A2      Scale BW3/4  Scale BW3/4 CYP2E1      Scale BW3/4  Scale BW3/4 CYP A      Scale BW3/4  Scale BW3/4 CYP3A7       Other CYPs      Scale BW3/4  Scale BW3/4 ADH      Scale BW3/4  Scale BW3/4 PK Pathway Metabolism: Phase I Development of Drug-Metabolizing Enzymes: Phase II • Ontogeny less well characterized than Phase I reactions • Glucouronosyltransferase (glucuronidation) is decreased in newborns and young children compared to adolescents and adults • Present by 24 wk gestational age • Morphine glucuronidation correlates with post-conceptional age • Morphine conjugate more potent (premies require increased dose for equivalent analgesia) • Clearance of most agents more efficient in prepubescent children than adults (relative to bodyweight) Developmental Pharmacology: Phase II Metabolism PK Pathway Premature Neonates Neonatal < 1 mo. Early infant Mid-Infant 3–5 mo. Late infanttoddler 6 – 24 mo. Older child Glucuonidation       N-acetylation       Metabolism: Phase Ii Developmental Pharmacology: Renal Elimination • Maturation of renal function dynamic • Begins with fetal organogenesis (9 wk gestational age) • Complete by early childhood • GFR correlates with nephrogenesis and postnatal renal and intrarenal bloodflow. Acquisition of Renal Function Developmental Pharmacology: Renal Elimination • Therapeutic implications • Estimation of renal function necessary for determining dose regimen for drugs with extensive renal clearance • Ex. Ceftazidime, famotidine, aminoglycosides. • Measurement of drug levels often necessary • Some drugs also alter renal maturation or renal blood flow . • Ex betamethsone, indomethacin Developmental Pharmacology: Pharmacodynamics • Very little data; most accepted practices are based on observation • Anecdotal evidence for altered response to • Warfarin • Cyclosporine • Midazolam • Erythromycin (intestinal motilin receptors) Criteria for Using a Drug in a Child or Infant • Has there been documented efficacy for the medication for the disorder in newborn or older infants/children. • Is the data from adequate clinical trials (randomized, controlled, size, power, similar age/maturity)? • Has the safety been established for pediatric population? Criteria for Using a Drug in a Child or Infant • Has the pathway of drug clearance been established in children/infants? • Is that pathway established in the child/infant you are treating (based on maturity or physical state)? • Is there reason to believe that pathway may be compromised in the specific child/infant (genetics, disease state, concomitant therapy)? • Have the pharmacokinetics been established in similarly aged children? Criteria for Using a Drug in a Child or Infant • Is there a safe route to administer the drug? (intact GI tract, central access, intact skin, nontoxic solvent) • Is displacement an issue for albumin binding or bilirubin displacement? • Are there technical issues surrounding administration, e.g. solvents, preservatives, volume? • Is there an established dose and interval appropriate for age and disease state of the child? • Have a plan for monitoring for appropriate response to the agent. • Look for adverse effects of the agent. Criteria for Using a Drug in a Child or Infant • The very small doses required in the most immature patients and the immature clearance pathways leave very little margin of error. Developing Age-specific Dosing Regimens • Official prescribing information usually does not have pediatric dosing regimens. • Developmental status adjusted regimens are highly specific for a given agent. • Use of established compendia and published guidelines provide the most reliable method of selecting an appropriate therapeutic agent and adjusting dose. Geriatric Pharmacology: Unique Physiology • Changes in underlying physiology occurs over time. • Altered, usually diminished, receptor sensitivity and responsiveness • The ability to mount a compensatory physiologic response is diminished. • Normal homeostatic mechanisms are blunted and sometimes produce inappropriate responses. • Even “healthy” elderly have diminished capacities. • Aging is a continuum and the aged are stratified by degree of age. • Young old is 65 – 75 years • Old – 75 – 85 years • Old old – age > 85 years • As age progresses so do the exceptional considerations. Geriatric Pharmacology: Unique Physiology • Body composition •  total body water,  lean body mass,  body fat;  serum albumin,  -1 acid glycoprotein • CNS •  weight and volume of the brain •  sensitivity to depressant drugs: ethanol, anticholinergic effects, antipsychotic agents. • CNS effects and side effects are exaggerated • Delirium and dementia complicate therapy. • ANS • Responsiveness and appropriate reflex effects are diminished. • Orthostatic hypotension - frequent side effect due to diminished capacity for response to agents with any degree of sympathetic blockade. Geriatric Pharmacology: Unique Physiology • Cardiovascular • • • • •  -adr receptor activity,  baroreceptor activity Cardiac output is generally fairly well maintained Cardiac disease and reserve capacity diminish with age. Adrenergic receptor sensitivity is altered. Any pro-arrhythmic side effect can be accentuated. • Endocrine • Atrophy of thyroid •  incidence of diabetes mellitus • Menopause, andropause Geriatric Pharmacology: Unique Physiology • Digestive tract •  gastric emptying time,  GI blood flow;  gastric pH,  intestinal transit time. • Hepatic •  liver size,  hepatic blood flow. • Some hepatic functions are better preserved than others. •  albumin • Alcohol use, gallstones, cholangitis, fatty liver (NASH), heart failure, and conditions requiring concomitant drugs can affect metabolism. Geriatric Pharmacology: Unique Physiology • Renal •  GFR,  renal blood flow,  tubular function • Renal function and size diminishes with age. • Pulmonary •  respiratory muscle strength,  chest wall compliance,  total alveolar surface • Most systems are more affected by disease than age alone. Geriatric Pharmacology: Unique Disease • The elderly accumulate diseases. Geriatric Pharmacology: Unique Polypharmacy • With the accumulation of disease these is an accumulation of treatments • “Polypharmacy” Multiple medications for multiple chronic diseases • Multiple physicians • Self-medication • Disproportionate use of drugs in the elderly. • 12% of population receive 30% of all prescriptions. • 2/3 use 1 or more drugs daily. • Ave 5 - 12 drugs daily • < 5% use no drugs. • 1/3 use 1 or more psychotropic drugs each year. • It is often difficult to distinguish between disease and adverse drug events. Geriatric Pharmacokinetics: Absorption • Age related changes are small. • Gastric/intestinal motility  • Surface area and blood flow  • Net negligible change in absorption • Less significant than disease-specific changes. • Effects of age on absorption for delayed and sustained release formulations have not been well-documented. • A diminished first-pass effect results in an increased bioavailability. Geriatric Pharmacokinetics: Distribution • Lean body mass and body water  • Vd (volume of distribution)  for water soluble drugs • Water soluble drug - conc.  • Ex. ethanol • Fat soluble drugs  conc. • Increased fat serves as a repository for fat soluble drugs • Ex. Amiodarone, desipramine, diazepam, haloperidol, digitoxin • Impact on drug therapy in general is not great. • Protein binding to albumin and -1 acid glycoprotein is more affected by disease than age. • Decreased albumin can result in increased free fraction of drugs. • Increased delivery to receptor • Increased drug interactions Volume of Distribution Geriatric Pharmacokinetics: Metabolism • Phase II reactions are better preserved than Phase I. • Disease and environmental factors have a greater impact on hepatic drug metabolism than age. • High extraction drugs may have decreased clearance attributable to diminished hepatic blood flow. Antipyrine Clearance Geriatric Pharmacokinetics: Elimination • Renal Elimination •  Cl and  t1/2 for renally cleared drugs and metabolites. • The age-related change in renal clearance is the most consistent and predictable change in pharmacokinetics. • The dose of most drugs that are renally cleared should be adjusted for renal function. • The adjustment method most frequently used is the Cockroft-Gault equation to estimate renal clearance. • This method is not without problems, but is simple and readily applicable in most situations. Estimating Renal Function • Cockcroft Gault estimation • Assumes steady state production of creatinine. • Very limited utility in critically ill, clinically unstable, malnourished or wasted patients. • Measure creatinine clearance or use extrinsic marker if critically important. • Other formulas may be more accurate in special populations. CLCr (ml/min) = (140 – age) (lean weight in kg) 72 (serum creatinine in mg/dL) (multiply by 0.85 for women) Geriatric Pharmacokinetics - Renal Function • Drugs with predominantly renal elimination and potentially serious toxic effects should have dosing adjusted based on renal function. Geriatric Pharmacokinetics – Drug Elimination • Drug dosing requires adjustment for changed pharmacokinetic parameters. t 1/2 = 0.693 X Vd Clearance Vd is smaller for water soluble drugs Clearance is usually diminished with age Geriatric Pharmacodynamics • Receptor alteration with age best documented for adrenergic receptors and autonomic nervous system. • Increased sensitivity to sedation. • Increased sensitivity to hypotensive (side) effects due to decreased baroreceptor function. • Diminished adaptive capacity most manifested as increased occurrence of adverse events with medications. • Treatment of elderly patients can be very complex because of multiple diseases and drug therapies that can produce adverse drug reactions. Appropriate Prescribing for Geriatric Patients • Obtain a complete drug history • Avoid prescribing before a diagnosis is made • Review medications regularly and before prescribing a new medication • Know the actions, adverse effects, and toxicity profiles of he medications you prescribe • Start low dose and titrate dose based on tolerability and response  Geriatric dictum: “Start low and go slow” Appropriate Prescribing for Geriatric Patients • Educate patient and/or caregiver about each medication • Avoid using one drug to treat the side effects of another • Attempt to use one drug to treat two or more conditions • Use combination products cautiously • Communicate with other prescribers • Avoid using drugs from the same class or with similar actions Adjusting Therapy for Special Populations Drug Information • On-line decision support • Institutional: CPOE (Computerized Physician Order Entry) • Guidelines, rules, protocols • Text-based (online and print) • Secialized information • Johns Hopkins: The Harriet Lane Handbook: A Manual for Pediatric House Officers, 16th ed © 2002 Mosby, Inc. • Geriatrics At Your Fingertips, 2005 by D Reuben, and Others. The American Geriatrics Society (AGS) • Literature (Medline, full-text, etc) • Exceptions • Investigational drugs • NME (New Molecular Entity) • Indication not labeled • Literature, FDA, Sponsors • Unusual patients (age, disease, indications) • International patients (online resources, Pharmaceutical regulatory agencies) Drug Information Age-specific • FDA, Government and professional organizations web sites • Medical departments of Pharmaceutical Manufacturers • Most have available physicians who have specialized knowledge of products • Different constraints on information sharing when physician-to-physician If there is no “Approved labeling” • Official compendia, professional organizations, published guidelines, adequate clinical trials, “standard of care”, etc. are usually sufficient. • In dire circumstances in the absence of published information extraordinary resources may be necessary. • Manufacturer’s Medical Department • Investigators • International sources Summary: Pediatric pharmacology • Children and infants, especially neonates, have different pharmacokinetic parameters than adults • Appropriate drug therapy cannot be assumed to identical to adults, even when adjusted for weight or body surface area. • Each agent is unique and requires adequate clinical studies before a drug can safely be used in children. Summary – Geriatric Pharmacology • Normal homeostatic mechanisms are blunted and sometimes produce inappropriate responses. • Metabolism and renal elimination are most often impacted • Phase II drug metabolizing reactions are better preserved than Phase I. • The dose of most drugs that are renally cleared should be adjusted for renal function. • Cockroft-Gault equation is frequently used to estimate renal function. Summary - Geriatric pharmacology cont’d • Disease and environmental factors have a greater impact on hepatic drug metabolism than age. • Therapeutic plan should include only agents with established efficacy. • Most drugs should started at lower doses and titrated more slowly. • Frequent review of the complete therapeutic plan to minimize interactions and side effects. • Adverse drug effects can mimic disease and should be included in the evaluation of a patient. • “Drugs are the great imitator of disease” C.R.C. Wyndham, MD