Download - Drugs & preg
Benha University Hospital, Egypt Email: [email protected]
Impact of the problem
Egypt: 86% takes drugs without prescription (Rizk et al,
1993)
KSA:
60% takes drugs (Alkhawaja,1991)
USA: 2%: Category A drugs 50%: Category B drugs 40%: Category C drugs 4%: Category D drugs 4%: Category X drugs (Andrade et al, 2004)
Teratogens • Teratos= monster, in Greek
• Any agent
{drug, infection, physical condition or deficiency} that
acts on embryo or fetus:
permanent alteration of morphology or function (Shepard, 1998).
Causes of congenital malformation Unknown or multifactorial: 70%
Genetic: 20%
Environmental: 10%
Drugs & chemicals: 5% Infection: 2%
Maternal disorders: 2%
Irradiation: 1%
Factors affecting the teratogenic
effect of the drug A. Fetal factors: I. Developmental stage :
1.Predifferentiation stage (0-7 days of gestation):
Death or no effect.
2.Differentiation stage (7-57 days of gestation):
Malformation
3.Post differentiation stage (after 57 days of
gestation):
Functional defects, Growth retardation
II. Genetic susceptibility : 1. Species differences: Thalidomide is teratogenic in human & not in
animals.
2. Individual differences: difference in maternal or fetal metabolism of the drug
B. Drug factors: I. The route, dose & duration of administration II. Effect of other agents: Excess vit. A: cleft palate & exencephaly in rats.
Excess vit A + Cortisone: Increased incidence
Excess Vit A+ Vit B: No teratogenic effect
III. Access to fetoplacental unit: Lipid solubility
Mol wt: > 600 not cross the placenta
Protein binding
Thickness of the placental membrane
Drugs not cross the placental membrane:
Erythromycin, TSH, ACTH
Drugs negliably cross: Insulin, Heparin, Thyroxin
S. choline, T. curarine, Guanthidine
Furadandin, Chlorapromazine
Appearance of teratogenic effect: • Immediate: Death & abortion
• At birth: Malformation
Functional defects (Streptomycin: nephrotoxic & ototoxic)
• Delayed: Carcinogenesis: DES
Mutagenesis:
Food & Drug Administration
(FDA) classification • 5 categories
RCT Animal Human • Varies according to gestational age • Updated
1. Category A: • RCT in humans: no fetal risk.
• E.g.:
Prenatal vitamins, not megavits K CL, citrate & gluconate,
Thyroxin
2. Category B: • Animal studies: no fetal risk &
No RCT in humans.
• E.g.
Penicillins, terbutaline,
Acetaminophen, cyclizine, antacids,
Prednisone, insulin, ampicilln,
Clindamycin, nitrofurantoin,
Miconazole, spiramycin,.
3.Category C: • Animal studies: fetal risk &
No human studies. • Given only when benefits outweighs the potential fetal harm. • E.g.
Furosemide, Rifampicin, βblockers,
Phenothiazine, methyl dopa, nifedipine,
Heparin, aminophyllin, gentamycin,
Chloroquin, acyclovir, cyclosporin,.
4.Category D: • Fetal risk in humans but the benefits may
outweigh the risk.
• Given only in serious disease , when no alternative. • E.g.
Phenytoin, valporic acid, diazepam,
Imipramine, captopril, thiazides,
Spironolactone, coumarine, chlorpropamide
Progestins, tetracyclin, streptomycin,
Quinine, methotrexate, vinblastin,
Azathioprine.
5. Category X: • Clear human risk that outweigh the benefits. • Contraindicated. • E.g.
Estrogen, androgens,
Aminopterin, isotretinoin,
Thalidomide
Administration Human Risk Animal
risk
Category
Yes No No A
Yes No studies No B
If benefits> Risk No studies Yes C
If No alternative Risk< Benefit D
Contraindicated Risk> Benefit X
T shaped uterus of
DES
Fetal alcohol syndrome
IUGR
Behavior disturbance
Brain defects
Cardiac defects
Spinal defects
Craniofacial anomalies
Phocomelia (limb reduction defects)
Bone defects
Anomalies of ear, CVS
www.perinatology.com
I. CNS
II. CV
III. Pulmonary
IV. GIT
V. Endocrine
VI. Skin
VII. Infections
VIII. Immunosuppresive
IX. Antineoplastic
X. Vitamins
I. CNS 1. General anesthesia: Thiopental: No increase in malformation
Nitrous oxide, Halothane: No increase of
malformation in humans but increase in animals
Ketamine {B}
D C B
Ibuprofen, indomethacin,
naproxin, pentazocine
Mepridine, morphine, Sulindac
{premature closure of D.
arteriosus}
Asprin, Codien (if used at term)
Aspirin
Codiene
Acetaminophen
Ibuprofen,
indomethacin,
naproxin,
pentazocine
Mepridine, morphine
Sulindac
2. Analgesic
Acetaminophen Vs asprin?: Acetaminophen
{Antiprostaglandin effect is short
bleeding time is not prolonged
Indomethacin
contraindicated after 34 w
D B
Nalorphine, levallorphan, cyclazocine Naloxone
D C B
Phenytoin (Dilantin):
Hydantoin syndrome
Phenobarbital, Valporic
acid: valporic syndrome,
Trimethadione
Carbamazepine
(tegretol):
carbamazepin
syndrome
Clonazepam
(Clonopin)
barbiturates
Mg sulphate
Metharbital
3. Narcotic antagonist:
4. Anticonvulsant
Fetal anticonvulsant
syndrome
Craniofacial
abnormalities
Broad nasal bridge
Epicanthal fold
Limb defects
Growth deficiency
Mental Deficiency
D C B
Tricyclic
antidepressants:
amitriptylin,
amoxapine,
imipramine
clomipramine,
nortriptyline
Benzodiazipines:
alprazolam,
diazepam
lithium
Monoamine oxidase
inhibitors:
isocarboxazid, phenelzine,
tranylcypromine
Tricyclic antidepressants:
desipramine, doxepin
Antipsychotics:
chlorpromazine, thioridazine,
perphenazine
Benzodiazipines:
clonazepam, lorazepam,
oxazepam
Selective
serotonin
reuptake
inhibitors:
fluoxetine,
paroxetine,
sertraline
Antipsychotic:
Clozapine
Bupropion
5. Psychotropic
Chlorpromazine: Negliably cross the placenta
Diazepam: 1st T: cleft lip.
Before delivery: hypotonia, hypothermia, respiratory
depression.
Imipramine: limb reduction defects
Lithium: Cardiovascular anomalies
II. Cardiovascular 1. Antihypertensives
D C
Angiotensin converting enzyme
inhibitors: (Captopril)
Nitroprusside
Reserpine
Methyldopa
Hydralazine, ß blockers,
Nifedipine (adalat)
Clonidine (catapress),
Prazosin (minipress)
Diazoxide (hyperstat)
Captopril: oligohydramnios, pulmonary hypoplasia, IUGR
ß blockers: propranolol (inderal), atenolol (tenormin), labetolol
(trandate)
2. Anticoagulant
D C B
Warfarin (coumarin):
warfarin syndrome&hge
Phenindione (dindivan)
Heparine
(conventional)
Streptokinase
Heparine (low mol wt
4000-6000 e.g.
enoxaparin
Urokinase
Exposure
6-13 w: 5% risk of F warfarin synd
nasal hypoplasia
stippled epiphyses
limb deformities
mental retardation
seizures.
2nd or 3rd T: 5% risk of fetal intracerebral hge.
If warfarin therapy is essential:
Avoid during 1st T {teratogenicity}
Avoid 2 to 4 w before delivery {reduce risk of hge}.
Women who conceive on warfarin& wish to
continue the pregnancy:
Vit K 10mg orally {reverse warfarin effect }
immediately therapeutic LMWH dose
3. Diuretics:
D C B
Thiazide: thrmbocytopenia
Spironolactone: antiandrogenic
Acetazolamide: limb abnormalities
Furosemide
Ethacrynic acid
Amiloride
4. Heart:
C B Digoxin, Quinidine, Procainamide Lidocaine
III. Pulmonary 1. Asthma
D C B
Triamcinolone
acetonide
Albuterol, Metaproterenol,
Betamethazone,
Beclomethazone,
Dexamethazone, Flunisolide,
Theophylline, Aminophylline
Epinephrine, ephidrine
Cromolyn
Terbutaline
Ipratropium
bromide
Prednisone,
Prednisolone
Prednisone & prednisolone are inactivated in the placenta
2. Antihistaminics
C B
Brompheniramine, Hydroxzine,
pheniramine
Azatadin, clemastine,
Cyclizine, Doxylamine
3. Cold
D C B
Iodide Phenylephrine
Pyrilamine
Pseudoephydrine, Oxymetazoline
Chlorpheniramine, Dextrome
thorphan
4. Antitussive & expectorants
X D C B
Iodinated
glycerol
Potassium iodide,
Sodium iodide
Codeine,
Guaifenesin
Hydrocodon
Amm.
chloride
IV. Gastrointestinal 1. Antiemetics
C B
Chlorpromazine, promethazine,
prochlorperazine, trimethobenzomide
Cyclizine
Meclizine
2. Antiulcer
X C B
Misoprostol
(uterine
contraction)
Omeprazole Sucralfate (not absorbed)
Antacids (poorly absorbed)
Ranitidine
Cemetidine (antiandrogenic)
Famotidine, nizatidine
3. Gallstone solubilizing agents
X B
Chenodiol Ursodiol
4. Laxatives & purgatives
C B
Casanthranol, Cascara sagrada, danthron,
docusate, mineral oil, phenolphthalein, senna
Lactulose
Mg sulphate
5. Antidiarrheals
D C B
Paregoric Kaolin, pectin, diphenoxylate Loperamide
V. Endocrine 1. Antidiabetics
C B
Chlorpropamide, tolazamide, Tolbutamide,
Acetahexamide, Glyburide, Glibpizide
Insulin
Metformin
Acarbose
2. Thyroid & parathyroid disorders
X D C B A
Sod
iodide
I131
P.thiouracil
Methimazole
Carbimazole
Lithium
carbonate
Protirelin
thyrotropin
Calcitonin Thyroid,
levothyroxin
Liothyronin
Thyroglobulinio
dothyrine,
liotrix
Methimazole: scalp defects
PTU 150 mg/d or carb 15 mg/d: unlikely to cause problems in the
fetus.
Iodides: goiter & hypothyroidism
3. Adrenal
D C B
Cortisone Betamethazone,
Beclomethazone,
Dexamethazone,
Triamcinolone
Prednisolone,
prednisone
4. Gynecologic disorders
X D C
Progestagens: norethindrone,
norethyndrel, norgestrel
Estrogens, Clomiphene
Androgens, Danazol,
Mifipristone
Progestagens:
ethisterone,
ethyndiol hydroxy
progestrone
Tamoxifen
Bromocriptin
DES: •Female: Uterus: T shaped, Vagina: adenosis, Vagina & cervix: adenocarcinoma (at 20 y) & abnormalities •Male: hypoplastic, un descended tsetse, epidedmal cysts
VI. Skin
X D C B
Vit A
derivatives: isotretinoin
(Accutane)
etretinate
(Tegison)
Thalidomide
Podophyllin
Tetracyclin Methotrexate
Azathioprine
Topical
corticosteroids
& tretinoin
Pyrilimine
Chloroquine,
Grisofulvin
Acyclovir,
zidovuidine
Dithranol& tar
Orphermine
Metronidazole
Lindane
Sulphur in
petroleum
Piperonal
butoxide
VII. Infections 1. Antibacterial
D C B
Tetracyclins
S.amide
Tobramycin
StreptomycinK
anamycin
Trimethoprime
Chloramphenicol
Gentamycin,
Neomycin,
Amikacin,
Vancomycin
Quinolones
Penicillin, Erythromycin,
Ampicillin, augmentin.
Cephalosporin, clindamycin,
azithromycin spectinomycin,
spiramycin
Nitrofurantoin, nalidexic acid,
S. amide.
Metronidazole
Polymyxin, Aztreonam
Tetracyclin: After 4th month when calcium starts to deposit in
bone:
yellow or brown discoloration of deciduous teeth,
hypoplasia of enamel
delayed bone development.
Chloramphenicol: Gray baby syndrome: cyanosis, collapse, death.
Trimethoprime: Folate antagonist
Sulphonamides: 3rd T: hyperblirubinaemia & neonatal jaundice
2. Antituberculosis
C B
Rifampicin, INH, PAS,
Ethionamide, Cycloserin, pyrazinamide
Ethmbutol
3. Antifungal
C B
Griseofulvin, fluconazole, itraconazole,
ketoconazole, miconazole, teraconazole
5 flucytosine, gentian violet
Miconazole,
clotrimazole
Amphotericin,
Nystatin
3. Antimalarial
D C B
Quinine Chloroquine, primaquine,
Pyrimethamine, Dapsone,
Quinacrine, quinidine
Proguanil
4. Antihelminthic
C B
Mebendazole, thiabendazole
Pyrantel, pyrvinium, quinacrine, Gentian violet
Piperazine
5. Amebicides
D C B
Carbarsone Chloroquine, iodoquinol,
paromomycin
Metronidazole
6. Antiviral
X C B
Ribavirin Acyclovir, Ganciclovir,
Zidovudine
Didanosine
Famciclovir
Ritonavir
VIII. Immunosupressive
D C
Azathioprine Cyclosporin
IX. Antineoplastic
X D C B
Aminopterin
Leuprolide
Methotrexate, 5
flurouracil, 6M.P
Doxorubicin,
daunorubicin, bleomycin
Cyclophosphamide,
melphalan, busulphan,
Cisplatin, vincristin,
vinblastin, Etopside
Cytosine,
arabinoside
Dactinomycin
Interferon alfa
Prednisone
X. Vitamins
X D C A
Etretinate
Isotretinoin
Tretinoin
systemic
ßCarotene,
Leucovorin,
Menadione/X,
Phytonadione,
Tretinoin
topical
Vitamins, multiple
Folic 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
Isotretinoin (Accutane) •Craniofacial malformation
Microtia or anotia, flat depressed nasal bridge
Malformation of the heart, CNS, & thymus
•Avoid pregnancy during treatment
Long acting contraceptive method is required
Etretinate (Tegison): (Psoriasis)
•Malformation has been described 13 ms after
discontinuation (Lammer, 1988)
Contraception for at least 2 y after TT (Geier et al, 1994)
Recommendation Before pregnancy: Familiar with teratogenic drugs
Avoid pregnancy if teratogenic drug
should be given
Ask about the LMP
1st T: Avoid drugs
Exception folic acid & vit C
If absolutely indicated: lowest number of drugs,
short time & minimal effective dose
2nd & 3rd T:
Beneficial & safe drugs
if indicated: short time & minimal effective dose
Last week: Avoid drugs that may affect neonates
If needed: stop 7-10 d before labor
ACE inhibitor
Alchol
Aminopterin
Androgens
Busulfan Carbamazepine Chlorbiphenyls Coumarins Cyclophosphamide
DES
Eteretinate
Isotretinoin
Lithium
Methimazole
Methotrexate
Penicillamine
Phenytoin
Radioactive iodine
Tetracycline
Trimethadione
Valporic acid
Teratogenic drugs
Aboubakr Elnashar
Benha University Hospital E-mail: [email protected]