Первый слайд презентации: Drugs in pregnancy
CSMU Department of O&G № 1 Docent Kamilova I.K.
The use of drugs in pregnant and lactating women requires a thorough understanding of the unique interactions between the mother, fetus/infant, and the pharmacologic agents that are used in therapy. Any agent that is consumed by a woman may have adverse effects on the fetus/infant.
The use of drugs during pregnancy G raviora quadem sunt remedia persculis ( some drugs worse than the disease - Lat.)
Therapeutic drug use is common and required in pregnancy for : Maternal condition Pregnancy related condition Fetal condition
Maternal condition commonly requiring therapy in pregnancy: Asthma Hypertension Psychiatric condition Diabetes Thyroid dyfhunction Autoimmune disorders
Pregnancy-related conditions commonly requiring therapy Gestational diabetes Gestational hypertension Preterm Posterm Hyperemesis (toxemia of pregnancy)
Fetal conditions commonly requiring drug therapy: Cardiac conditions Impending preterm delivery IUGR Intrauterine distress
Слайд 9: Critical periods of development:
1 - progenesis - is meiosis (the stage of maturation of germ cells), as well as the process of fertilization. 2 - embryogenesis: implantation (6-8 days), placentation and development of axial organ rudiments (3-8 weeks); 3 – fetal period: the period of enhanced development of the brain (15-20 week), the period of formation of the basic functional systems of the body (20-24th week) 4 - the process of birth.
First-trimester drug exposure has the largest risk of malformations and ideally all drug therapy should be stopped before attempting conception.
Слайд 11: Drugs considered to be human teratogens (not exhaustive)
ACE (adrenal cortical extract) inhibitors androgens antineoplastics (some) carbamazepine carbimazole danazol diethylstilboestrol
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ethanol lithium misoprostil penicillamine phenytoin tetracyclines thalidomide valproic acid vitamin A & derivatives e.g. isotretinoin warfarin
Drugs may be divided into three groups: Do not cross the placenta, and therefore does not cause direct harm to the fetus; cross the placenta, but no adverse effects on the fetus; cross the placenta and accumulate in fetal tissues, also has a damaging effect.
Слайд 14: FDA Rating System for the Teratogenic Effects of Drugs
The FDA, the government agency that oversees the safety of drugs, provides the most widely used system to grade the teratogenic effects of medications. The FDA assigns a safety category for medications by using a 5-letter system: A, B, C, D, and X. This safety category must be displayed on the labels of all drugs.
A category Summary: Fetal risk not revealed in controlled studies in humans Labeling: "Studies in pregnant women have not shown that [the drug] increases the risk of fetal abnormalities if administered during the first [second, third, or all] trimester( s ) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, [the drug] should be used during pregnancy only if clearly needed."
B category Summary: Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Labeling: "Reproduction studies have been performed in [animals] at doses up to [X] times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to [the drug]. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
C category Summary: Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Labeling: "[The drug] has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) in [species] when given in doses [X] times the human dose. There are no adequate and well-controlled studies in pregnant women. [The drug] should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
D category Summary: Fetal risk shown in humans; use only if benefits outweigh risk to fetus Labeling: "The drug] can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus
X category Summary: Contraindicated; benefit does not outweigh risk Labeling: "The drug may [or can] cause fetal harm when administered to a pregnant woman The drug is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus."
Oxytocin (Syntocinon) Octapeptide Strong rhythmical contraction of myometrium Large doses- sustained contraction(↓ placental blood flow & fetal hypoxia/death) Clinical use: - IOL (IVI 3U syntocinon+50 ml of saline) - Augment slow labour (IVI same as above) -3 rd stage of labour- 5 U IM for HTN,cardiac disease - IVI 40 U in 500ml saline ( PPH) -Surgical termination of preg./ERPC- 5U slow IV
Ergometrine Sustained myometrial contraction & vasoconstriction Syntometrine IM: 5U syntocinon(rhythmic contraction in 2min) + 500µg ergometrine(sustained contraction in 7 min) Side effects – Nausea, vomiting, abdominal pain, chest pain, palpitation, severe HTN, Stroke & MI Contraindication- HTN, Cardiac disease Clinical use: - Management of 3 rd stage - Management of PPH - 2 nd dose give. Alternatively IV ergometrine can be given (works with in 40 sec)
Dinoprostone ( prostin E2 ) Vaginal pessary /gel Clinical use: IOL – 3mg 6hrs apart ( no more than 2 pessaries in 24hrs and max. 3 doses) Side effect: Nausea,vomiting, diarrhoea, fever, Uterine hyperstimulation, HTN, bronchospasm Advantages : - Mobile patient -Reduce need for syntocinon
Carboprost ( Hemabate) Sustained myometrial contraction & vasoconstriction Syntometrine IM: 5U syntocinon(rhythmic contraction in 2min) + 500µg ergometrine(sustained contraction in 7 min) Side effects – Nausea, vomiting, abdominal pain, chest pain, palpitation, severe HTN, Stroke & MI Contraindication- HTN, Cardiac disease Clinical use: - Management of 3 rd stage - Management of PPH - 2 nd dose give. Alternatively IV ergometrine can be given (works with in 40 sec)
Atosiban(Tractocile) Oxytocin receptor antagonist Inhibition of uncomplicated preterm labour between 24-33 weeks ( Tocolytic ) Contraindication: severe PET, eclampsia, IUGR, IUD, placenta previa, placental abruption, abnormal CTG, SROM after 30/40 Side effects: Nausea,vomiting,headache, hot flushes, tachycardia, hypotension & hyperglycemia Dose- Stat IVI then continue infusion until no contraction for 6 hrs.
Other tocolytics Salbutamol inhaler- 100 mcg x 2 puffs stat Terbutaline- 250 mcg subcutaneous Clinical use: both drugs are used for short term. (i) relaxing uterus at C/S (ii) ECV procedure Side effects: Headache, palpitation, tachycardia, MI,arrhythmias, hypotension & collapse
Nifedipine Calcium Channel blocker Clinical use: Mild to moderate- 5-20 mg TDS/PO Severe HTN- 10 mg Retard/PO Tocolytic - Incremental doses every 20 min until contraction stop, then 20 mg TDS/PO Side effects: Headache,dizziness,palpitation, tachycardia, hypotension,sweating & syncope
Mild /Moderate HP Methyldopa: -Dose: 250mg BD/TDS, PO max dose 3g /day -Side effects: Headache,dizziness,dry mouth, postural hypotension,nightmares, mild psychosis, depression,hepatitis & jaundice - Important to stop drug in postnatal period Labetolol 100-200mg BD/TDS PO max 2.4g/24hr ACE inhibitors are contraindicated in pregnancy
Severe Pre eclampsia / HP IV Labetolol (ß blocker): - Side effects: headache, nausea, vomiting, postural hypotension & liver damage - Contraindication: Asthma, marked bradycardia IV hydralazine (vasodilator) : - Side effects: headache,nausea, vomitting, dizziness, flushing, tachycardia, palpitation & hypotension - Because of hypotension preload with gelofusin adv. - Contraindication- SLE, severe tachycardia & MI
Magnesium Sulphate Clinical use: Prevention & treatment of seizure in eclampsia / severe pre eclampsia Dose: 4g IV stat then 1g/ hr to be continued 24hr after last seizure Side effects: nausea,vomiting,flushing, drowsiness,confusion,loss of tendon reflexes, hypotension, decrease U/O, respiratory depression, arrhythmias,cardiac arrest Because of toxicity, Mg levels monitored
Drugs in early pregnanc y Mifepristone- 200mg PO Mechanism: Antiprogestogenic steroid Sensitizes myometrium to prostaglandin-induced contractions & ripens the cervix Clinical use: Medical termination of pregnancy Medical management of miscarriage/IUD Side effects: Gastro intestinal cramps, rash, urticaria, headache,dizziness, Contraindication: severe asthma
Misoprostol Synthetic prostaglandin PO/PV route Clinical use: - Medical TOP - Medical management of miscarriage/ IUD ( For 1st trimester single dose of 400mcg From 12- 34 weeks 400mcg 3hrly,max 5 doses) - Postpartum hemorrhage- 800mcg PR/PV Side effects: nausea,vomiting, diarrhoea, abdominal pain
Methotrexate Cinical use: Medical management of ectopic pregnancy Dose 50mg per kg/m2 Criteria- adenexal mass, non viable pregnancy hCG < 3000U, haemoperitonuem < 150ml Side effects: Disadvantage : repeated hCG levels, emergency surgery Advantage: Avoid surgery, tube preserved
Menorrhagia / dysmenorrhea Mefenamic acid: - NSAID, reduces bleeding by 25% - Dose: 250-500mgx TDS D1-3 of cycle or PRN - Side effects: Gastro-intestinal discomfort nausea, diarrhoea, bleeding/ulceration Tranexamic acid: - Antifibrinolytic,reduces bleeding by 50% - Dose: 1g TDS/QDS D1-4 of cycle - Contraindication: thromboembolic disease - Side effects: nausea,vomiting,diarrhoea, thrombo embolic event
Progestogens Progesterone is a hormone that naturally occurs in the human body. Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. ART Women with previous preterm labours - cyclogest pessary 200mg PV/PR daily till 36 weeks Following IVF/ICSI- Gestone inj + cyclogest pessary
Efficient, effective and safe use of drugs during pregnancy involves the following conditions : • prescribe only established the security of their applications, with well-known pathways of metabolism in order to avoid possible side effects; due to the impossibility of determining the period of final completion of embryogenesis (in the absence of urgent and uncontested evidence) it is appropriate to postpone the use of drugs to 22-24 weeks of pregnancy; in the course of treatment requires careful monitoring of the mother and the fetus.
periods of pregnancy, when the fetus is most susceptible to the damaging effects of dru gs: 1 Up to 11 days from the moment of conception. 2. On the 11th day prior to the third week, when the fetus begins the period of organogenesis. 3. Between 4 and 9 weeks of when the danger of fetal growth retardation, but teratogenic practically does not occur. 4. The fetal period (9th week before birth). In this period, the growth of structural defects usually do not occur, but may be in breach of postnatal functions and various behavioral abnormalities.
Слайд 38: Critical periods of fetus development
Pre-embryonic (days 0 – 17 post-conception): drug exposure during this time is not usually considered to pose risk of malformations. An ‘all or nothing response’ is said to occur ie. there is early abortion or no adverse effect on fetal development. However, the half-life of the drug must be considered because many drugs remain in the maternal circulation for a long period after discontinuation.
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Embryonic (days 18 – 56 post-conception): This is the most important time in terms of risk of fetal malformations.
Drugs, the use of which is contraindicated in any period of pregnancy tetracycline antibiotics - violate the bone formation in the fetus and have hepatotoxicity; chloramphenicol (chloramphenicol ) - because of the risk of suppression of bone marrow function and the possibility of life-threatening so-called "gray baby syndrome"; fluoroquinolones - have a damaging effect on the cartilage between interarticular growth of the fetus and newborn; co- trimoxazole ( biseptol and its analogues) - significantly increase the risk of congenital anomalies of the fetus; rifampicin, lincomycin, ethionamide, chloroquine ( delagil ), griseofulvin, levorin
Drugs, the use of which is contraindicated in any period of pregnancy Other drugs: All statins (lovastatin, simvastatin, Mevacor, Zocor); indirect anticoagulants ( fenilin, pelentan );• Many antihistamines (diphenhydramine, pipolfen, suprastin ); oral hypoglycemic agents; antigonadotropnym drugs ( danazol, Clomid ); androgens; Many antidepressants, barbiturates, antipsychotics (haloperidol, teralen, tizertsin ); benzodiazepines; antiparkinsonian agents ( parkopan, cyclodol, NAC); Non-steroidal anti-inflammatory drugs (meloxicam, phenylbutazone ).
Слайд 42: continuation
Fetal period (days 56 – term): The risk of malformations is lower, but some abnormalities may still occur because development of organs/tissues such as the central nervous system, teeth and genitalia continues. For example, ethanol exposure may affect central nervous system development, and tetracyclines may adversely discolor deciduous teeth and suppress bone growth
Слайд 43: Pharmacological risks
Can be predicted based on the mechanism of action of the drug The risk of some perinatal complications may be reduced by gradually reducing the maternal dose towards the end of the third trimester
Слайд 44: The effects of pregnancy on drug disposition (pharmacokinetics)
The physiological changes that occur with pregnancy may affect pharmacokinetics. These effects vary with the drug and with the individual, are generally difficult to predict and frequently poorly studied.
Слайд 45: continuation
Oral availability: Gastrointestinal motility may be reduced during pregnancy and this may result in delayed absorption of orally administered drugs. However, in the vast majority of cases this is unlikely to be of clinical significance as the total amount of drug that is systemically available will not change appreciably
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Distribution: Maternal water and fat content increases in pregnancy and may increase the volume of distribution of drugs. This should only impact on those drugs that are initiated with a loading dose, when higher doses may be required.
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Plasma albumin concentrations decrease in pregnancy and may result in reduced protein binding of some drugs.
For most drugs these changes should not impact on drug dosing because the unbound (active) concentration should not change. However, problems may arise when drug concentrations are used to tailor drug therapy ( eg. anticonvulsants). Routine measured drug concentrations are usually the total concentrations ie. bound plus unbound (free). Total drug concentrations may decline in pregnancy so for drugs such as phenytoin it is important to measure unbound concentrations just prior to and during pregnancy.
Слайд 49: Metabolism/elimination:
Maternal drug clearance often increases because of changes that include increased renal and hepatic blood flow and enzyme induction. This generally means that increased maintenance doses of both metabolized and renally eliminated drugs may be required in pregnancy.
For example, drugs that are extensively renally eliminated ( eg. penicillins ) will have enhanced clearance in pregnancy because of increased glomerular filtration rates. Increased hepatic metabolism of drugs is variable  but can be expected to result in increased dosage requirements in the third trimester for agents such as phenytoin and methadone.
Слайд 51: General principles
Avoid all drugs in pregnancy where possible, especially in the first-trimester. Herbal and other complementary therapies are often perceived by the lay public as 'safe'. Unfortunately, data on many of these products are very limited and insufficient to determine their safety in pregnancy. In general, herbal remedies should be avoided during pregnancy.
Слайд 52: continuation
Consider tapering and discontinuing unnecessary pharmacotherapy prior to attempting conception. Remember that some drugs or their metabolites may have long half-life and persist for some time after stopping therapy. Many conditions are self-limiting and do not require drug treatment. Reassurance or lifestyle measures (e.g. avoidance of migraine triggers) may be sufficient.
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Where possible, delay treatment until after results of laboratory testing (e.g. swabs), or until after delivery. If drug therapy is needed, select drugs with the most established safety record.
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Use the lowest effective dose for the shortest possible time. Note: poor control of some maternal disease states may carry significant risk to the development of the foetus. In addition, the severity or frequency of some maternal diseases (e.g. migraines) may improve in pregnancy allowing a reduction in the dosage of some drugs, or cessation of treatment.
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It is also important to realise that some mothers may be very anxious about the risks that their drug therapy poses to their baby. This may lead to noncompliance with drug therapy, or unnecessary pregnancy terminations.