drug safety (1)
TRANSCRIPT
HOW SAFE
ARE DRUGS USED
IN PREGNANCY
TERATOGEN Any agent chemical,
viruses,environmental agents , physical factors and drugs that acts during embryonic or fetal development to produce a permanent alteration of form or function
HADEGAN-agent that interferes with normal maturation and function of an organ
TROPHOGEN-agent that alters growth (affects process occuring after
organogenesis or even after birth)
CRITERIA FOR PROOF OF HUMAN TERATOGENECITY Careful delineation of clinical cases Rare environmental exposure associated
with rare defect,with atleast 3 reported cases-easiest if defect is severe
Proof that the agent acts on the embryo or fetus directly or indirectly
Proven eposure to agent at critical times in prenatal development
The association must be biologically plausible
CRITERIA FOR PROOF OF HUMAN TERATOGENECITY Consisitent findings by 2 or more
epidimiological studies of high quality.
Teratogenicity in experimental animals,especially primates.
GENERAL CONSIDERATIONS
Almost all drugs cross the placenta to Some extent Weigh therapeutic benefits of drug to mother against its risk potential to developing fetus
FACTORS MODIFYING TERATOGENICITY 1. Animal species and Race often animal study
data of either safety or teratogenicty don not indicate the definite and conclusive proof of being same in human being .
2. Chemical- nature , dose , specificity , Dose . Gestation period of exposure , duration of exposure , their absorption and circulation as free / protein bound form ,rate of detoxification . Excretion / clearance from body, ability to cross placenta , concentration in fetal tissue etc.
Physiological changes in pregnancy also modify drug effect and on fetus ---
(a) Absorption is altered due to delay in gastric emptying by increased progesterons.
(b) increased GFR increases clearance thruogh Kidneys.
FACTORS MODIFYING TERATOGENICITY
(c). Increased liver enzyme activity by increased levels of Estrogen and progeston lead to fast clearance .
(d). How and how much drug / chemical is able to cross placental barrier ---to reach to fetus , water soluble substances pass through easily by direct effusion depending upon concentration gradient ,Low molecular weight substances cross fast, while macro sized and with high molecular weight substances do not cross placenta , Free molecules cross easily as compared to Protein bond .Some chemicals need active transfer mechanism like Phosphorilization.
FACTORS MODIFYING TERATOGENICITY
4. Period of Gestation and Exposure to teratogen
Teratogens can cause cell death , alter tissue proliferation and growth pattern( hypoplasia , aplasia , asynchronous growth)., interferring with cellular differentiation or other morphogenic process.
Tertogenic effect is maximum during period of organogenesis ( bb3-8 -10 weeks )after LMP( 35 –70 days post LMP ).Mental physical / maturaton of organ function and their coordination to each other and growth of ear , eye , gonads occur in later weeks of gestation .
PLANCENTAL TRANSFER OF DRUGS
DEPENDS ON :1. Molecular weight2. Concentration of free drugs3. Lipid solubility4. Utero placental blood flow5. Placental surface area.6. More transfer of drugs at term
86% of women take medication during pregnancy
Despite this , most drugs are not labeled for use during pregnancy
1/2 of pregnancies unplanned
<50% of women know they are pregnant by 4th week and ~20% still don’t know by 8th week
GENERAL CONSIDERATIONS
FDA DRUG CATEGORIES
FDA DRUG CATEGORIES
Administration Human Risk Animal risk
Category
Yes No risk No risk
A
Yes No adequate studies
No risk
B
If benefits> Risk
No adequate studies
Risk C
If No alternative
Risk< Benefit D
Contraindicated Risk> Benefit X
A review of 152531 pregnant women in 4yrs-
64% women were prescribed other drugs then vitamins in 270 days, which were
Category C – 37.8% Category D -4.8% Category X -4.6%
Hence a planned pregnancy should be the answer
TERATOGENICITY OF DRUGS IN
PREGNANCY
FACTORS THAT INFLUENCE TERATOGENECITY
Nature of agent Dose Route Frequency of exposure Duration of exposure Gestational timing Concurrent illness Genetic susceptibility(mother, fetus)
TIMING OF TERATOGEN EXPOSURE AND HAZARDS BEFORE DAY 31 : All or none effect(cell
death or malformation)
Day 31 to 71 : Effects depend on amount of drugs and duration of exposure.
AFTER DAY 71 : DES related anomalies around 20 weeks.
Fetal alcohol syndrome in late pregnancy.
GESTATIONAL PERIOD AND TERATOGENECITY
MECHANISM OF TERATOGENECITY
DISRUPTION OF FOLIC ACID METABOLISM
Leads to deficient methionine production and RNA, DNA synthesis.
Preconceptional folate deficiency leads to neural tube defects, cleft lip and palate
EPOXIDE AND ARENA DRUGS
Are oxidative inter metabolites of drugs like hydantoin and carbamazipine
Have carcinogenic and teratogenic potential unless detoxified by fetal epoxidehydrolase
ENVIRONMENT AND GENES : Genotype of the embryo and their susceptibility to teratogens.
MATERNAL disease AND DRUGS EXPOSURES : Causes gene mutation and chromosomal anomalies.
HOMEOBOX GENES : Regulatory genes are dysregulated by teratogens.
Paternal Exposures
The process by which germ cells mature into functional spermatogonia takes 64 days, drug exposure at any time during the 2 months prior to conception could result in a mutation.
During intercourse a drug in seminal fluid could directly contact the foetus.
Paternal germ cell exposure to drugs or environmental agents may alter gene expression
DRUGS OR SUBSTANCES SUSPECTED OR PROVEN TO BE HUMAN TERATOGENS
Alcohol Angiotensin-converting enzyme inhibitors and
angiotensin-receptor blockers Aminopterin Androgens Bexarotene Bosentan Carbamazepine Chloramphenicol Chlorbiphenyls Cocaine Corticosteroids (High doses) Cyclophosphamide
Danazol Diethylstilbestrol (DES) Efavirenz Etretinate Isotretinoin Leflunomide Lithium Methimazole Methyl mercury Methotrexate Misoprostol Mycophenolate Paroxetine Penicillamine
Phenobarbital Phenytoin Radioactive iodine Ribavirin Streptomycin Tamoxifen Tetracycline Thalidomide Tobacco Toluene Tretinoin Valproate Warfarin
ANTICONVULSANTS
Trimethadione and Paramethadione-Category D
D C B
Phenytoin (Dilantin): Hydantoin syndromePhenobarbital, Valporic acid: valporic syndrome, Trimethadione
Carbamazepine (tegretol): carbamazepin syndromeClonazepam (Clonopin)barbiturates
Mg sulphateMetharbital
Anticonvulsant
Fetal anticonvulsant syndrome
Craniofacial abnormalities
Broad nasal bridge
Epicanthal fold
Limb defects
Growth deficiency
Mental Deficiency
PHENYTOIN-FETAL HYDANTOIN SYNDROME
CARDIOVASCULAR DRUGS
Cardiovascular disordersAntihypertensivesD CAngiotensin converting enzyme inhibitors: (Captopril)NitroprussideReserpine
MethyldopaHydralazine, ß blockers, Nifedipine Clonidine Prazosin Diazoxide
Captopril: oligohydramnios, pulmonary hypoplasia, IUGRß blockers: propranolol (inderal), atenolol (tenormin), labetolol (trandate)
DiureticsD C BThiazide: thrmbocytopeniaSpironolactone: antiandrogenicAcetazolamide: limb abnormalities
FurosemideEthacrynic acid
Amiloride
Others C BDigoxin, Quinidine, Procainamide Lidocaine
ANGIOTENSIN CONVERTING ENZYME INHIBITORS- (ENALAPRIL, LISINOPRIL) AND ANGIOTENSIN RECEPTOR BLOCKERS ‘ LOSARTAN
Oligohydromnios
Renal anomalies
Neonatal renal failure
Pulmonary hypoplasia
Hypoclavaria
Growth restriction
Death
SPIRONOLACTONE(ANTI-ANDROGEN)
Feminisation of male fetus (short phallus and bifid scrotum)
Amiodaron –Category D (hypothyroidism)
DIURETICS: Reduced placental perfusion and fetal compromise , thrombocytopenia and hyponatremia IUGR
WARFARIN
Fetal-contradi syndrome skeletal and facial abnormalities optic atrophy Microcephaly chondrodysplasia puncta.
CONTRADI SYNDROME
RETINOIDS
VITAMIN A
•avoid doses higher than the recommended daily allowance of 5000 IU
BEXAROTENE
•contraindicated during pregnancy.
•eye and ear abnormalities.
• cleft palate and incomplete ossification.
•male patients who have partners who could become pregnant are advised to use condoms during sexual intercourse if they are taking bexarotene and for one month after discontinuing therapy
ISOTRETENOIN(used in acne)
•first-trimester exposure- high rate of foetal loss
•malformations (26 fold)
•microtia or anotia
-agenesis or stenoses of the external ear canal
-cleft palate and maldevelopment of the facial bones and cranium
-cardiac anomalies
-hydrocephalus
- thymic abnormalities
ETRETINATE -TERATOGENECITY SIMILAR TO ISORETINOIN-anomalies are observed even when conception occurs after discontinuation (2yrs)
TRETINOIN first-trimester topical use results in fetal defects similar to those associated with isotretinoin
ANTIMICROBIALS
Infections1. AntibacterialD C B
TetracyclinsTobramycinStreptomycinKanamycin
TrimethoprimeChloramphenicolGentamycin, Neomycin, Amikacin,VancomycinQuinolones
Penicillin, Erythromycin, Ampicillin, augmentin. Cephalosporin, clindamycin, azithromycin spectinomycin, spiramycinNitrofurantoin, nalidexic acidMetronidazolePolymyxin, Aztreonam
TETRACYCLINE –YELLOW BROWN DISCOLORATION OF DECIDOUS TEETH,BONE GROWTH DEFORMATION
CHLORAMPHINICOL-GRAY BABY SYNDROME(CYANOSIS,PERIPHERAL VASCULAR COLLAPSE,DEATH)
OTHER ANTIBIOTICS
DRUGS SIDE EFFECTS AND COMPLICATIONS
Aminoglycosides –Category D
Auditory or vestibular damage and nephrotoxicity
Quinolones Arthropathy in animal studies
Anti Fungal- Griseofulvin Central nervous system and skeleton anomalies in animals
Fluconazole and Itraconazole: Category C
skull abnormalities, cleft palate, humeral-radial fusion, and other arm abnormalities
ANTILEPROBIC DRUGS Dapsone to be avoided in third trimester.
DRUGS FETAL OR NEONATAL AFFECTION AND COMMENT
Long acting sulphonamides
Neonatal hemolysis,jaundice and kernicterus
Nitrofurantoin Hemolysis In newborn if used at term
Metronidazole No evidence of foetal or neonatal toxicity, high dose regimen should be avoided
OTHER ANTIBIOTICSDRUGS SIDE EFFECTS AND
COMPLICATIONS
Aminoglycosides Auditory or vestibular damage and nephrotoxicity
Quinolones Arthropathy in animal studies
Sulphonamides Hyperbilirubinemia and neonatal jaundice when used in 3rd trimester
ANTIMALARIALS
MEFLOQUINE- 5 fold increased risk of still births
chloroquine,quinine and quinidine are generally considered safe in pregnancy in therapeutic doses
Quinine Category D drug
ANTIVIRALS
Amantadine , efavirenz and rabavarin are in category x- Hydrocephalus and limb abnormalities in rodents
Anti retrovirals eg.lamivudine, nelfinavir, nevirapine, stavudine, or zidovudine are Category C drugs
AntimalarialD C BQuinine Chloroquine, primaquine,
Pyrimethamine, Dapsone ,Quinacrine, quinidine
Proguanil
Antihelminthic
C BMebendazole, thiabendazolePyrantel, pyrvinium, quinacrine, Gentian violet
Piperazine
Amebicides
D C BCarbarsone Chloroquine,
iodoquinol, paromomycin
Metronidazole
AntiviralX C BRibavirin Acyclovir,
Ganciclovir, Zidovudine
DidanosineFamciclovirRitonavir
Antituberculosis
C BRifampicin, INH, PAS, Ethionamide, Cycloserin, pyrazinamide
Ethmbutol
AntifungalC BGriseofulvin, fluconazole, itraconazole, ketoconazole, miconazole, teraconazole5 flucytosine, gentian violet
Miconazole, clotrimazoleAmphotericin, Nystatin
NSAIDS AND ANALGECIS
D C BIbuprofen, indomethacin, naproxin, pentazocineMepridine, morphine, Sulindac {premature closure of D. arteriosusAsprin, Codien (if used at term)
AspirinCodiene
AcetaminophenIbuprofen, indomethacin, naproxin, pentazocineMepridine, morphineSulindac
Analgesic
COX-2 INHIBITORS,ASPIRIN- safe in low doses
(HIGH DOSE)
- impairment of blastocyst implantation - increase risk of neonatal haemorrhage - oligohydromnios - premature closure of ductus arteriosus - persistent pulmonary hypertension and -kernicterus in newborn
ASPIRIN -HIGH DOSES IN LAST FEW WEEKS CAUSES PREMATURE CLOSURE OF DUCTUS ARTERIOSUS, PERSISTENT PULMONARY HYPERTENSION AND KERNICERUS IN NEWBORN
ASPIRIN-PERSISTENT PULMONARY HYPERTENSION
LEFLUNOMIDE
pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis currently contraindicated in pregnancy. CAUSES- hydrocephalus, eye anomalies skeletal abnormalities embryo death
VitaminsX D C AEtretinateIsotretinoin
Tretinoin systemic
ßCarotene, Leucovorin, Menadione/X, Phytonadione, Tretinoin topical
Vitamins, multipleFolic acid/C, Niacin/C, Niacinamide/C, Pantothenic acid/C, Pyridoxine/C, Riboflavin/C, Thiamin/C, Vitamin B12/C, Vitamin C/C, Vitamin E/C Calcefediol/D, calcitriol/D, Cholecalciferol/D, Dihydrotachysterol/D Vitamin D/D, Vitamin A/X
Antineoplastic
X D C B
AminopterinLeuprolide
Methotrexate, 5 flurouracil, 6M.PDoxorubicin, daunorubicin, bleomycinCyclophosphamide, melphalan, busulphan, Cisplatin, vincristin, vinblastin, Etopside
Cytosine, arabinosideDactinomycinInterferon alfa
Prednisone
IMMUNOSUPPRESANTS
CORTICOSTEROIDS(PREDNISOLONE,HYDROCORTISONE)- HIGH DOSES
-CAUSES FETAL AND NEONATAL ADRENAL SUPPRESSION-IUGR(PROLONGED USE)
MYCOPHENOLATE MOFETIL -CATEGORY D CAUSES-bilateral microtia-anotia -atresia of the external auditory canals- oral clefts
ANTI-NEOPLASTIC DRUGSCYCLOPHOSPHAMIDE -missing and hypoplastic
digits, -cleft palate- single coronary artery-imperforate anus- fetal-growth restriction -microcephaly
METHOTREXATE AND AMINOPTERIN
-growth restriction-failure of calvarial ossification, -craniosynostosis- hypoplastic supraorbital ridges, -small posteriorly rotated ears, --micrognathia- severe limb abnormalities
TAMOXIFEN Category D(Human data awaited)
HORMONES
TESTOSTERONE AND ANABOLIC STEROIDS,ANDROGENIC PROGESTINS,DANAZOL
Extreme and irreversible virilization Liver dysfunction Mood and libido disorders Exposure of a female fetus results in
virilization, (labioscrotal fusion after first-trimester exposure and phallic enlargement from later fetal exposure )
DIETHYL STILBOESTROL-VAGINAL ADENOSIS,CERVICAL HOODS, UTERINE HYPOPLASIA OF THE FEMALE OFFSPRING
NORMAL VAGINA VAGINAL ADENOSIS
T shaped uterus of DES
- High doses ablates the foetal thyroid and increases the future risk for childhood thyroid cancer
RADIOACTIVE IODINE
ANTI-PSYCHIATRIC MEDICATIONS
Category D Drugs
Tryclyclic Antidepressant-Imipramine, Nortriptyline,AmitryptylineBenzodiazepines-Alprazolam, Chlordiazepoxide-Category DDiazepam-Category DMidazolam –Category D
LITHIUM –EBSTEIN ANOMALY –from first trimester exposure
NARCOTICS : CNS depression , apnea , bradycardia hypothermia
LITHIUM-NEONATAL HYPOTHYROIDISM EBSTEIN ANOMALY
D C BTricyclic antidepressants: amitriptylin, amoxapine, imipramine clomipramine, nortriptylineBenzodiazipines: alprazolam, diazepamlithium
Monoamine oxidase inhibitors:
isocarboxazid, phenelzine, tranylcypromineTricyclic antidepressants: desipramine, doxepinAntipsychotics: chlorpromazine, thioridazine, perphenazineBenzodiazipines: clonazepam, lorazepam, oxazepam
Selective serotonin reuptake inhibitors: fluoxetine, paroxetine, sertralineAntipsychotic: ClozapineBupropion
Psychotropic
OTHER DRUGS
KNOWN TERATOGENS-ALCOHOL
FETAL ALCOHOL SYNDROME
VIRAL VACCINES
All live viral vaccines are potentially dangerous to the foetus
RELATIVE CONTRINDICATED DRUGS BIOLOGICS eg etanercept infliximab adalimumab
THALIDOMIDE(MALFORMATIONS IN 20% FETUSES)
most notorious human teratogen
Bone defects- abnormal shape or size to total absence of a bone or limb segment—phocomelia.
upper limb phocomelia after exposure during days 27 to 30 days
Lower limb phocomelia was associated with exposure during days 30 to 33
gallbladder aplasia at 42 to 43 days
duodenal atresia at 40 to 47days
Phocomelia (limb reduction defects)
Bone defects
Anomalies of ear, CVS
RECREATIONAL DRUGS
AMPHETAMINES Methamphetamine - associated with symmetrical fetal-growth restriction (NO TERATOGENECITY)
COCAINE -vascular disruption within the embryo, foetus, or placenta, highest after the first trimester -stillbirth -skull defects ,microcephaly,behaviour problems-limb reduction-urinary tract defects-ileal atresia-cardiac anomalies,-visceral infarcts-seizures-hyperthermia and sudden death
OPIATES
HEROIN -foetal-growth restriction-perinatal death-withdrawal symptoms such as tremors, irritability, sneezing, vomiting, fever, diarrhea, and occasionally seizures are observed in 40 to 80 percent of newborns born to heroin-addicted women-postnatal growth -normal in most casesmay be mild developmental delay and behavioural disturbances
METHADONE -low birth weight babies-withdrawal symptoms similar to heroin but more frequent and prolonged(upto 3wks)
TOBACCO •foetal growth restriction•abortions •pre term delivery•placenta previa and abruption•subfertility•clefts
MARIJUANA -low birth weight-teratogenic in high doses
ERGOTS-DIHYDROERGOTAMINE,ERGOTAMINE
Pregnancy Category X Oxytocic properties could cause
IUGR by vascular disruption or increased uterine tone
Chronic exposure is contraindicated
DRUGS FOR MIGRAINETRIPTANS(5 HT1 AGONISTS)
Category CLimited human data exists,
sumatriptan has been associated with VSDs in several cases
OBSTETRIC ANALGESIA AND
ANESTHESIA
A-PARENTRAL NARCOTICSDRUGS COMMENTS
Pethidine (Meperidine) Pethidine does not inhibit uterine contraction so has less adverse effects on baby.
Fentanyl serious respiratory depression.So require continuous pulse oximetry monitoring and close nursing surveillance
Butorphanol (Stadol). Causes drowsiness and dizziness.Less nausea and vomiting.Less respiratory depression
B- INTRATHECAL ANALGESIA
PROBLEMS
pruritus (60-100%).nausea (25-60%).urinary retention (10-35%).
C- INHALATIONAL ANALGESIA :
Most commonly used mixture is Entonox (an equal mixture of NO & Oxygen).
Provides quick with short duration of effect.
Not suitable for prolonged use from early labor, so most suitable is late in labor or while awaiting epidural analgesia.
Adverse effects include nausea & light headedness.
AMOUNT OF DRUG EXCRETED INTO BREAST MILK IS DEPENDENT UPON
chemical properties of drug Molecular weight lipid solubility of the drug the mechanism of transport, the degree of ionization, and change in plasma pH degree of protein binding the plasma pH Drug concentration Exposure time
MATERNAL MEDICATION EFFECTS ON LACTATION AND THE NEONATE
Oral pill Suppression of lactation
Bromocriptine Suppression of lactation
Ergot Suppression of lactation
Metronidazole Anorexia, blood dyscrasias ,irritability
Anti-thyroid drugs,radio active iodine
Hypothyroidism,goitre,granulocytosis
Warfarin Safe in therapeutic doses
Cytotoxic drugs Risk of immune suppression.Risks may outweight the benefits depending on individual drug
Lithium Lethargy, hypotonia, lithium toxicity
SUMMARY
Minimum therapeutic dose to be given for shortest duration.
Well tried drugs preferable to newer alternatives
Drugs should be avoided for first 71 days of pregnancy.
Patient must be counseled about the beneficial effects of the drugs and potential risk to the foetus.
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