drug safety (1)

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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