Issues of pharmacotherapy during pregnancy and lactation are very relevant. A significant number of pregnancy complications, as well as extragenital diseases. encountered during it, demand drug therapy, often multicomponent. The same applies to the lactation period.
At the same time, many general practitioners and doctors of narrow specialties are completely unaware of the dangers of certain drugs for a pregnant woman, her fetus and a breastfed child. Pharmacists also often dispense medications without taking the above into account. The consequences of such rash actions can be negative. It should become an immutable rule for doctors of any specialty and pharmacists (pharmacists) before prescribing (selling) any medications for a woman of reproductive age, it is necessary to clarify the presence or absence of pregnancy or lactation. Pregnancy is a specific condition of a woman, which requires increased caution when prescribing medications. The balance between the degree of risk and the potential benefit of prescribing a drug is the main problem of pharmacotherapy during pregnancy. Medicinal substances can be divided into three groups (Karpov O.I., Zaitsev A.A., 1998):
1) Do not penetrate the placenta, therefore not causing direct harm to the fetus;
2) Penetrating the placenta, but not exerting harmful influence to the fruit;
3) Penetrating through the placenta and accumulating in the tissues of the fetus, and therefore there is a risk of damage to the latter.
Most drugs penetrate the placenta due to diffusion and (or) active transport. The efficiency of penetration depends on a number of factors (size of lipid-soluble drug particles, degree of ionization and protein binding, thickness of the placental membrane and blood flow rate in the placenta). With increasing gestational age, the degree of transplacental diffusion of drugs into the fetal bloodstream and amniotic fluid increases. The embryotoxic properties of drugs largely depend on the period of intrauterine development of the fetus and the pharmacological activity and dose of the drug.
The administration of medications requires special attention and caution in the first weeks of pregnancy and the perinatal period. It is always necessary to evaluate the relationship between possible risk complications and the expected positive effect of the drug. In addition to embryotoxic use drug therapy is fraught with the manifestation of a teratogenic effect, which includes the appearance in a newborn of not only organic, but also functional abnormalities. Towards development congenital anomalies may result from genetic disorders, uterine abnormalities, infections (especially viral), fetal trauma, hormone or vitamin deficiencies (especially folic acid), various physical factors(overheating, excessive ultraviolet exposure, radiation exposure), as well as smoking, alcohol and drug use.
The rapidly growing fetal organs are highly vulnerable to toxic effects due to multiple cell divisions. Tissues grow fastest during organ formation. In this phase, the damaging effects of drugs or viruses may include the destruction of cellular junctions, deformation of cells and the cessation of their normal growth. Drugs can cause delays in general or mental development, which can manifest themselves throughout childhood. After the end of the embryogenesis period, there is no longer any fear of the occurrence of developmental defects. If the drug has a toxic effect on early stage of embryo development, then it will have the most dangerous consequences for the unborn child.
The following critical periods in the life of the embryo are distinguished, i.e. when he is most sensitive to the damaging effects of drugs:
1) From the moment of conception until 11 days after it.
2) From the 11th day to the 3rd week, when organogenesis begins in the fetus. The type of defect depends on the gestational age. After the completion of the formation of any organ or system, disturbances in their development are not observed.
3) Between the 4th and 9th weeks, when the risk of delayed fetal development remains, but the teratogenic effect practically no longer appears.
4) Fetal period: from the 9th week until the birth of the child. During this period of growth, structural defects, as a rule, do not occur, however, disruption of postnatal functions and various behavioral abnormalities are possible.
The American Federal Food and Drug Commission (FDA) offers the following classification of all drugs:
Category A - the drugs are completely harmless to the fetus, i.e. there is no evidence of their influence on the incidence of congenital anomalies or damaging effects on the fetus (for example, many vitamins);
Category B - Animal experiments have not shown any harmful effects, but there are no control studies in pregnant women. This category also includes drugs that are harmful to animals but not to humans (for example, penicillin, digoxin, epinephrine);
Category C - animal studies have shown teratogenic or embryotoxic effects medicines to the fetus, but no controlled studies have been conducted in humans. It is suspected that they may cause reversible damage due to pharmacological properties, but not causing the development of congenital anomalies. These drugs can be used only in those conditions where the benefits of their use outweigh the potential risk to the fetus (these include furosemide, verapamil, beta-blockers).
CategoryD- drugs that cause or are suspected of causing congenital anomalies or irreversible damage to the fetus. The risk to the fetus must be weighed against the potential benefit of using this drug, which under certain circumstances may outweigh the risk.
CategoryX - Animal and human studies have shown clear risk to the fetus associated with high risk development of congenital anomalies or permanent damage to the fetus. It should not be used during; it is not recommended for women wishing to become pregnant (since it is possible to take this drug in the “very early” stages of pregnancy, i.e. before the woman finds out about the presence of pregnancy)
Thus, it is advisable to avoid prescribing medications during pregnancy unless there are absolute indications for their use. The classic statement is true: the main contraindication is the absence of indications. If a woman of childbearing age must receive drug therapy, reliable contraception is necessary.
Rational and effective application medications during pregnancy, according to O.I. Karpov and A.A. Zaitsev (1998), presupposes the fulfillment of the following conditions:
- It is necessary to use drugs only with established safety for use during pregnancy, with known metabolic pathways, in order to provide for possible side effects.
- The duration of pregnancy must be taken into account. Since the time period for the final completion of embryogenesis cannot be determined, the use of medications should be postponed until the 5th month of pregnancy.
- During treatment, careful monitoring of the condition of the mother and fetus is necessary.
If treatment of a disease in a pregnant woman poses a certain risk to the fetus, the doctor must explain to the patient in detail all the positive and negative aspects of such treatment.
The use of medications during lactation is also not without certain problems. It is well known that medications used by a nursing woman have a pharmacological effect on the child. While in adults there is a close correlation between the dose of the drug and body weight, and in many cases the dose of the drug is the same for any age, in children it is necessary to take into account the typical characteristics of the different age periods of childhood. For example, the newborn period is characterized by functional and morphological immaturity; an infant is characterized by a rapid increase in weight and length, increased water content in the body, transient antibody deficiency syndrome and increased metabolism, etc. Therefore, the prescription of medications to nursing women must necessarily ensure complete safety for the breastfed child.
The tables below contain official data from manufacturers of certain drugs on the possibility of their use during pregnancy and lactation. This data may sometimes be inconsistent with other sources.
“YES” - the company allows the use of the drug.
“NO” - the use of the drug is contraindicated.
“WITH CAUTION” - the drug is used only according to vital signs.
Table 1. POSSIBILITY OF USING MEDICINES DURING PREGNANCY AND LACTATION
|
PHARMACOLOGICAL GROUP AND NAME OF THE DRUG |
PREGNANCY |
LACTATION |
||
|
Antiarrhythmic drugs |
||||
|
CAREFULLY |
||||
|
Amiodarone (cordarone) |
||||
|
Potassium preparations (potassium chloride, panangin, asparkam) |
||||
|
Lidocaine |
CAREFULLY |
CAREFULLY |
||
|
Novocain-amide |
||||
|
Rhythmonorm |
||||
|
Ethacizin |
||||
|
Antiplatelet agents and anticoagulants |
CAREFULLY |
|||
|
Indirect anticoagulants (pelentan, phenylin) |
||||
|
Dipyridamole (chimes) |
CAREFULLY |
|||
|
Pentoxifylline (trental, agapurine) |
NO (according to some literature data, allowed if there is convincing evidence) |
|||
|
Streptokinase and other drugs for systemic thrombolysis (avelisin, cabikinase) |
||||
|
Fraxiparine |
CAREFULLY |
CAREFULLY |
||
|
Antihypertensive drugs |
||||
|
Apressin |
||||
|
Guanethidine (octadine) |
||||
|
Diazoxide (hyperstat) |
||||
|
Clonidine (hemitone, catapressan) |
CAREFULLY |
CAREFULLY |
||
|
Methyldopa (aldomet, dopegyt) |
CAREFULLY |
|||
|
Papaverine |
||||
|
Prazosin (minipres) |
||||
|
Rauwolfia alkaloids (reserpine, raunatine) and preparations containing them (adelfan, brinerdine, cristepine, sinepres, trirezide, etc.) |
||||
|
Phentolamine (Regitine) |
CAREFULLY |
CAREFULLY |
||
|
Beta blockers Atenolol |
CAREFULLY |
CAREFULLY |
||
|
Labetolol |
CAREFULLY |
|||
|
Metoprolol |
||||
|
Nadolol (korgard) |
||||
|
Oxprenol (Trazicor) |
||||
|
Pindolol (whisken) |
||||
|
Propranolol (anaprilin, obzidan) |
CAREFULLY |
CAREFULLY |
||
|
Calcium channel blockers (Ca antagonists) Verapamil (isoptin, finoptin, lekoptin, falicard, etc.) |
CAREFULLY |
CAREFULLY |
||
|
Diltiazem (cardil) |
||||
|
Isradipin (lomir) |
CAREFULLY |
|||
|
Nifedipine (adalat, corinfar, cordafen, phenigidine, etc.) |
CAREFULLY |
|||
|
Lipid-lowering drugs Atromid, lovastatin, |
||||
|
Cholestipol (cholestide) |
||||
|
Cholestyramine |
||||
|
Diuretics Amiloride |
CAREFULLY |
|||
|
Acetazolamide (diacarb, fonurite) |
NO - in the 1st trimester |
|||
|
Spironolactone (aldactone, veroshpiron) |
NO - in the 3rd trimester |
|||
|
Triamterene |
||||
|
Furosemide (Lasix, Urix, Difurex) |
||||
|
Chlorothiazide (hypothiazide) |
NO - in the 1st trimester |
|||
|
Chlorthalidone(hygroton) |
CAREFULLY |
CAREFULLY |
||
|
Ethacrynic acid (uregitis) |
||||
|
ACE inhibitors(captopril, capoten, enalapril, enap, etc.) |
||||
|
Nitrates Isosorbide dinitrate (isocet, cardicate, nitrosorbide) |
CAREFULLY |
CAREFULLY |
||
|
Nitroglycerine |
||||
|
Sodium nitroprusside |
||||
|
Sympathomimetic agents Dobutamine, dobutrex, dopamine, dopamine |
CAREFULLY |
CAREFULLY |
||
|
Isoproterenol (isadrin) |
||||
|
Norepinephrine (norepinephrine) |
||||
|
Phenylephrine (mesaton; a component of Coldrex-type drugs |
||||
|
Epinephrine (adrenaline) |
CAREFULLY |
|||
|
Drugs that affect cerebral blood flow and improve brain metabolism Nimodipine (Nimotop) |
CAREFULLY |
CAREFULLY |
||
|
Cinnarizine (stugeron) |
||||
|
Aminalon, gammalon |
||||
|
Instenon |
CAREFULLY |
CAREFULLY |
||
|
Glutamic acid |
||||
|
Sodium hydroxybutyrate (GHB) |
||||
|
Picamilon |
||||
|
Piracetam (nootropil) |
||||
|
Encephabol (pyritinol) |
||||
|
Cerebrolysin |
||||
|
Cardiac glycosides(strophanthin, digoxin, corglycone, etc.) |
CAREFULLY |
|||
|
Other vasoactive agents |
||||
|
Hawthorn |
||||
|
Sulfocamphocaine |
||||
|
Solcoseryl (Actovegin) |
||||
|
Phosphocreatine (neotone) |
||||
|
Detralex |
||||
|
Bronchodilators Eufillin |
CAREFULLY |
CAREFULLY |
||
|
Orciprenaline (alupent, asthmapent) |
||||
|
Salbutamol |
||||
|
Terbutaline (bricanil) |
||||
|
Fenoterol (Berotec) |
||||
|
Mucolytic and expectorant agents Ambroxol (lazolvan) |
NO - in the 1st trimester |
|||
|
Ammonium chloride |
||||
|
Acetylcysteine (ACC) |
||||
|
Bromhexine |
NO - in the 1st trimester |
|||
|
Antitussives |
CAREFULLY |
CAREFULLY |
||
|
Glaucine (glauvent) |
||||
|
Oxeladin (paxeladin, |
||||
|
Libexin |
||||
|
Antiallergic drugs Astemizole (Gistalong) |
||||
|
Diphenhydramine (diphenhydramine) |
||||
|
Clemastine (tavegil) |
CAREFULLY |
CAREFULLY |
||
|
Loratadine (Claritin) |
||||
|
Promethazine (diprazine, pipolphen) |
||||
|
Terfenadine (Trexyl) |
||||
|
Chloropyramine (suprastin) |
||||
|
Cromolyn sodium (inthal) |
YES - inhalation; NO - orally |
|||
|
Inhaled corticosteroids(beclomethasone, becotide, etc.) |
||||
|
N-2 - histamine blockers Ranitidine (Histac) |
CAREFULLY |
CAREFULLY |
||
|
Famotidine (quamatel, ulfamide) |
||||
|
Cimetidine (histodil) |
||||
|
Proton pump blocker omeprazole (omez) |
||||
|
M-anticholinergics Atropine sulfate |
CAREFULLY |
CAREFULLY |
||
|
Hyoscyamine (belladonna extract) |
CAREFULLY |
CAREFULLY |
||
|
Hyoscine butyl bromide (buscopan) |
CAREFULLY |
CAREFULLY |
||
|
Pirenzipine (gastril, g astrocepin) |
NO - 1st trimester |
|||
|
Antacids De-nol (proyaz) |
||||
|
Sucralftate (venter) Antacids (Almagel, Maalox, Gestid, Phospholugel, Rennie, etc.) |
||||
|
ProkineticsGastrointestinal tract Domperidone (Motilium) |
||||
|
Metoclopramide (cerucal, raglan) |
CAREFULLY |
|||
|
Cisapride |
||||
|
Antidiarrheals Activated carbon |
||||
|
Attapulgite (kaopectate) |
||||
|
Diosmectite (smectite) |
||||
|
Hilak-forte |
||||
|
Loperamil (imodium) |
NO - in the 1st trimester |
|||
|
Salazopyridazine (sulfasalazine) |
||||
|
Laxatives Bisacodyl |
CAREFULLY |
CAREFULLY |
||
|
Castor oil |
||||
|
Magnesium hydroxide |
||||
|
Guttalax |
||||
|
Regulax |
CAREFULLY |
|||
|
Antiemetics Doxylamine (donormin) |
||||
|
Ondasetron (Zofran) |
CAREFULLY |
CAREFULLY |
||
|
Tropisterone (navoban) |
CAREFULLY |
CAREFULLY |
||
|
Doxylamine (donormil) |
||||
|
Regulators of intestinal microflora (eubiotics) ( Bifikol, bifiform, colibacterin, lactobacterin, linex, baktisubtil, bifidumbacterin, |
||||
|
Choleretic agents(allochol, cholenzym). |
||||
|
Multienzyme drugs(festal, digestal, mezim, trienzyme, etc.) |
||||
|
Hepatoprotectors |
||||
|
NO - 1st trimester |
||||
|
Silibinin (silibor, karsil, legalon) |
||||
|
Essentiale, lipostabil |
||||
|
Antienzymes(Gordox, Trasylol, Contrical, etc.) |
CAREFULLY |
CAREFULLY |
||
|
Prostaglandins(misoprostol) |
||||
|
Antihyperglycemic drugs |
||||
|
Oral hypoglycemic drugs |
||||
|
Drugs that regulate thyroid function Levothyroxine (L-thyroxine) |
||||
|
Triiodothyronine (thyrocomb) |
||||
|
Mercazolil Potassium iodide |
CAREFULLY |
|||
|
Antigonadotropic drugs Danazol (danone) |
||||
|
Clomiphene, clostilbegite |
||||
|
Tamoxifen (zitazonium) |
||||
|
Sex hormone preparations Estrogens and estrogen-containing products |
||||
|
Dydrogesterone (duphaston) |
||||
|
Medroxyprogesterone (Provera, Depo-Provera) |
||||
|
Vitamins(All) |
||||
|
Iron sulfate preparations (actiferrin, tardiferon, ferrogradumet, etc.) |
||||
|
Drugs affecting the central nervous system Sodium valproate (Depakine, Convulex) |
||||
|
Carbamazepine (tegretol, finlepsin) |
CAREFULLY |
CAREFULLY |
||
|
Magnesium sulfate |
||||
|
Primidone (hexamidine) |
CAREFULLY |
|||
|
Trimethine |
||||
|
Phenytoin (diphenin) |
CAREFULLY |
CAREFULLY |
||
|
Ethosuximide (Suxilep) |
||||
|
Antidepressants Amitriptyline (tryptisol, Elivel) |
CAREFULLY - |
|||
|
Desipramine (petylyl) |
CAREFULLY |
|||
|
Doxepin |
||||
|
Imipramine (imisin, melipramine) |
||||
|
Clomipramine (anafranil) |
||||
|
Sertraline (Zoloft) |
CAREFULLY |
CAREFULLY |
||
|
Nortriptyline |
CAREFULLY |
|||
|
Pyrazidol |
||||
|
Fluoroacyzine |
||||
|
Fluoxetine (Prozac) |
||||
|
Barbiturates Amobarbital, pentobarbital (ethaminal sodium) |
||||
|
Phenobarbital (and drugs containing it: bellaspon, valocordin, bellataminal, sedalgin, etc.) |
CAREFULLY |
|||
|
Benzodiazepines Alprazolam (cassadane) |
||||
|
Diazepam (Relanium, Seduxen, Sibazon, Faustan, Reladorm) |
CAREFULLY |
CAREFULLY |
||
|
Clonazepam (antelepsin) |
||||
|
Lorazepam |
CAREFULLY |
CAREFULLY |
||
|
Midazolam (dormicum) |
CAREFULLY |
CAREFULLY |
||
|
Nitrazepam (radedorm, eunoctine) |
CAREFULLY |
|||
|
Oxazepam (nozepam, tazepam) |
||||
|
Temazepam (signopam) |
||||
|
Triazolam |
||||
|
Phenazepam |
||||
|
Flunitrazepam (Rohypnol) |
||||
|
Trunxen |
||||
|
Chlordiazepoxide (Elenium) |
||||
|
Neuroleptics Alimemezin (teralen) |
||||
|
Haloperidol (senorm) |
||||
|
Droperidol |
||||
|
Tizercin |
||||
|
Neuleptil |
||||
|
Etaperazine |
||||
|
Piportil |
||||
|
Propazine |
||||
|
Metherazine |
CAREFULLY |
CAREFULLY |
||
|
Majeptyl |
||||
|
Thioridazine (Melleril, Ridazine, Sonapax) |
||||
|
Triphthazine (stelazine) |
||||
|
Fluphenazine (Moditen) |
CAREFULLY |
|||
|
Chlorpromazine (aminazine) |
CAREFULLY |
CAREFULLY |
||
|
Antiparkinsonian drugs Bromocriptine (Parlodel) |
||||
|
Levodopa (Nakom, Sinemet) |
||||
|
Parkopan (cyclodol) |
||||
|
Sedatives |
||||
|
Valerian |
||||
|
Meprobamate |
||||
|
CNS stimulants(caffeine) |
CAREFULLY |
|||
|
Non-narcotic analgesics(antipyretics) Analgin (and drugs containing it: tempalgin, toralgin, renalgan, etc.) |
||||
|
Paracetamol |
||||
|
Phenacetin |
CAREFULLY |
CAREFULLY |
||
|
Ketorolac (ketanov) |
||||
|
Narcotic analgesics and their antagonists Buprenorphine (no-pen, norfin) |
YES; NO - if for a long time |
CAREFULLY |
||
|
Butorphanol (moradol) |
NO; used only to prepare for childbirth |
|||
|
YES; NO - if for a long time |
CAREFULLY |
|||
|
Naloxone |
CAREFULLY |
|||
|
Pentazocine (fortral) |
NO - in the 1st trimester |
|||
|
Tramadol (tramal) |
CAREFULLY |
|||
|
Promedol |
YES; NO - if for a long time |
CAREFULLY |
||
|
Fentanyl |
CAREFULLY |
CAREFULLY |
||
|
Glucocorticosteroids Betamethasone |
||||
|
Hydrocortisone |
||||
|
Dexamethasone |
CAREFULLY |
CAREFULLY |
||
|
Cortisone |
CAREFULLY |
CAREFULLY |
||
|
Prednisolone, prednisone, methylprednisolone |
CAREFULLY |
CAREFULLY |
||
|
Triamcinolone (kenacort, berlicort, kenalog, polcortolone) |
CAREFULLY |
CAREFULLY |
||
|
Nonsteroidal anti-inflammatory drugs (NSAIDs) |
||||
|
Acetylsalicylic acid (aspirin) |
NO - 1st and 3rd trimesters |
CAREFULLY |
||
|
Diclofenac (ortofen, revodina, voltaren) |
CAREFULLY |
CAREFULLY |
||
|
Ibuprofen (Brufen) |
||||
|
Indomethacin (metindole) |
CAREFULLY |
CAREFULLY |
||
|
Ketoprofen (ketonal) |
NO - 1st and 3rd trimesters |
|||
|
Meloxicam (movalis) |
||||
|
Naproxin (naproxen) |
CAREFULLY |
CAREFULLY |
||
|
Piroxicam |
NO - in the 3rd trimester |
|||
|
NO - in the 1st and 3rd trimester |
||||
|
Phenylbutazone (butadione) |
||||
|
Antigout drugs Allopurinol (milurite) |
||||
|
Probenecid (Benemid) |
||||
|
Antimicrobial agents Antibiotics Azlocillin |
CAREFULLY |
CAREFULLY |
||
|
Amoxicillin (ospamox, flemoxin, hiconcil) |
CAREFULLY |
CAREFULLY |
||
|
Amoxicillin + clavulanic acid (amoxiclav, augmentin) |
CAREFULLY |
CAREFULLY |
||
|
Ampicillin |
||||
|
Benzylpenicillin |
||||
|
Retarpen (extensillin) |
||||
|
Carbenicillin |
||||
|
Cloxacillin |
||||
|
Oxacillin |
||||
|
Piperacillin |
||||
|
Ticarcillin |
CAREFULLY |
CAREFULLY |
||
|
Cefadroxil (Duracef) |
||||
|
Cefazolin (kefzol, reflin, cefamezine) |
||||
|
Cephalexin |
||||
|
Cephalotin (Keflin) |
||||
|
Cefapirin (cefatrexil) |
||||
|
Cefradine |
||||
|
Cefaclor (Vercef) |
||||
|
Cefamandole (mandole) |
||||
|
Cefoxitin |
||||
|
Cefotetan |
||||
|
Cefuroxime (zinacef, zinnat, ketocef) |
||||
|
Moxalactam |
||||
|
Cefixime |
||||
|
Cephodisim |
||||
|
Cefoperazone (cephobid) |
||||
|
Cefotaxime (claforan) |
||||
|
Cefpyramide |
||||
|
Ceftazidime (Fortum) |
||||
|
Ceftriaxone (lendacin, longacef, rocephin) |
||||
|
Cefepime (maxipim) |
||||
|
Cefpirom (keiten) |
||||
|
Imipinem (tienam) |
||||
|
Meropenem (meronem) |
CAREFULLY |
|||
|
Aztreonam (azaktam) |
CAREFULLY |
CAREFULLY |
||
|
Amikacin |
||||
|
Gentamicin |
CAREFULLY |
|||
|
Kanamycin |
CAREFULLY |
CAREFULLY |
||
|
Neomycin |
CAREFULLY |
|||
|
Netilmicin (netromycin) |
CAREFULLY |
CAREFULLY |
||
|
Streptomycin |
CAREFULLY |
CAREFULLY |
||
|
Tobramycin (brulamycin) |
CAREFULLY |
CAREFULLY |
||
|
Doxycycline (Vibramycin, Unidox) |
NO - in the 2nd trimester |
CAREFULLY |
||
|
Metacycline (Rondomycin) |
CAREFULLY |
|||
|
Tetracycline |
CAREFULLY |
|||
|
Azithromycin (sumamed) |
CAREFULLY |
CAREFULLY |
||
|
Josamycin (vilprafen) |
CAREFULLY |
CAREFULLY |
||
|
Clarithromycin (clacid) |
CAREFULLY |
CAREFULLY |
||
|
Midecamycin (macropen) |
||||
|
Oleandomycin |
CAREFULLY |
|||
|
Roxithromycin (Rulid) |
||||
|
Spiramycin (Rovamycin) |
||||
|
Erythromycin |
CAREFULLY |
CAREFULLY |
||
|
Rifamycin |
||||
|
Rifampicin (benemicin, rifadin) |
||||
|
Clindamycin (Dalacin C) |
||||
|
Lincomycin |
||||
|
Chloramphenicol (chloramphenicol) |
||||
|
Vancomycin |
CAREFULLY |
|||
|
Spectinomycin (trobicin) |
||||
|
Fosfomycin (phosphocin) |
CAREFULLY |
CAREFULLY |
||
|
Mupirocin (Bactroban) |
||||
|
Fusafungin (bioparox) |
||||
|
Monocomponent sulfonamides(sulgin, sulfadimethoxine, sulfadimezin, norsulfazole, etazol, etc.) |
CAREFULLY |
|||
|
Co-trimoxazole(trimethoprim+methoxazole) Bactrim, berlocid, biseptol, groseptol, oriprim, sumetrolim) |
||||
|
Fluoroquinolones(maxavin, norfloxacin, nolicin, norbactin, norilet, zanocin, ofloxacin, tarivid, abactal, pefloxacin, tsiprinol, tsiprobay, tsiprolet, ciprofloxacin, tsifran, enoxacin) |
||||
|
Quinolines Oxolinic acid (gramurin) |
||||
|
Nitroxoline (5-NOK) |
NO - in the 3rd trimester |
|||
|
Nalidixic acid (nevigramone, negram) |
NO - in the 1st trimester |
|||
|
Pipemidic acid (palin, pimidel) |
NO - in the!th and 3rd trimester |
|||
|
Nitrofurans Furacilin |
||||
|
Nitrofurantoin (furadonin) |
||||
|
Nifuratel (makmiror) |
||||
|
Furazidin (furagin) |
||||
|
Furazolidone |
||||
|
Antituberculosis drugs Isoniazid |
||||
|
Pyrazinamide |
||||
|
Prothionamide |
||||
|
Phtivazid |
||||
|
Ethambutol |
CAREFULLY |
CAREFULLY |
||
|
Ethionamide |
||||
|
Antiprotozoal agents Plaquenil |
NO - in the 3rd trimester |
CAREFULLY |
||
|
Metronidazole (metrogyl, nidazole, trichopolum, flagyl, Klion D) |
NO - in the 1st trimester |
|||
|
Ornidazole (tiberal) |
CAREFULLY |
|||
|
Tenonitrazole (atrican-250) |
||||
|
Tinidazole (phasizhin) |
NO - in the 1st trimester |
|||
|
Chloroquine (delagil) |
||||
|
Antifungal agents Amphotericin B |
||||
|
Griseofulvin |
||||
|
Itraconazole (orungal) |
CAREFULLY |
CAREFULLY |
||
|
Ketoconazole (nizoral) |
||||
|
Clotrimazole (Canesten) |
NO - in the 1st trimester |
|||
|
Miconazole (Dactarine) |
CAREFULLY |
CAREFULLY |
||
|
Natamycin (pimafucin) |
||||
|
Naftifine (exoderil) |
||||
|
Nystatin |
CAREFULLY |
|||
|
Terbinafine (Lamisil) |
CAREFULLY |
|||
|
Fluconazole (Diflucan) |
||||
|
Antivirus products Acyclovir (Virolex, Zovirax, herpevir) |
CAREFULLY |
CAREFULLY |
||
|
Remantadine |
CAREFULLY |
|||
|
Ribavirin (virazole) |
||||
|
Zidovudine (cidovudine), retrovir |
||||
LITERATURE
- "Obstetrics and Gynecology", ed. V. Beck, 3rd ed., trans. from English M. 1997, 743 p.
- Bobev D.Ivanova I. “Diseases of the newborn,” 3rd ed., trans. from Bulgarian Sofia, 1982, 296 p.
- Bratanov B. “Clinical Pediatrics”, volume 2.trans. from Bulgarian Sofia, 1983, 523 p.
- Jeveson P.J., Chau A.W. “Pharmacokinetics of antimicrobial drugs during pregnancy” in the book “Reproductive Health”, volume 2, pp. 232-354, trans. from English.1988.
- Karpov O.I. ,Zaitsev A.A. “The risk of using drugs during pregnancy and lactation”, St. Petersburg, 1998, 352 p.
- Kumerle H.P. (ed.) “Clinical pharmacology during pregnancy” in 2 volumes, M. 1987.
- Mashkovsky M.D. “Medicines” in 2 volumes, ed. 13, Kharkov, 1997, 1152 p.
- Serov V.N., Strizhakov A.N. Markin S.A. “Practical obstetrics” M. 1989. 512 pp.
- Tarakhovsky M.L., Mikhailenko E.T. (ed.) “Pharmacotherapy in obstetrics and gynecology”, Kyiv, 1985, 216 p.
CHAPTER 6. FEATURES OF CLINICAL PHARMACOLOGY IN PREGNANT, NURSING MOTHERS, NEWBORN AND ELDERLY
FEATURES OF CLINICAL PHARMACOLOGY IN PREGNANT WOMEN
The widespread use of drugs in the treatment of pregnant women is an objective reality, determined by the observed deterioration in the health of women of childbearing age and the increase in the average age of first-time mothers. The complexity of the problem of the safety of using drugs for the treatment of pregnant women is largely determined by the fact that drugs can affect both the processes of formation and functioning of germ cells, and the multi-stage process of pregnancy itself (fertilization, implantation, embryogenesis, fetogenesis). Despite the fact that no drug is introduced into practice without experimental evaluation of its teratogenicity, at least 3% of all congenital malformations are associated with drug use. This is due to the fact that the teratogenic effects of drugs in humans are difficult to predict based on experimental data obtained on animals (for example, experiments did not reveal the teratogenicity of the true teratogen thalidomide*). Currently, about 60-80% of pregnant women take drugs (antiemetics, analgesics, sleeping pills, sedatives, diuretics, antibiotics, antacids, antihistamines, expectorants, etc.). In some cases, due to polypharmacy (on average, a pregnant woman takes four medications, not counting multivitamins and iron supplements), it is not possible to determine the culprit of the malformations. In addition, identifying these serious complications of drugs is complicated by the presence of other possible causes of fetal development abnormalities (for example, viral infections, occupational hazards, alcoholism, etc.).
Based on data from clinical and experimental studies, drugs are divided according to the degree of risk to the fetus (Table 6-1) into categories from A (no evidence of risk) to D (risk proven), and category X is also distinguished (absolutely contraindicated for pregnant women). PM
Table 6-2. Medicines absolutely contraindicated during pregnancy (category X)
Medicines classified as category D have the necessary therapeutic effect, but preference in certain situations should be given to other drugs with similar pharmacological properties (but not included in category D) and only for health reasons they can be prescribed to pregnant women (Table 6-3).
Table 6-3. Medicines with teratogenic effects (category D)
End of table. 6-3
Critical periods of pregnancy
In intrauterine development, there are critical periods that are characterized by increased sensitivity to teratogenic effects, including drugs.
The initial period of intrauterine development. From the moment of fertilization until implantation of the blastocyst (end of the 1st, beginning of the 2nd week of pregnancy). During this period, the maximum risk of embryotoxic effects of drugs is observed, which most often manifests itself in the death of the embryo before pregnancy is established.
The period of embryogenesis (from the 16th day after fertilization to the end of the 8th week of intrauterine development). The unfavorable effect of drugs is manifested by teratogenicity and embryotoxicity, with the possible occurrence of congenital malformations, embryo death, spontaneous miscarriage, and premature birth. During the period of organogenesis and placentation, the most sensitive phase of development is the first 3-6 weeks after fertilization (the period of embryonic organ formation). The critical periods of damage to different organs differ due to temporal differences in tissue differentiation.
The period of fetogenesis (from the 9th week of intrauterine development until birth), during which the action of drugs can cause a slowdown in fetal growth. However, specific effects cannot be completely excluded, since the development of the eyes, ears, teeth, and central nervous system
occupies a significant part of the fetal period. Exposure to drugs or other substances during the fetal period may have long-term effects on behavioral responses and mental development child.
Features of pharmacokinetics of drugs in pregnant women
Suction features. During pregnancy, the contractile and secretory functions of the stomach are reduced, which leads to slower absorption of poorly soluble drugs. At the same time, the absorption of other drugs may be increased as a result of an increase in the time spent in the intestine caused by a decrease in its motility. Individual differences in drug absorption in pregnant women depend on the duration of pregnancy and the condition of cardio-vascular system, gastrointestinal tract and physicochemical properties of drugs.
Features of distribution. During pregnancy, changes in the volume of circulating blood, the amount of water, fat, glomerular filtration, and protein content in plasma affect the speed and efficiency of drug distribution.
An increase in the volume of extracellular fluid, circulating blood volume, renal blood flow and glomerular filtration in a pregnant woman, as well as the entry of drugs into the fetus and amniotic fluid lead to a decrease in the concentration of some drugs in the blood plasma of pregnant women (compared to non-pregnant women).
During pregnancy and in the early postpartum period (from the 15th week of pregnancy to 2 weeks after birth), a decrease in the binding of drugs to plasma proteins, primarily albumins, was noted, which is due to a decrease in their quantity (15-30%), competition for binding with proteins between drugs and unsaturated fatty acids, the concentration of which increases significantly during pregnancy. A decrease in the degree of binding to proteins leads to the fact that the concentration of the free fraction of drugs increases significantly (for example, diazepam - more than 3 times).
Features of metabolism. During pregnancy, multidirectional changes in the activity of many liver enzymes involved in phases I and II of drug metabolism are noted, and for a number of enzymes this activity varies depending on the duration of pregnancy (for example, the activity of the cytochrome P-450 3A4 isoenzyme is increased throughout the entire period of pregnancy). A decrease in the activity of the cytochrome P-450 1A2 isoenzyme leads to a progressive increase in the half-life of caffeine (in the first trimester of pregnancy it increases
veins 5.3 hours, in II - 12 hours and in III - 18 hours). The intensity of hepatic metabolism is affected by changes in hormonal regulation, the ratio of cardiac output and hepatic blood flow.
Features of breeding. As a result of a significant increase in the glomerular filtration rate in pregnant women (70%) and a decrease in the degree of protein binding, drug elimination increases. In late pregnancy, the rate of renal elimination is significantly influenced by body position. Pathological pregnancy introduces additional changes in the pharmacokinetics
Features of pharmacokinetics of drugs in the placenta
The main exchange of xenobiotics between mother and fetus occurs primarily through the placenta. The development of the placenta begins in the first week of pregnancy through the differentiation of the trophoblast, which originates from the surface cellular layer of the fertilized egg. During pregnancy, the placenta undergoes functional changes, which allows for the exchange of substances between the fetus and the mother. It has been shown that the placenta morphologically and functionally plays the role of an organ responsible for the transport, metabolism and excretion of drugs for the fetus (due to the immaturity of these systems during intrauterine development of the fetus). The previous assumption that the placental barrier provides natural protection to the fetus from exposure to exogenous substances is true only to a limited extent. Under physiological and pathological conditions, placental metabolism is an active function of the placental membrane, which exercises selective control over the passage of xenobiotics through it.
The placenta performs numerous functions, such as gas exchange, transport of nutrients and waste products, and production of hormones, functioning as an active endocrine organ vital for a successful pregnancy. Such nutrients how glucose, amino acids and vitamins pass through the placenta through special transport mechanisms, which occur in the maternal part of the apical membrane and the fetal part of the basement membrane of the syncytiotrophoblast. At the same time, the removal of metabolic products from the fetal circulatory system through the placenta into the maternal circulatory system also occurs through special transport mechanisms. For some compounds, the placenta serves as a protective barrier for the developing fetus, preventing the passage of various xenobiotics from mother to fetus, while for
For others, it facilitates their passage both to and from the fetus, functioning overall as a xenobiotic detoxification system.
Transport of drugs in the placenta
There are 5 known mechanisms of transplacental exchange: passive transfer, active transport, facilitated diffusion, phagocytosis and pinocytosis. The last two mechanisms are of relative importance in the transport of drugs in the placenta, and most drugs are characterized by active transport.
Passive diffusion- a form of metabolism in the placenta that allows the drug molecule to move along a concentration gradient. The amount of drugs transferred through the placenta by passive diffusion depends on their concentration in the mother’s blood plasma, the physicochemical properties of the drug and the placenta. Passive diffusion is characteristic of low molecular weight, fat-soluble, predominantly non-ionized forms of drugs. However, the rate of passive diffusion is so low that equilibrium concentrations in the blood of the mother and fetus are not established. Only the fraction of drugs not bound to protein can diffuse freely across the placenta. The binding of drugs to plasma proteins changes the total concentration in the blood plasma of the fetus and mother. In a number of maternal diseases (for example, preeclampsia), the number of proteins that bind drugs is reduced, which leads to an increase in the transport of drugs to the fetus. The rate of transfer across the placenta depends mainly on the concentration of the non-ionized form of a particular drug at a given blood pH, lipid solubility and molecular size. Fat-soluble substances in non-ionized form easily diffuse through the placenta into the fetal blood (phenazone, thiopental). Drugs with a molecular weight of more than 500 Daltons often do not completely pass through the placenta (for example, various heparins). The difference between fetal and maternal pH affects the fetal/maternal concentration ratio for the free drug fraction. Under normal conditions, the pH of the fetus is practically no different from the maternal pH. During labor, fetal pH may decrease significantly, resulting in decreased elimination of essential drugs from the fetus to the mother (eg, fetal lidocaine concentrations are higher, which may cause adverse effects in the fetus or newborn).
Active transport Drug delivery through the placental membrane is typical for drugs that are structurally similar to endogenous substances and depends not only on the size of the molecule, but also on the presence of a carrier substance (transporter). Active drug transporters are located either on the maternal part of the apical membrane or on the fetal membrane
parts of the basement membrane where they transport drugs into or out of the syncytiotrophoblast.
The placenta contains various transporters that eliminate drugs from the placenta into the maternal or fetal circulatory system, as well as transporters that move substrates both into and out of the placenta. There are transporters that regulate the movement of drugs only into the placenta. It is believed that the type of transporters in the placenta and changes in their activity and expression during pregnancy may be important for modulating the effectiveness and toxicity of the effects of drugs on the fetus.
Transporters that eliminate drugs from the placenta are P glycoprotein, a family of proteins associated with multidrug resistance and breast cancer resistance protein. The substrate of these transporters is wide range Drugs: some cytostatics, antiviral drugs, drugs affecting the central nervous system, cardiovascular drugs.
It has now been shown that the gene encoding glycoprotein P has polymorphism, which can lead to changes in its activity, leading to an increase in the degree of drug exposure to the fetus.
Metabolism of drugs in the placenta
Cytochrome P-450 represents a group of enzymes involved in the synthesis and catabolism of steroid hormones, the metabolism of a large number of drugs and toxic substances. Placental isoenzymes of cytochrome P-450 are contained in the endoplasmic reticulum of trophoblast cells. During pregnancy, multidirectional changes in the activity of phase I isoenzymes (CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1) and phase II enzymes (UDP-glucuronyltransferase, etc.) of drug metabolism in the placenta are noted. The type, quantity and activity of cytochrome P-450 isoenzymes vary depending on the period of gestation and the health of the mother. Most cytochrome P-450 isoenzymes are expressed in the first trimester of pregnancy, when there is the greatest likelihood of exposure to teratogens. A variety of maternal and environmental factors can influence the activity of enzymes that metabolize drugs in the placenta (for example, drug metabolism is reduced in the placenta of mothers who take drugs, alcohol, or smoke).
Features of pharmacokinetics of drugs in the fetus
Suction features. The exchange of xenobiotics between mother and fetus occurs mainly through the placenta. In addition, PM
absorbed through the skin of the fetus or through the digestive tract from swallowed amniotic fluid. The amount of absorbed drug will depend on the volume of amniotic fluid absorbed (at the end of pregnancy it is 5-7 ml/h). Due to the early appearance of glucuronyl transferase activity in the small intestinal mucosa, conjugates excreted by the fetal kidneys can be reabsorbed, which leads to recirculation of some drugs and prolongation of their effect on the fetus.
Features of distribution. Typically, in the early stages of pregnancy, the distribution of drugs tends to be more uniform than in later stages.
Hydrophilic drugs have a larger volume of distribution, while lipophilic drugs accumulate mainly in the last trimester of pregnancy.
Drugs bind to blood plasma proteins to a lesser extent, since the protein content in fetal blood plasma is lower than in the blood of a pregnant woman and newborn. In addition, a decrease in the protein-binding capacity of the blood plasma of a pregnant woman (competitive relationships with endogenous substrates - hormones, free fatty acids) can have a significant impact on the distribution of drugs in the pregnant-placenta-fetus system. This leads to an increase in the content of the free fraction of drugs and increases the risk of their exposure to the fetus, aggravated by the peculiarities of its blood circulation. After passing through the placenta, drugs enter the umbilical vein, 60-80% of the blood from which passes to the liver through portal vein, and about 20-40% enters through the shunt (ductus venosus) into the inferior vena cava and reaches the heart and brain, bypassing the liver. The BBB in the fetus is not fully developed, so the concentration of a drug in the cerebrospinal fluid and in the brain can reach the same values as the concentration of this drug in the blood plasma.
Features of metabolism. The metabolism of drugs in the fetus is slower than in adults. The activity of enzymes involved in the microsomal oxidation of drugs is detected already at the end of the first trimester, however, they are more active in relation to endogenous substances. The organs of biotransformation of xenobiotics in the fetus (in descending order of importance) are the adrenal glands, liver, pancreas and gonads. During metabolism, some drugs are oxidized to epoxides, which in most cases cause the teratogenic effect of drugs. The concentration of cytochrome P-450 in the adrenal glands is higher than in the liver. Different isoenzymes of cytochrome P-450 acquire functional activity at different times during intrauterine development of the fetus, which causes different oxidative capacity in relation to
the use of various drugs, sometimes classified as one group of substances. For example, theophylline undergoes metabolic transformations earlier and faster than caffeine. A unique ability of fetal liver tissue to methylate theophylline was discovered, converting it into caffeine. Other enzymes and enzymatic processes in the fetus lag behind in functional activity. The prevalence of sulfate conjugation in the prenatal period may be a consequence of hormonal influences during pregnancy. Biotransformation of drugs by binding to glucuronic acid is limited; its deficiency is partially compensated by sulfation.
Features of breeding. The low degree of functional maturity of the kidneys in the fetal period leads to their differences from the kidney function of adults in relation to the excretion of most drugs. Due to the significantly reduced blood flow in the fetus, the filtration rate and active tubular secretion are low.
Drugs that enter the amniotic fluid can enter the fetal gastrointestinal tract and be reabsorbed in the intestine. The main excretory organ for most fetal metabolic products and drugs is the placenta.
Features of pharmacodynamics of drugs in the fetus
The question of the sensitivity of the fetal body's receptors to drugs has not been studied enough. There is an opinion that already at the most early stages During fetal development, receptors sensitive to the action of drugs appear. The severity of the effect of a drug on the fetus determines the speed of transplacental movement of the drug, the duration of pregnancy, and the characteristics of metabolism in the mother, fetus, and placenta.
Maturation of receptors in fetal organs occurs at different dates intrauterine development. For example, at a gestation period of 12-24 weeks, β-adrenergic receptors function, while α-adrenergic receptors are still inactive.
Particular issues of the use of drugs in pregnant women
Antimicrobial drugs. Conducted pharmacoepidemiological studies show that the average frequency of prescription of antimicrobial drugs in pregnant women is 12.3%. The need to prescribe antimicrobial drugs may arise even in the absence of infectious diseases in the mother, and in the event of the development of infectious diseases in the fetus or a high risk of their occurrence. For example, prevention and therapy of toxoplasmosis in the fetus with spiramycin, prevention of HIV infection with antiretroviral drugs.
Most antimicrobial drugs have low molecular weight and readily cross the placenta, creating therapeutic concentrations in the fetal blood that are comparable to maternal drug concentrations. The classification of antimicrobial drugs according to the degree of safety for the fetus is presented in Table. 6-4.
Table 6-4. Classification of antimicrobial drugs according to safety categories for use in pregnant women
Penicillins (especially semisynthetic ones) and cephalosporins penetrate the placenta, creating a therapeutic concentration in the tissues of the fetus (they usually do not have a toxic effect on the fetus). The ability of penicillins to penetrate the placental barrier is inversely related to the degree of binding to plasma proteins.
Macrolides (erythromycin, roxithromycin, azithromycin) penetrate the placenta poorly and create low concentrations in the fetal circulatory system. With regard to the studied macrolides, there was no increase in the incidence of fetal anomalies when used in pregnant women.
Streptomycin quickly passes through the placenta (its concentration in the blood of the fetus is about 50% of the content in the blood of the pregnant woman) and can have a neurotoxic (including ototoxic) effect and cause various disorders in the structure of the bone skeleton.
In the last trimester of pregnancy, sulfonamides (especially long-acting ones) should not be prescribed, as they intensively bind to plasma proteins, displace bilirubin and can cause jaundice in newborns. In addition, sulfonamides (as well as nitrofurans) can cause hemolytic anemia in children with glucose-6-phosphate dehydrogenase deficiency. Co-trimoxazole can disrupt folic acid metabolism in both mother and child.
Metronidazole and trimethoprim are not used in the first trimester of pregnancy due to the high risk of embryotoxicity.
Anti-inflammatory drugs, if necessary, are recommended to be used in small doses and for short periods. Low doses of acetylsalicylic acid (40-150 mg/day) are considered relatively safe. When using NSAIDs in late pregnancy, due to inhibition of prostaglandin synthesis and, accordingly, weakening of labor, complications are possible in the form of post-term pregnancy, bleeding in the fetus and the pregnant woman, premature closure of the ductus arteriosus with the formation of pulmonary hypertension. The latter is often caused by strong NSAIDs, such as indomethacin and diclofenac (Table 6-5).
Table 6-5. Side effects and use of anti-inflammatory drugs during pregnancy
Antiemetic drugs. Symptoms of early gestosis are found in 80% of pregnant women in the form of nausea and vomiting in the morning. These symptoms appear in the 4th week of pregnancy and disappear (most often spontaneously) in the 12-14th week. About 20% of pregnant women continue
You may experience nausea and vomiting throughout pregnancy. There is usually no need for drug therapy for this condition. If vomiting leads to severe dehydration, weight loss, and the development of metabolic acidosis, pharmacotherapy is safer for the pregnant woman and fetus. After excluding organic diseases of the central nervous system and gastrointestinal tract, pyridoxine (50-100 mg/day) is prescribed, often in combination with promethazine (10-25 mg/day), metoclopramide (10 mg IM or 5 mg IV every 6 hours). Metoclopramide is prescribed mainly for intractable vomiting and, as a rule, only in late pregnancy.
Neuroleptics and tranquilizers. Chlorpromazine, in some cases used to treat gestosis, penetrates the placental barrier (its concentration in the fetal blood is about 50% of the content in the mother's blood), does not have a teratogenic effect, but can have a hepatotoxic effect and cause retinopathy. For sleep disturbances, pregnant women can be prescribed diazepam in moderate doses, but it is not used in the last weeks of pregnancy (it can cause respiratory depression in the newborn).
Antihypertensive drugs prescribed when diastolic blood pressure increases above 90 mm Hg. Methyldopa and some selective β-blockers (metoprolol) can be used in small doses. Propranolol in a pregnant woman can increase the tone of the uterus, reduce cardiac output, cause hypotrophy of the placenta, and in the fetus, passing unchanged through the placenta, cause bradycardia, hypoxia, hypoglycemia, hyperbilirubinemia, and reduce compensatory tachycardia in response to hypoxia. Parenteral administration of magnesium sulfate to a pregnant woman before childbirth can lead to a decrease in skeletal muscle tone and severe lethargy in the newborn. Thiazide diuretics can cause thrombocytopenia and electrolyte imbalance.
Hormonal drugs. Estrogens and progestins should not be used in the first 4 months of pregnancy due to the risk of impaired development of the heart and limbs and the possibility of pseudohermaphroditism in male fetuses. The teratogenic effect of hormonal contraceptives is described as VACTERL syndrome (vertebral, anal, cardiac, tracheal, esophageal, renal anomalies and abnormal structure of the limbs). The teratogenic effect of glucocorticoids is manifested by the development of cataracts and adrenal hypoplasia, but the risk of their side effects for the fetus is incomparably less than the benefit for a pregnant woman with severe systemic connective tissue diseases or bronchial asthma.
Anesthesia drugs, narcotic analgesics, sleeping pills.
Diethyl ether, chloroform, nitrous oxide*, penetrating the placenta, can cause depression of the respiratory center in the fetus, and therefore they are not recommended for use for pain relief during labor and cesarean section. Morphine, barbiturates, and benzodiazepines also quickly pass through the placental barrier and depress the fetal respiratory center (their concentration in the fetal central nervous system is higher than in pregnant women). If a pregnant woman abuses these drugs, they can cause withdrawal syndrome in the newborn.
Anticoagulants. Heparin sodium does not cross the placenta and is recommended for use in pregnant women if necessary. Indirect anticoagulants cross the placenta unchanged and can cause hemorrhage in the fetus even in the absence of symptoms hemorrhagic syndrome in a pregnant woman. In the first trimester of pregnancy, indirect anticoagulants can cause embryotoxic and teratogenic effects (nasal hypoplasia, shortening of the arms, short fingers, eye atrophy, cataracts, bone development abnormalities).
Vitamins and herbal preparations. Hypo- and hypervitaminosis can lead to fetal developmental disorders. Vitamin B2 deficiency causes limb development abnormalities, splitting hard palate; vitamin A - cleft palate and anencephaly; folic acid - malformations of the cardiovascular system, visual organs (micro- and anophthalmia, cataracts); vitamin C (as well as its excess) - termination of pregnancy (vitamin C deficiency also leads to increased capillary permeability and impaired tissue respiration); vitamin E deficiency - disruption of the development of the embryo and its death (in newborns, abnormalities of the brain, eyes and skeletal bones are found).
Medicinal plants. TO medicinal plants, the preparations of which are not recommended for use by pregnant women due to the content of pyrrolizidine alkaloids, which have a teratogenic effect, include barberry, black cohosh, fumaria, common juniper, sea kelp, wormwood, and pennyroyal.
Antiepileptic drugs. The use of antiepileptic drugs during pregnancy increases the incidence of congenital anomalies in the fetus by 2-3 times compared with the population as a whole (anomalies of the central nervous system, heart and genital organs, intrauterine growth retardation, various structural abnormalities of the facial skull - short, saddle nose). Antiepileptic therapy during pregnancy should be carried out with one drug, in minimally effective doses, under the control of the concentration of the drug in the serum.
mouth of blood and prenatal diagnostic tests(Ultrasound, amniocentesis, α-fetoprotein, etc.). Pre-concentration intake of folic acid (prevention of neural tube defects in the fetus) and vitamin K* during the month before birth (prevention of hemorrhagic syndrome in the newborn) is recommended.
Hypoglycemic drugs. During pregnancy, preference is given to insulin preparations. Sulfonylurea derivatives are safer than biguanides. Their use, however, should be stopped 4 days before the expected birth to avoid the development of hypoglycemia in the newborn. Hypoglycemic drugs for oral administration in pregnant women are used if they were effective before pregnancy, if hyperglycemia developed during diabetes mellitus, previously controlled by diet, if hyperglycemia is first detected during pregnancy and is not controlled by diet.
Principles of pharmacotherapy for pregnant women
When prescribing drugs to pregnant women, the following factors should be taken into account.
Not a single drug (even for local application) should not be considered absolutely safe for the fetus, since most drugs with a molecular weight of up to 1 kDa pass through the placenta, and in some cases those with a large molecular weight, due to pinocytosis and other transport mechanisms. The permeability of the placenta increases by 32-35 weeks of pregnancy. Stressful situations and gestosis can increase the permeability of the placenta. With diabetes mellitus, preeclampsia, and arterial hypertension in late pregnancy, there is a relative decrease in the speed of placental blood flow, which, on the one hand, limits the flow of drugs to the fetus, and on the other hand, reduces their content in the outflowing blood.
The potential benefit from the use of drugs must exceed the potential risk to the pregnant woman and fetus from their side effects.
The pharmacodynamic effects of drugs in pregnant women and the fetus can vary significantly.
There is a relationship between the stage of pregnancy and the effect of drugs.
Some drugs may have delayed adverse effects on the fetus.
Changes in the pharmacokinetics of drugs in women during pregnancy determine the need for appropriate adjustment of the single dose, frequency of administration and route of administration.
The duration of action of the drug in the fetus (including unwanted effects) significantly more than in women, which is due to the low rate of their inactivation and excretion.
The concentration of drugs in the fetus is affected by:
Drug dosage regimen - single dose, frequency of administration, route of administration, purpose, duration of treatment;
Functional state of the gastrointestinal tract, cardiovascular system, liver, kidneys of the pregnant woman and fetus, placenta;
Physico-chemical properties of drugs - molecular weight, lipophilicity, ionization, binding to blood plasma proteins, distribution;
Features of the pharmacokinetics of drugs in the fetus.
Peculiarities clinical pharmacology in lactating women
Most drugs taken by a nursing mother are excreted in milk. Often, when using nursing drugs, especially for a long time, with a narrow therapeutic range, undesirable reactions may occur in children (Table 6-6). A number of drugs (for example, those affecting the secretion of prolactin, the intensity of blood supply to the mammary gland) can reduce or even stop lactation, which, of course, is also unfavorable in most cases. The passage of the drug into milk is accompanied by its binding to proteins and fat droplets. The main mechanisms for the transfer of drugs from maternal blood plasma into milk are diffusion, pinocytosis and apical secretion. Non-ionized molecules, especially those with a small molecular weight (up to 200 Da), easily pass into milk, but easily ionized, tightly bound to plasma proteins - poorly. Weak alkalis, to a greater extent than weak acids, accumulate in milk, which has a lower pH than blood plasma. To reduce the intake of drugs into the child’s body through mother’s milk, it is recommended to take a long break between taking drugs and breastfeeding. The amount of drugs entering the newborn's body along with milk is usually 1-2% of the dose taken by the mother. Therefore, most of them are relatively safe for children (the possibility of a sensitizing effect of drugs cannot be ruled out). However, there are drugs that are contraindicated for use in nursing mothers, and if their use is necessary, breastfeeding should be stopped (Table 6-7). The individual sensitivity of newborns to a particular drug should also be taken into account. For example, some sulfonamide drugs are excreted in milk in small quantities but can cause hemolytic anemia in neonates with glucose-6-phosphate dehydrogenase deficiency. Medicines entering milk in quantities
In conditions in which they are relatively safe for the newborn, if liver or kidney function is impaired, they accumulate in the mother’s body, and their concentration in breast milk increases. For example, with chronic renal failure (CRF) in the mother, the concentration of the main metabolite of streptomycin, dihydrostreptomycin, in breast milk increases 25 times.
Table 6-6. Side effects of medications in a child when taken by a nursing mother
End of table. 6-6
Table 6-7. Drug therapy in breastfeeding women
End of table. 6-7
FEATURES OF CLINICAL PHARMACOLOGY IN NEWBORNS
In the fetal period, the systems of metabolism and excretion of drugs are not sufficiently perfect, reaching the adult level of functioning only in certain months after birth (Table 6-8).
Table 6-8. Maturity level various systems body of a newborn depending on age
Suction. In newborns, especially premature ones, the secretion of hydrochloric acid is significantly reduced, the rate of gastric emptying is usually slow and reaches maturity only by 6-8 months.
The intensity of peristalsis and, consequently, the speed of passage of food through the intestines is in most cases unpredictable and only in a small proportion of newborns depends on the nature of feeding. All of the above causes significant differences in the degree and rate of drug absorption in children of different age periods. For example, in newborns up to 15 days, a delay in absorption of phenytoin, rifampicin, ampicillin, and cephalexin is observed. The absorption of digoxin and diazepam does not significantly depend on age. The bioavailability of drugs with high hepatic clearance (for example, propranolol) in newborns may be less than in older children, with significant individual differences noted.
In addition to physiological factors, drug absorption can also be influenced by various pathological conditions. With diarrhea, the absorption of ampicillin is impaired, and with steatorrhea, the absorption of fat-soluble vitamins is impaired. The absorption of drugs after intramuscular administration depends mainly on the blood supply to the muscles and the presence of certain pathological conditions (for example, edema), and therefore varies widely.
When transdermal administration of drugs to newborns, their absorption should be more intense than in adults. Therefore, for example, if local administration of glucocorticoids is necessary, the least toxic drug is chosen. Boric acid, which is part of many powders, can be absorbed through the skin and cause diarrhea, aggravate prickly heat and some other skin diseases. Even through intact skin of newborns, aniline derivatives (found in dyes on linen) can be absorbed, causing methemoglobinemia.
Distribution of medicines. Differences in the distribution of drugs in children of different age groups depend on the relative water content (in premature infants - 86% of body weight, in full-term ones - 75%, by the end of the 1st year of life - about 65%), on the ability of the drug to bind to proteins and tissue receptors, circulatory conditions, the degree of permeability of histagema barriers (for example, the permeability of the blood-brain barrier for most lipophilic drugs is significantly increased). Thus, in the brain of newborns, the concentration of morphine is higher than in older children. Acidosis, hypoxia and hypothermia also contribute to a more rapid penetration of these drugs into the central nervous system, and therefore they are almost never used in anesthesiological practice in newborns, and in children aged 6 months to one year they are used in lower doses.
With acidosis (very typical for sick children), the distribution of drugs is generally significantly changed: the absorption of acidic drugs by tissues is increased, and alkaline drugs are decreased (the effect of pH on the degree of ionization of weak electrolytes). The toxic effects of acetylsalicylic acid in children are noted more often than in adults, since with a decrease in blood pH, the degree of ionization of salicylates decreases, which leads to an increase in their penetration through tissue barriers. The renal clearance of salicylates is increased with increasing urine pH.
In newborns, the volume of extracellular fluid is approximately 45% (in premature infants - up to 50%) of body weight, while in children aged 4-6 months - 30%, 1 year - 25%; Its intensive daily exchange is also noted (in an infant, 56% of the extracellular fluid is exchanged, in an adult - only 14%). This facilitates the rapid penetration of hydrophilic drugs into the extracellular fluid and their equally rapid elimination. At the same time, newborns have a reduced amount of fat: it accounts for approximately 3% of total body weight in premature infants, 12% in full-term infants (compared to 30% in children aged 1 year and 18% in young healthy people). Since the distribution of drugs between extracellular fluid and fat depot occurs in accordance with their lipo- and hydrophilicity, these properties of drugs play a leading role in the distribution of drugs. Drugs that are highly soluble in water and slightly bind to proteins penetrate intensively into the extracellular fluid, and their concentration in the blood decreases. Therefore, it is sometimes advisable to dose drugs (for example, sulfonamides, benzylpenicillin, amoxicillin) based on extracellular fluid, and not on total body weight. With dehydration or shock, the volume of extracellular fluid is reduced, and the concentration of water-soluble drugs in the blood plasma increases, and therefore the likelihood of side effects increases.
The volume of distribution of many drugs (digoxin, anticonvulsants, sedatives, tranquilizers) in children is higher than in adults. The volume of distribution (as opposed to the half-life) does not have the same clear dependence on age, and this indicator reaches adult values faster than the half-life.
Binding to plasma proteins. In newborns, compared to adults, the binding of drugs to blood plasma proteins is less (therefore, the concentration of the free fraction of drugs is higher), since they have less blood plasma proteins (in particular albumins), there are qualitative differences in the binding ability of proteins, as well as high concentrations of free fatty acids, bilirubin and hormones (entered the body in the prenatal period)
Riode), competing with drugs for binding to plasma proteins. Albumin content, their binding capacity, as well as total proteins reach adult levels by the end of the 1st year of life. Impaired binding of drugs to proteins is often observed in newborns and children with acidosis, uremia, nephrotic syndrome, with insufficient protein intake from food, as well as in case of poisoning with certain drugs. The drugs themselves can also disrupt the binding of endogenous substances to proteins. Thus, salicylates and most sulfonamides, which actively bind to plasma albumin, displace bilirubin. When the concentration of unconjugated bilirubin in the blood plasma increases, jaundice occurs; bilirubin easily penetrates the BBB (especially against the background of acidosis, hypothermia, hypoglycemia). This interaction may increase the risk of bilirubin encephalopathy in the newborn. Water-soluble derivatives of vitamin K have a similar effect on the connection of bilirubin with plasma proteins.
Metabolism of drugs
As in adults, the main organ responsible for drug metabolism in newborns is the liver. Since the cytochrome P-450 system becomes fully developed only at the time of birth, it functions more slowly than in adults. Phase I reactions, as well as methylation, are reduced at birth. This leads to the formation of various metabolites in newborns. For example, neonates metabolize approximately 30% of theophylline to caffeine compared to adults. Most phase I reaction enzymes reach adult levels by 6 months, and alcohol dehydrogenase activity appears by 2 months, reaching adult levels by 5 years (Table 6-8).
Synthetic phase II reactions are responsible for the removal of endogenous substances and many exogenous ones. Immaturity of the glucuronidation pathway may lead to the development of Gray's syndrome in neonates receiving chloramphenicol. Premature and full-term neonates die from this syndrome due to the development of anemia and vascular collapse due to high concentrations of unconjugated chloramphenicol, the half-life of which is 26 hours in these patients, compared with 4 hours in older children.
In newborns, conjugation reactions are more intense than in adults. For example, in children, paracetamol is excreted primarily as a sulfated conjugate, and in adults as a glucuronide. Phase II reaction enzymes reach adult levels between 3 and 6 months of life.
Oxidative hydroxylation in newborns (especially premature infants) proceeds slowly, and therefore the excretion of phenobarbital, lidocaine, phenytoin and diazepam is sharply reduced. Thus, the half-life of diazepam decreases with age (38-120 hours in premature infants, 22-46 hours in full-term newborns and 15-21 hours in children aged 1-2 years). Due to these pharmacokinetic features, a significant accumulation of the drug and its metabolites is observed in newborns when diazepam is prescribed to pregnant women shortly before birth. The intensity of ester hydrolysis is also reduced in newborns, since the activity of esterases depends on age. This is what explains respiratory depression and bradycardia in newborns when local anesthetics are used to anesthetize labor.
In addition to age-related physiological characteristics of metabolism, there are other factors that influence the rate of biotransformation of drugs in newborns.
The rate of metabolism of drugs also depends on their binding to plasma proteins: for example, weak binding of phenytoin leads to an increase in the rate of its metabolism.
A number of diseases and pathological conditions have an additional impact on the biotransformation of drugs and, accordingly, influence the strength or even modify their pharmacodynamic effects, which complicates rational pharmacotherapy of newborns. The half-life of most drugs is prolonged in early childhood, which determines the need to reduce the dose of the drug or increase the interval between doses. The maximum increase in the half-life of drugs is observed in premature newborns, then it gradually decreases, reaching 50% of the value in adults after 1-2 months.
Excretion. Renal blood flow rate, glomerular filtration and tubular secretion are reduced in full-term and preterm infants. Therefore, the frequency of the dosing regimen, especially in newborns less than 3-4 weeks old, should be reduced. Thus, aminoglycosides are prescribed every 8 hours for older children, every 12 hours for full-term infants, and every 24 hours for premature newborns. The glomerular filtration rate of full-term infants is about 50% of the adult level, reaching it by 1 year of life. The rate of renal blood flow reaches adult levels between 5 and 12 months. The maturity of the functioning of tubular secretion comes later than glomerular filtration. In newborns, the excretion of organic anions, such as benzylpenicillin, furosemide, and indomethacin, is reduced. Tubular secretion and reabsorption reach adult levels by 7 years of life.
neither. There is a connection between the excretion of electrolytes and the postnatal development of hormonal regulation of this process. The reason for low urine concentration in newborns is considered not to be a lack of antidiuretic hormone, but to the low sensitivity of receptors to it. High levels of aldosterone and renin in the blood of newborns are a compensatory reaction to a decrease in the sensitivity of receptors to these hormones. Features of the excretion of water and electrolytes in the neonatal period must be taken into account when carrying out infusion therapy and administration of diuretics. The use of electrolytes, especially sodium bicarbonate, should be limited as sodium excretion is reduced in newborns. It is recommended to avoid the administration of sodium in the first 3 days of life, and the administration of potassium is permissible only if the kidneys are functioning normally. Given the tendency to retain water and electrolytes, the administration of diuretics to newborns is indicated, especially during infusion therapy. However, given the immaturity of the kidney transport systems and the insufficient supply of drugs to renal tubules To provide a diuretic effect, the dose of thiazide diuretics must be increased compared to doses in adults. The effect of furosemide or other loop diuretics is not associated with the accumulation of the drug in the tubular cells. However, it should be taken into account that in a newborn, due to reduced filtration and tubular secretion, the half-life of furosemide is 8 times longer than in adults and is 4-9 hours (in adults 30-70 minutes).
FEATURES OF CLINICAL PHARMACOLOGY
MEDICINES IN ELDERLY PEOPLE
Geriatric pharmacology is a section of clinical pharmacology that studies the principles of dosing and the characteristics of the interaction of drugs in elderly and senile patients, as well as ways to increase their body’s resistance to the undesirable effects of drugs. Pharmacotherapy of patients in this age group is complicated by the presence of several diseases, and, accordingly, the use of various drugs, an increased risk of adverse drug reactions (in patients over 60 years of age they are observed 1.5 times more often than in young people), changes in the pharmacokinetics and pharmacodynamics of drugs in older people. The occurrence of undesirable drug reactions may also be due to the fact that the patient mixed up the drug, took an extra dose, etc.
Features of pharmacokinetics of drugs in elderly people
Suction. Elderly people are characterized by progressive hypokinesia of the stomach and intestines. A decrease in the evacuation function of the stomach leads to a slower entry of drugs into the small intestine. This is of particular importance when using drugs with a short half-life and acid-resistant drugs. A decrease in the rate of absorption may also be due to atrophic changes in the mucous membrane of the stomach and intestines, and a decrease in blood flow in the gastrointestinal tract. In elderly patients, achlorhydria often occurs, which can cause a decrease in the solubility of some drugs, such as tetracyclines, and indirectly reduce their bioavailability. The absorption of most drugs absorbed by diffusion remains virtually unchanged, while the level of absorption of drugs absorbed by active transport (for example, calcium, iron, vitamins, etc.) may be reduced.
A decrease in drug absorption is also observed with intramuscular injection, which may cause a decrease in the rate of onset of the therapeutic effect. The reasons for this may be a decrease in blood flow in skeletal muscles and a decrease in physical activity elderly patients.
Distribution. Hypoalbuminemia, a decrease in the amount of proteins that bind drugs, a decrease in muscle mass, an increase in fat mass, and a decrease in water in tissues change the distribution of drugs in the elderly and, accordingly, the pharmacokinetics of drugs (Table 6-9). An age-related decrease (about 20%) in albumin concentration is known due to a decrease in the rate of their hepatic synthesis. These changes affect the concentration of the free drug fraction for a number of drugs with high binding capacity (phenytoin, warfarin, promedol*), which can lead to the development of side effects when prescribing standard doses.
A decrease in the rate of distribution of most drugs occurs due to a deterioration in the speed of blood flow, a decrease in blood supply various organs and tissues due to sclerosis of blood vessels and a decrease in cardiac output.
Metabolism. A decrease in blood supply to the liver, its protein synthesizing and detoxification functions causes a lower intensity of drug metabolism in the elderly. Intensity of reactions
Phase I metabolism decreases with age, conjugation reactions
Phase II does not change. In a carefully controlled study, there was a significant dependence of the half-life
diazepam from age. At the age of 20 years, the half-life was 20 hours. This value increased linearly and amounted to 90 hours in 80-year-old patients (Table 6-10). This pattern of increasing half-life with age persists for a number of drugs, which is due to a decrease in metabolism and clearance LS or both together (see Table 6-10).
Table 6-9. Some age-related changes, affecting the pharmacokinetics of drugs
Table 6-10. Half-life of some drugs in young and elderly people
Excretion. The excretory function of the kidneys deteriorates with age. This is associated with a decrease in renal blood flow, glomerular filtration, tubular secretion, as well as a decrease in the amount
nephrons. It has been found that in people starting at age 20, kidney function decreases by 10% for each subsequent 10 years of life. This must be taken into account when choosing a dosage regimen for drugs that are primarily excreted by the kidneys (for example, penicillin, digoxin). In the elderly, even a normal creatinine concentration does not always indicate normal renal excretory function. Considering the inferiority of hepatic metabolism and decreased excretory function of the kidneys, initial doses of drugs in the elderly should be reduced by 30-50%.
Features of pharmacodynamics of drugs in elderly people
In elderly patients, it is possible to develop difficult to predict, atypical, inadequate to the amount of administered drugs and even paradoxical reactions when using, for example, cardiac glycosides, glucocorticoids, nitrates, adrenomimetics and adrenergic blockers, some antihypertensive drugs, analgesics, barbiturates, benzodiazepine tranquilizers, antiparkinsonian and antiepileptic drugs . This is facilitated by changes in the density or sensitivity of receptors, decreased physical activity, dysfunction of the gastrointestinal tract, hypovitaminosis, deterioration of blood supply to tissues, etc. As a result, barbiturates, for example, often cause impaired consciousness or paradoxical agitation, nitrates and procainamide - a stronger decrease in blood pressure and possible worsening of cerebral circulation than in middle-aged patients, narcotic analgesics - more rapid depression of the respiratory and stimulation of the vomiting centers.
Delirium and cognitive impairment are common in older adults when prescribed psychotropic medications. The risk of adverse drug reactions increases when a patient receives several drugs, and when more than 6 types of drugs are prescribed, it increases 14 times.
Principles of pharmacotherapy in the elderly
The question of prescribing a particular drug should be decided only after a comprehensive analysis of its effect on the body of an elderly patient, guided by the following principles.
It is necessary to take into account the increased sensitivity of older people to drugs (especially to cardiac glycosides, antihypertensive drugs, tranquilizers, antidepressants), as well as the patient’s mental state and social factors.
The drug dosage regimen must be strictly individual. At the beginning of treatment, drugs are prescribed in doses approximately 2 times lower than
than for middle-aged patients. Then, gradually increasing the dose, the individual tolerance of the drug is established. Upon reaching therapeutic effect the dose is reduced to maintenance (as a rule, it is lower than the dose prescribed to middle-aged patients).
If possible, oral administration of liquid dosage forms should be avoided, since due to decreased visual acuity and hand tremors, elderly patients have difficulty dosing them.
In stationary conditions medical personnel should be given Special attention monitoring the timely intake of prescribed drugs, since patients may forget to take the next dose of the drug or take it again.
When prescribing several drugs, it should be taken into account that elderly age- risk factor for dangerous drug interactions. The dosage regimen should be based on experience, knowledge of changes in pharmacokinetics, the nature of the disease and the physiological status of organs and tissues involved in the adsorption, distribution, metabolism and excretion of drugs.
The need to prescribe drug therapy to breastfeeding women is by no means a rare situation in our time. And if in acute illness mild degree gravity or chronic pathology in a state of partial remission, you can try to cope without medications, then in cases life-threatening or the health of the mother, this possibility is not even discussed. No doctor will leave a patient with purulent mastitis and the threat of sepsis without antibiotic therapy or a woman with progressive macroprolactinoma without bromocriptine. In such situations, Ukrainian doctors usually recommend avoiding breastfeeding. Is such a recommendation always justified? It turns out not. In developed countries, where artificial feeding is not considered a worthy alternative to natural feeding, such a formal approach has long been abandoned. European experts not only allow, but also strongly recommend preserving lactation in most cases of drug treatment for a nursing mother. To do this, you need to know the basic principles of prescribing medications during lactation, as well as be able to choose the optimal drug.
About this in his report within the framework of the XIV Russian national congress“Man and Medicine” (Moscow, April 16) was told by Lyudmila Stackelberg (Berlin Center for Pharmacovigilance
and embryonic toxicity).
The main sources of information for a doctor when assessing the safety of drugs prescribed during lactation are the instructions for use of the drug, pharmacological reference books, manuals on clinical pharmacology and therapy. In most cases, this information is not enough for the doctor to give a complete and comprehensive consultation to the patient during breastfeeding. Therefore, several years ago, a call center was created at the Berlin Center for Pharmacovigilance and Fetal Toxicity, whose task is to provide advice to doctors, as well as pregnant and lactating women themselves, on issues of drug therapy. What questions most often interest our patients?
Having analyzed the calls received by the center in 2006 (a total of 11,286 calls), we found that about 63% of questions related to taking medications during pregnancy, 35% during lactation, and 2% about taking medications by the child’s father. The most frequently asked questions were about the safety of psychotropic, antihistamine, anti-inflammatory, hormonal, antibacterial drugs and analgesics.
How to assess the safety of a particular drug and the possibility of its use during lactation? Of course, this is determined by the pharmacokinetic characteristics of the drug. Moreover, in in this case pharmacokinetics is studied from the point of view of a three-component model: mother - mammary gland - child.
First of all, the route of entry of the drug into the mother’s body, its distribution, metabolism and excretion are taken into account. An equally important factor is the characteristics of metabolism in the mammary gland, the degree and mechanism of transition into milk (passively, with the help of a carrier, actively). The transfer of medications into breast milk is facilitated by the following properties: low molecular weight, low degree of dissociation, alkaline environment, good fat solubility, low degree of protein binding. It should be remembered that in the first two to three days after birth, the structure of the mammary glands is such that substances with a large molecular weight (immunoglobulins, lipids, etc.) can penetrate into the milk, although this does not pose a danger due to the small amount of colostrum produced.
The pharmacokinetics of the drug in the child’s body must also be taken into account: oral bioavailability, metabolism, distribution in the child’s body, the possibility of penetration through hematohistological barriers, and routes of excretion.
Oral bioavailability refers to the ability of a drug to reach systemic circulation after oral administration. Medicines with insignificant oral absorption or practically not absorbed from gastrointestinal tract, or are neutralized in the liver before entering the systemic circulation. Drugs with virtually zero oral absorption are insulin, infliximab, gentamicin, omeprazole, ceftriaxone, heparin and enoxaparin.
Thus, we can highlight the main properties of drugs with low risk during breastfeeding:
- short half-life;
- inactive or rapidly excreted metabolites;
- low relative dose;
- low toxic potential;
- low oral bioavailability.
The two most widely used indicators help assess the risk to the child during maternal drug therapy - the relative childhood dose and the ratio of the concentration of the drug in mother's milk and the child's plasma. The relative child dose is understood to be a portion of the maternal daily dose medications in%, calculated per kilogram of mother’s body weight, which the child will receive with full breastfeeding during the day, based on the child’s body weight.
The ratio of drug concentrations in breast milk to infant plasma is used to assess the accumulation or dilution of a drug in milk relative to maternal plasma.
There are a number of ways to minimize the risk of drug therapy for a nursing mother. In some cases, it is possible to postpone treatment to a later date or to stop taking medications altogether. When it is not possible to stop prescribing medications, the doctor must, of course, choose drugs with minimal passage into breast milk. For some diseases, the optimal solution may be to change the form or method of administration of the drug, for example, inhalation instead of tablet forms, etc.
One of the most important principles of drug therapy during lactation is a pause between feedings while peak concentrations are reached. active substance in maternal blood plasma and milk. If the treatment regimen allows, the drug should be taken before the child's longest period of sleep, in most cases in the evening. When it is impossible for the mother to refuse treatment, and the drug risk for the child exceeds the benefits of breastfeeding, they resort to either a temporary pause or refusal to feed the child with breast milk.
The greatest caution when medicinal therapy for a nursing mother should be observed in the following cases: the neonatal period, premature babies, sick children, the use of high dosages or long-term treatment.
I would like to draw attention to situations in which, despite the prevailing opinion about the need to give up breastfeeding, such a drastic step is not necessary. Our experience shows that lactation can be maintained with local anesthesia, the use of hormonal contraceptives, bromocriptine, cabergoline, tetracyclines, sulfonamides, co-trimoxazole, glucocorticosteroids, heparin and low molecular weight heparins, oral anticoagulants (prophylactic administration of vitamin K to a newborn in the first 4 weeks of life, 1 mg 3 times a week is necessary).
Analysis of literature data and statistical indicators allows us to conclude that doctors tend to overestimate side effect drug therapy of the mother on the child’s body. Thus, Ito et al. (1993), having studied the effect on children of medications used by a nursing mother (number of child-mother pairs - 838), found that only in 11% of cases there were mild symptoms in the child (against the background of antibiotic therapy - “ a soft chair", the use of psychotropic drugs - sedation, antihistamines - excitability, etc.). None of the children experienced any severe side effects from maternal drug therapy.
Having analyzed one hundred references in the literature today about the occurrence of side effects in breastfed children during the treatment of mothers, Anderson et al. found that there was a probable connection between symptoms and medication in 47 cases, and a possible connection in 53 cases. In 3 cases there were deaths, and in all cases psychotropic drugs were used, and the children had additional significant factors risk. I would like to draw your attention to the fact that 78 children out of a hundred were under 2 months (63 were newborns), and only four were older than 6 months.
One of deaths child after drug therapy for the mother was described by Koren et al. (Lancet, 2006). After analgesic therapy in connection with the episiotomy (paracetamol 1000 mg 2 times a day + codeine 60 mg 2 times a day), the mother experienced a state of somnolence. From the 2nd day, the dose of drugs was halved, but the child began to experience a weakening of the sucking reflex, and from the 7th day - lethargy. On the 12th day, gray skin was observed, and on the 13th day the child’s death was declared. Post mortem, the concentration of the morphine-active metabolite codeine in the blood and milk was determined, which was 70 and 87 ng/ml, respectively. In the child and mother, familial polymorphism of the CYP2D6 enzyme was established with the subsequent development of intense ultra-fast metabolism of codeine to morphine.
The most problematic group of medications used during lactation are psychotropic drugs. Nevertheless, under strict medical supervision, lactation can be maintained in many neuropsychiatric diseases. Based on our experience, the safest antiepileptic drugs for a child are gabapentin, valproate, levetiracetam, and vigabatrin.
We believe that a nursing mother can take antidepressants if necessary. Many tricyclic antidepressants and selective serotonin reuptake inhibitors have a low relative dose (the exceptions are doxepin and fluoxetine, which should not be taken during lactation).
The data we have accumulated allow us to conclude that among neuroleptics, phenothiazines, clozapine, risperidone, quetiapine, and olanzapine can be used as monotherapy. A mother can be allowed to feed a baby with breast milk while taking lithium drugs only if the parents insist, since lithium has a long half-life (17-24 hours, up to 96 hours in newborns), low molecular weight, zero binding to plasma proteins and 100% oral bioavailability. In this case, constant medical monitoring and regular determination of the concentration of lithium in the child’s plasma are necessary.
When prescribing benzodiazepines, drugs with a short half-life should be selected and used in low doses for a short time. The most favorable properties are those of drugs such as oxazepam (low fat solubility, relative dose less than 1%) and lormetazepam (relative dose 0.04%, degree of plasma protein binding 88%, inactive metabolite).
When prescribing antiepileptics and antipsychotics during lactation, several basic rules should be remembered. Typically, monotherapy with these drugs is well tolerated by children. When combination therapy must be strictly observed individual approach with constant monitoring of the child's condition. It is necessary to warn the mother that if the slightest symptoms appear, it is necessary to consult a doctor and, if possible, determine the concentration of the active substance in the child’s blood serum.
In addition to combination therapy with psychotropic drugs, it is quite problematic to prescribe drugs such as cytostatics, radionuclides and iodine-containing contrast agents during lactation, as well as the use of iodine-containing antiseptics on a large surface of the body. In each specific case, the decision is made individually; in many cases, temporary or permanent cessation of breastfeeding may be necessary.
It is important for a practicing physician to know which drugs from the most commonly prescribed groups of drugs should be chosen when treating a nursing mother. Non-steroidal anti-inflammatory drugs can be used: ibuprofen, flurbiprofen, diclofenac, mefenamic acid. They enter milk in small quantities, have a short half-life and form inactive metabolites. The use of salicylates, ketoprofen, fenbufen (active metabolites), naproxen, piroxicam ( a long period half-life), indomethacin (variable half-life due to enterohepatic circulation).
At pain syndrome The drugs of choice during lactation may be paracetamol (combinations with codeine, caffeine), ibuprofen, acetylsalicylic acid (in isolated cases), for migraines - sumatriptan. For the purpose of antibacterial therapy, penicillins, cephalosporins, erythromycin, roxithromycin can be prescribed.
A group of researchers studied the safety of metronidazole in nursing mothers. The ratio of the concentration of the active substance in mother's milk and baby's plasma is 0.9. When taking a single dose of 2 g per os or long-term therapy of 1.2 mg/day, the concentration of the active substance in milk measured after 2-4 hours averaged 21 mcg/ml, the maximum was 46 mcg/ml (Erickson, 1981; Heisterberg, 1983 ; Passmore, 1988). The relative dose did not exceed 20% (average 12%) and corresponded to the pediatric dosage of metronidazole. Among the 60 mother-child pairs observed, no cases of specific toxicity were noted. Thus, the research conducted allows us to recommend continuing breastfeeding, using metronidazole in the evening after the last feeding.
For the treatment of bronchial asthma in a nursing mother, inhaled glucocorticoids, beta-2-adrenergic agonists, cromones, theophylline can be used, with allergic diseases- loratadine, cetirizine.
When prescribing drug therapy to a nursing woman, the effect of drugs on lactation should also be taken into account. A number of drugs are dopamine antagonists and stimulate prolactin secretion and lactation. These include antipsychotics (phenothiazines, haloperidol, risperidone, levosulpiride), α-methyldopa, domperidone, metoclopramide, reserpine. Ergotamine derivatives (bromocriptine, cabergoline, lisuride, methylergometrine), amphetamines, diuretics, and estrogens have the opposite effect.
Summarizing all of the above, we can determine the basic principles of drug therapy during lactation. Firstly, it should be remembered that the lack of information about the tolerability of a particular drug during lactation does not mean the absence of danger. In addition, the results of new studies on the safety of such therapy are regularly emerging, and recommendations for the use of drugs in breastfeeding women may change over time.
However, you should not overdramatize the situation. Toxic reactions in children during maternal drug treatment appear quite rarely and in most cases are mild. Currently, experts emphasize that the need for a pause during lactation occurs rarely, and refusal of breastfeeding occurs in isolated cases. For most therapeutic indications There are drugs of choice that are practically safe for a breastfed baby. If possible, monotherapy should be carried out; with a long course of treatment, the drug should be taken in the evening, after the last feeding.
More detailed information You can find out about the work of the Berlin Center for Pharmacovigilance and Embryonic Toxicity on the website: www.embryotox.de.
L. Stackelberg
Prepared by Natalya Mishchenko
IN clinical practice A family doctor often encounters situations when a nursing mother needs to prescribe drug therapy, which often leads to a dilemma: is it possible to continue breastfeeding (BF) while taking prescribed medications, is there a risk for the baby and lactation when using medications, or, all Should you stop breastfeeding? For a long time it was believed that
When using most medications, a nursing mother must, at least temporarily, interrupt breastfeeding. This approach was due to the lack of information regarding the pharmacokinetics of drugs, in particular, the degree of their accumulation in breast milk, as well as the lack of information about the effects of most drugs on the infant.
Considering the undoubted benefits of breastfeeding for both the child and the mother, great attention has always been paid to this issue. Thus, in 1983, the American Academy of Pediatrics for the first time published information on the use of medications for breastfeeding, taking into account their effects on the mother, baby and the lactation process itself. This information is constantly supplemented and updated and, today, fortunately, many gaps have been filled. One of the most authoritative online resources where you can find comprehensive information on this issue is the LactMed database, which is used by doctors from all over the world, and we encourage our domestic colleagues to do the same.
By the way, it should be noted that in Ukrainian and Russian instructions for drugs, the information may differ radically from international recommendations and often contains a ban on use during lactation, while the world has accumulated a lot of positive experience in using these drugs in breastfeeding women. This is most often due to the fact that it is not economically profitable for the manufacturer or distributor to go through all the procedures to obtain permission to use the drug during lactation.
In August 2013, an updated publication from the American Academy of Pediatrics was released, which emphasizes that in most cases, breastfeeding should be continued against the background of drug therapy and cessation of feeding may be justified only in certain situations: when taking antidepressants, anxiolytics, antipsychotics, opioids analgesics, cytostatics, radiopharmaceuticals (for example, I 131), drugs for the treatment of drug addiction. Not recommended for breastfeeding medicinal herbs, taking into account that often unacceptable concentrations of pesticides and heavy metal salts are found in herbal medicines; in addition, their effect on the child’s body is difficult to predict, given the complex composition. Cases of deaths have been described when using the herb yohimbe and some others.
In general, it is recognized that doctors advise stopping breastfeeding unnecessarily often, while the use of most drugs (including antibiotics, and even vaccines, with the exception of smallpox vaccine and yellow fever) is acceptable and safe.
General practitioner Sergei Makarov
The pharmacokinetic characteristics of drugs prescribed during this period are of fundamental importance for the implementation of effective and safe pharmacotherapy in the postpartum period. According to P. J. Lewis (1982), 2/3 of all medications used clinically in pregnant women are used in the postpartum period. The maximum amount of drugs entering breast milk does not exceed 1-2% of the dose administered to a nursing woman, and therefore probably has no effect on the child's body.
The entry of drugs and their metabolites into breast milk is influenced by the same factors as their passage through other lipid membranes. The drug, which is in the body of a nursing woman, enters the milk through the epithelial cells of the mammary glands. The epithelial lipid membrane is a barrier between slightly alkaline serum blood and breast milk, which has a slightly acidic reaction.
The transfer of drugs from the blood into breast milk depends on the molecular weight of the drugs, their chemical properties, dissociation constant, solubility in lipids, degree of ionization (pKa), degree of binding to proteins in the woman’s blood serum and breast milk, and the pH value of breast milk. The pH level of breast milk varies between 6.35 and 7.65. These fluctuations can significantly affect the level of excretion of drugs into breast milk.
Low molecular weight drugs pass into breast milk by passive diffusion; a higher degree of transition is characteristic of non-ionized drugs that are lipid soluble. The passage of partially ionized drugs through the membrane depends on the pH of the medium and the M/P coefficient (M is the concentration of the drug in breast milk; P is the concentration in plasma). It has been established that the M/P coefficient is lower for drugs that have an acidic reaction than an alkaline one [Soradi I., 1980].
Non-ionized fat-soluble substances with minimal ability to bind to plasma proteins diffuse better into breast milk. In order for a drug to get from the blood into the alveolar cells of the mammary gland, it needs to pass through the capillary endothelium, interstitial fluid, and cell membranes. Since non-ionized drug molecules are fat soluble, and fat is main component cell membranes, drugs with low molecular weight (less than 200 Da), non-ionized and with high lipid solubility (for example, antipyrine) can quickly pass from the blood into breast milk.
So, according to Ph. O. Andersen (1979), along with breast milk, the child’s body receives such drugs as indomethacin, antibiotics of the chloramphenicol group, benzylpenicillin, tetracyclines, sulfonamides, nalidixic acid, neodicoumarin, reserpine, aminazine and other phenothiazine derivatives, psychotropic, anticonvulsant drugs.
Factors such as the level of blood flow in the mammary gland, daily production of breast milk, its fat and protein composition, as well as the coincidence of the time of feeding the child and the mother taking the drug are also important.
Leading, but not always decisive factor is the ratio of drug concentrations in breast milk and maternal serum. An unfavorable effect of the drug on an infant is usually observed in cases where this coefficient is ≥1. This, however, does not mean that side effects must necessarily occur at a given ratio. The amount of the drug that passes through breast milk to the baby depends on the degree of absorption of the drug in the mother’s digestive tract. For example, digoxin, which has a relatively high M/P ratio, is not detected in the child’s blood in toxic concentrations. At the same time, some medicinal substances for which this coefficient is low can cause adverse reactions in children.
