FEATURES OF DRUGS ACTION DURING PREGNANCY

• 1 слайд

  Features of drugs action during pregnancy, lactation and in children
  

• 2 слайд

  Drug use in pregnancy
  Drugs can be harmful for the unborn child!!!
  
  THE PLACENTA
  Drugs pass placenta by passive diffusion
  lipid barrier between maternal and embryonic/fetal circulations
  slow process (used during caesarean section)
  non-ionized drugs pass more rapidly
  most drugs are small enough to passexceptions: growth hormone, conjugated steroids
  cuts peak concentrations in maternal plasma
  

• 3 слайд

  Drug use in pregnancy
  effects of toxic drugs
  • malformation
  
  • growth retardation
  
  • fetal death
  
  • functional defects in newborn
  
  • premature birth
  Drugs should be used with caution during pregnancy
  

• 4 слайд

  Drug use in pregnancy
  Use of drugs in pregnancy is not always wrong
  
  Some examples:
  • High fever is harmful for the fetus in the first
  months.
  Use of paracetamol is better then no
  treatment
  • Diabetes during pregnancy needs intensive
  therapy with insulin
  • Folic acid protects against spina bifida
  • Anti-epileptics are teratogenic. But an epileptic
  insult may provoke harmful anoxia for the fetus.
  

• 5 слайд

  Drug use in pregnancy
  Toxic chemicals and irradiation can damage
  Oocytes:
  • all female germ cells develop prenatally. No
  germ cells are formed after birth
  • Oocytes are in situ and not multiplying.
  • teratogenic effects can become apparent after
  fertilization, maybe long after the presence of
  damage
  • EMEA does not allow women with childbearing
  potential to take part in first in man studies
  
  

• 6 слайд

  Drug use in pregnancy
  Is damaged sperm teratogenic?
  • Spermatozoa are continuously produced
  • Damaged spermatozoa are slower and arrive late
  when the oocytes is already fertilized → mostly not harmful?
  • May lead to infertility
  → paternal teratogenicity cannot fully be excluded.
  advice: use of condoms when the man is taking
  products that are suspected to be harmful
  termination of pregnancy because of paternal
  teratogenicity is not justified
  

• 7 слайд

  Drug use in pregnancy
  The first trimester (day 8 – end of month 2)
  Is the most important period for teratogenicity
  Is period of formation of organs
  3rd – 9th month
  Less risk for malformations
  except for urogenital tract and central nervous system
  More functional effects
  i.e. aminoglycosides nephro- & ototoxicity
  salicylates increased risk of bleeding
  

• 8 слайд

  Drug use in pregnancy
  drugs have effects in newborn
  • avoid CNS depressants
  floppy infant syndrome
  • avoid drugs with increased bleeding risk
  like anticoagulants, salicylates
  increased risk of cerebral hemorrhage during delivery
  • NSAIDS and salicylates ↓ uterine contractility
  

• 9 слайд

  Drug use in pregnancy
  spontaneous malformations (=unknown origin)
  2-4 %
  Additional risk from drugs is small for most drugs
  evidence for teratogenic effects
  • golden standard is randomized controlled trial
  (RCT). ethical objections
  • epidemiologic studies cannot establish proven
  causality
  • large species differences in teratogenic effects
  No drug is proven free from teratogenic effects
  

• 10 слайд

  Drug use in pregnancy
  Risk classification (FDA)
  
  Category A:
  
  Controlled studies in women fail to demonstrate
  a risk to the fetus in the first trimester (and there
  is no evidence of a risk in later trimesters), and
  the possibility of fetal harm appears remote.
  

• 11 слайд

  Drug use in pregnancy
  Category B:
  Either animal reproduction studies have not
  demonstrated a fetal risk but there are no
  controlled studies in pregnant women,
  or
  animal-reproduction studies have shown an
  adverse effect (other than a decrease in fertility)
  that was not confirmed in controlled studies in
  women in the first trimester (and there is no
  evidence of a risk in later trimesters).
  

• 12 слайд

  Drug use in pregnancy
  Category C:
  
  Either studies in animals have revealed adverse
  effects on the fetus (teratogenic or embryocidal
  or other) and there are no controlled studies in
  women,
  or
  studies in women and animals are not available.
  
  Drugs should be given only if the potential
  benefit justifies the potential risk to the fetus.
  

• 13 слайд

  Drug use in pregnancy
  Category D:
  
  There is positive evidence of human fetal risk,
  but the benefits from use in pregnant women
  may be acceptable despite the risk (e.g., if the
  drug is needed in a life-threatening situation or
  for a serious disease for which safer drugs cannot be used or are ineffective).
  

• 14 слайд

  Drug use in pregnancy
  Category X:
  
  Studies in animals or human beings have
  demonstrated fetal abnormalities, or there is
  evidence of fetal risk based on human experience
  or both,
  and
  the risk of the use of the drug in pregnant women
  clearly outweighs any possible benefit.
  
  The drug is contraindicated in women who are or
  may become pregnant.
  
  

• 15 слайд

  Anti-infectives
  Penicillins
  Cephalosporins
  Carbapenems
  Fluoroquinolones
  Macrolides
  Aminoglycosides
  Sulfonamides
  Miscellaneous Antibiotics
  Antivirals
  Antiretrovirals
  Antifungals
  

• 16 слайд

  Penicillins
  Category B in pregnancy
  Cross the placenta easily and rapidly
  Concentrations equal maternal levels
  
  
  Lactation
  Crosses in low concentrations
  Compatible with breastfeeding
  

• 17 слайд

  Cephalosporins
  Category B in pregnancy
  
  Cross the placenta during pregnancy
  Some reports of increased anomalies with specific cephalosporins
  (cefaclor, cephalexin, cephradrine)
  Primarily cardiac and oral cleft defects
  
  Lactation
  Excreted into breastmilk in low concentrations
  Considered compatible with breastfeeding
  

• 18 слайд

  Carbapenems
  (ertapenem, imipenem, meropenem)
  Category B/C/B in pregnancy
  Likely cross the placenta
  Very little human data
  
  Lactation
  Excreted into breastmilk in low amounts
  Unknown effects but likely low clinical significance
  

• 19 слайд

  
  Fluoroquinolones
  
  Pregnancy Category C
  Not recommended in pregnancy
  Cartilage damage in animals
  Safer alternatives usually exist
  
  Lactation
  Excreted into breastmilk
  Limited human data
  AAP says compatible with breastfeeding
  

• 20 слайд

  Macrolides
  (azithromycin, clarithromycin, erythromycin)
  Pregnancy Categories B/C/B
  Cross the placenta in low amounts
  Limited data with azithromycin and clarithromycin
  
  Lactation
  Erythromycin compatible
  Others probably compatible
  

• 21 слайд

  Aminoglycosides
  (amikacin, gentamicin, tobramycin)
  Pregnancy Category C
  Rapidly cross placenta
  Enter amniotic fluid through fetal circulation
  
  Lactation
  Compatible with breastfeeding
  Not absorbed through GI tract
  

• 22 слайд

  Sulfonamides
  Pregnancy Category C
  Readily cross the placenta
  Concerns of use at term
  
  Lactation
  Excreted into breastmilk in low levels
  Use should be avoided in premature infants
  

• 23 слайд

  Tetracyclines
  (doxycycline, minocycline, tetracycline)
  Pregnancy Category D
  Can cause problems with teeth and bone and other defects/effects
  Have been linked to maternal liver toxicity
  
  Lactation
  Compatible with breastfeeding
  Serum levels in infants undetectable
  

• 24 слайд

  Miscellaneous Antibiotics
  Aztreonam
  Pregnancy Category B, likely safe in pregnancy, little human data
  Lactation – Compatible per AAP
  Clindamycin
  Pregnancy Category B, commonly used
  Lactation – Compatible per AAP
  
  

• 25 слайд

  Miscellaneous Antibiotics
  Linezolid
  Pregnancy Category C, no human data available
  Lactation – unknown, myelosuppression in animals
  Metronidazole
  Pregnancy Category B, carcinogenic in animals, avoid in 1st trimester if possible
  Lactation – hold feeds for 12-24hrs afterward
  

• 26 слайд

  Miscellaneous Antibiotics
  Nitrofurantoin
  Pregnancy Category B, possible hemolytic anemia with use at term
  Lactation – Compatible, avoid with G-6-PD deficiency
  Trimethoprim
  Pregnancy Category C, potentially problematic early in pregnancy
  Lactation – Compatible as combination drug
  

• 27 слайд

  Miscellaneous Antibiotics
  Vancomycin
  Pregnancy Category B, compatible
  Lactation – likely compatible, not absorbed
  
  

• 28 слайд

  Antivirals
  (acyclovir, famciclovir, valacyclovir)
  Pregnancy Category B
  Acyclovir and valacyclovir readily cross the placenta
  Can be used for HSV treatment and suppression
  Lactation
  Acyclovir and valacyclovir are compatible
  Famciclovir should be avoided
  

• 29 слайд

  Antiretrovirals/NRTI
  (abacavir, didanosine (ddI), emtricitabine (FTC))
  Pregnancy Categories C/B/B
  Maternal benefit usually outweighs fetal risk
  Cross the placenta
  Limited data with each do not show increased risk of anomalies
  Didanosine has been associated with severe lactic acidosis w/ or w/o pancreatitis
  

• 30 слайд

  Antiretrovirals/NRTI
  (lamuvidine (3TC), stavudine (d4T))
  Pregnancy Category C
  Maternal benefit usually outweighs fetal risk
  Cross the placenta by simple diffusion
  Data with lamivudine show no increased risk of anomalies
  Stavudine has been associated with severe lactic acidosis w/ or w/o pancreatitis
  All NRTIs have been possibly linked to mitochondrial dysfunction postnatally
  

• 31 слайд

  Antiretrovirals/NRTI
  (tenofivir, zalcitabine (ddC), zidovudine (AZT))
  Pregnancy Category B/C/C
  Maternal benefit usually outweighs fetal risk
  Cross the placenta by simple diffusion
  Limited data with zalcitabine do not show increased risk of anomalies
  Zidovudine is commonly used, but may cause neonatal anemia
  Limited data with tenofivir show low risk of teratogenicity
  

• 32 слайд

  Antiretrovirals/NNRTI
  (delavirdine, efavirenz, nevirapine)
  Pregnancy Category C
  Maternal risk usually outweighs fetal risk
  Likely cross into fetus (nevirapine readily)
  Delavirdine has possible VSD risk, but limited human data
  Efavirenz is associated with anomalies in monkeys, limited human data, possible NTD
  Nevirapine can cause hepatotoxicity and rash
  Nevirapine can be used as a single dose in labor to prevent HIV transmission
  

• 33 слайд

  
  Antiretrovirals/PI
  
  Pregnancy Category B/C
  Maternal benefit usually outweighs fetal risk
  Likely cross the placenta
  All PIs can cause hyperglycemia
  Atazanavir can cause hyperbilirubinemia
  Indinavir can cause nephrolithiasis
  
  
  
  

• 34 слайд

  Antiretrovirals/Fusion Inhibitor
  (enfuvirtide)
  Pregnancy Category B
  Maternal benefit usually outweighs fetal risk
  Very large molecule (4492 daltons), likely does not cross placenta
  Animal data does not show risk
  No human data available
  Hold during first trimester if possible
  

• 35 слайд

  Antifungals/Azoles
  (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
  
  Pregnancy Categories C/C/C/D/D
  Likely cross placenta
  Fluconazole > 400mg/day seems to be associated with cranio-facial abnormalities
  Itraconazole appears to have low risk
  Ketoconazole can impair testosterone and cortisol synthesis
  No data in humans is available for voriconazole, increased risk in animals
  

• 36 слайд

  Antifungals/Azoles
  (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
  Lactation
  Fluconazole is compatible per AAP
  Itraconazole could concentrate in milk and body tissues, not recommended
  Ketoconazole is compatible per AAP
  No data with voriconazole, not recommended
  
  

• 37 слайд

  Antifungals/Echinocandins
  (anidulofungin, caspofungin, micafungin)
  Pregnancy Category C
  No data with anidulofungin
  No human data with caspofungin, single case at UVA, animal data suggests risk
  
  Lactation
  No human data, but probably compatible
  

• 38 слайд

  Antifungals/Polyenes
  Amphotericin B
  
  Pregnancy Category B, compatible, lipid complexes also compatible
  Lactation – no data available
  
  

• 39 слайд

  Migraine Headache Therapy
  Triptans
  Ergots
  Butalbital
  Caffeine
  Dichloralphenazone
  Isometheptene
  
  
  

• 40 слайд

  Triptans (5-HT1 agonists)
  Pregnancy Category C
  Limited human data exists, sumatriptan has been associated with VSDs in several cases
  No data available in humans for almotriptan, eletriptan, frovatriptan, or zolmitriptan
  Limited human data exists with naratriptan and rizatriptan, although animal data indicates moderate risks
  Pregnancy registry available for exposures
  
  

• 41 слайд

  Triptans (5-HT1 agonists)
  Lactation
  Cross into breastmilk and may concentrate
  No reports of human lactation with almotriptan, frovotriptan, naratriptan, rizatriptan, or zolmitriptan
  Sumatriptan is compatible per AAP
  Eletriptan is likely compatible with low concentrations
  

• 42 слайд

  Ergots
  (Dihydroergotamine, ergotamine)
  Pregnancy Category X
  Oxytocic properties could cause IUGR by vascular disruption or increased uterine tone
  Early exposure appears safe, not teratogens
  Chronic exposure is contraindicated
  
  Lactation
  Contraindicated
  

• 43 слайд

  Butalbital and Caffeine
  Butalbital
  Pregnancy Category C, can see neonatal withdrawal symptoms with long-term use
  Lactation – not recommended
  Caffeine
  Pregnancy Category B, doses generally lower than that in coffee
  Lactation – compatible
  
  

• 44 слайд

  Dichloralphenazone and Isometheptene (Midrin)
  Dichloralphenazone
  Pregnancy Category B
  Lactation – similar agent considered compatible
  Isometheptene
  Pregnancy Category C, extremely limited data
  Lactation – potentially compatible
  
  

• 45 слайд

  
  Safe Drug Administration in children
  Administration of drugs during the first year of life can be a challenge due to rapid changes in body size, body composition, and organ function.
  

• 46 слайд

  The Neonate – birth to 4 weeks
  

• 47 слайд

  Neonate - Absorption
  Two major factors affect the absorption of drugs
  
  pH dependent passive diffusion
  Gastric emptying
  
  
  

• 48 слайд

  Gastric pH
  Gastric pH (6-8) is directly related to the presence of amniotic fluid in the stomach
  
  Postnatally, gastric acid secretory capacity appears after the first 24 to 48 hours and gastric acidity decreases during the first weeks of life
  
  
  Adult values are achieved at about 3 months of life
  

• 49 слайд

  Gastric pH in premature infant
  
  In the premature infants, gastric pH may remain elevated due to immature acid secretion
  

• 50 слайд

  Delayed Absorption in neonate
  Prolonged emptying is seen in premature infant
  
  In the neonatal period the emptying rate is variable and prolonged
  
  Delayed absorption may also be a result of diminished pancreatic enzyme function and bile acid secretion.
  
  

• 51 слайд

  Absorption from skin and muscle in neonate
  Percutaneous absorption may be drastically increased due to immature epidermis and increased skin hydration
  
  Absorption from intramuscular site may be unpredictable and decreased due to insufficient blood flow, poor muscle tone, and compromised muscle oxygenation
  
  
  

• 52 слайд

  Distribution drugs in children
  Distribution of drugs within the body is influenced by the amount and character of plasma proteins, and relative size of fluid, fat and tissue compartments of the body.
  Total body water
  Plasma proteins
  
  

• 53 слайд

  Total Body Water
  85 % in pre-term infant
  78% in neonate
  60% at 1 year
  64 % in childhood (10 to 15 year old)
  60% in adults
  54% in elderly
  
  

• 54 слайд

  Metabolism in infants
  Hepatic enzyme activity and plasma / tissue esterase activity are both reduced during the neonatal period
  The enzyme activity increases as the infant ages but can be compromised in cases of severely malnourished infants and children
  Plasma half-life 2 to 3 times longer in neonates
  
  
  
  
  

• 55 слайд

  Neonate Renal Excretion
  Renal Excretion
  At birth, glomerular function is more advanced that tubular function this persists until about 6 months of age.
  This effects the efficiency at which the kidneys eliminate drugs.
  This is especially important in the administration of aminoglycosides
  
  

• 56 слайд

  Infant – 5 weeks to 1 year
  

• 57 слайд

  Infant - Absorption
  Low acidity in stomach until around 2 years of age
  
  Gastric emptying still delayed
  
  Percutaneous absorption: continue to be increased through childhood
  

• 58 слайд

  Absorption - IM
  Injected drugs are often erratically absorbed because of variability in muscle mass amount children and illness
  
  IM generally avoided due to pain and possibility of tissue damage
  
  

• 59 слайд

  Absorption - transdermal
  May be enhanced in young children because the stratum corneum is thin and the ratio of surface area to weight is much greater than for older children and young adults
  
  Skin disruptions (abrasions, burns, eczema) increase absorption
  

• 60 слайд

  Absorption – transrectal
  Transrectal is dependent on placement of the drug within the rectal cavity
  Good for drugs such as acetaminophen (Tylenol)
  
  Diazepam in status Epilepticus
  

• 61 слайд

  Absorption - lungs
  Varies less by physiologic parameters and more by reliability of the delivery device
  
  
  
  Beta agonists may be used for asthma, pulmonary surfactant for hyaline membrane disease
  
  

• 62 слайд

  Meds via mask
  

• 63 слайд

  Infant - Distribution
  Protein-binding capacity reaches adult values within 10 to 12 months
  
  
  
  Higher doses (mg / kg) of water-soluble drugs are required in younger children due to higher percentage of their body weight in water
  

• 64 слайд

  Infant – Hepatic Metabolism
  Complete maturation of the liver develops by one year
  
  
  
  Cytochrome P-450 enzyme system in the small bowel and liver are the most important factor in drug metabolism
  

• 65 слайд

  Infant – Renal Excretion
  Renal elimination depends on plasma protein binding, renal blood flow, GFR and tubular secretion all are altered in the first two years of life.
  
  

• 66 слайд

  Drug Dosing
  Dosing in children less than 12 years is always of function of age, body weight or both
  When very accurate levels dosing in needed, dose adjustments should be based on plasma drug concentration
  

• 67 слайд

  Child – 1 to 12 years
  

• 68 слайд

  Pharmacokinetics in children
  After one year similar to adults
  They metabolize drugs faster than adults until around age 2 years
  Metabolism declines again at puberty
  Increase in dosage or reduction in dosing interval may be needed for drugs that are eliminated by hepatic metabolism