Drugs and lactation Jiří Slíva, MD., Ph.D.

Number of breast-feeded children in the U.S. AAP, 2005

Lactation and adherence to treatment cca 90 % of women take some medication during the first week after delivery some medicaments, not exactly contraindicated during pregnancy, can decrease the intensity of lactation women tend to disrupt lactation in case of short-term therapy (e.g. antimicrobial agents), or they are non-compliant to prescribed medication approximately 7 % of women disrupt lactation up to 15 % of women do not start taking ATBs at all

Frequency of ADRs in lactating women prospective trial (n = 838) with breast-feeded children, whose mothers were taking various preparations no serious adverse reaction was recorded however 11.2 % of women described non-serious ADRs – women were using: antibiotics (19.3 %) analgesics (11.2 %) antihistaminics (9.4 %) sedatives/antidepressants/antiepileptics (7,1 %) commonly recorded postantibiotic diarrhea, drowsiness after strong analgesics, antiepileptics, antidepressants, or irritability after antihistaminics Data on file

Transfer of drugs to maternal milk depends on pharmacokinetics of drug in maternal body perfusion of mammary gland milk composition physico-chemical properties of drug pH of both plasma and milk amount of milk synthesis The average plasma pH is 7.4, and the mean pH of breast milk is lower at 7.2 (Begg, Duffull, Hackett, & Ilett, 2002). Drugs that are weakly basic (i.e., more alkaline) tend to concentrate to a greater extent in the more weakly acidic breast milk, as opposed to the less weakly acidic plasma since acids attract bases (Auerbach & Riordan, 1998). Furthermore, weak bases are nonionized in the maternal plasma. This increases their ability to be transferred into breast milk, and thus, they may have a greater potential to become ion-trapped in the breast milk. Conversely, drugs that are weak acids are ionized in maternal plasma, which minimizes their diffusion into breast milk. For example, antihistamines and erythromycin, drugs that are weakly basic, would be more likely to cross cell membranes from maternal plasma into breast milk than would penicillins, which are weakly acidic (Banta-Wright, 1997).

Ad pH value average plasma pH is 7.4 average pH of breast milk is lower at 7.2 thus… drugs that are weakly basic tend to concentrate to a greater extent in the more weakly acidic breast milk, as opposed to the less weakly acidic plasma since acids attract bases weak bases are nonionized in the maternal plasma => increased ability to be transferred into breast milk weak acids are ionized in the maternal plasma => low diffusion into breast milk i.e., antihistamines and erythromycin, drugs that are weakly basic, would be more likely to cross cell membranes from maternal plasma into breast milk than would penicillins, which are weakly acidic

Transfer of drugs to maternal milk almost every drug crosses into maternal milk mostly via passive diffusion (e.g. H2 blockers, penicillins, nitrofurantoin and others.) also via active transport (e.g. cimetidine) transcellular diffusion breast-feeding can protect from abstinence syndrome in neonates, whose mothers were treated by barbiturates etc.

Drugs affecting milk formation Increase metoclopramide reserpine imipramine fenothiazine sulpirid TSH Decrease bromocriptine estrogens androgens antihistaminics barbiturates apomorphine levodopa pyridoxine

Drugs contraindicated during breast-feeding Cytostatics – immunosuppression, neutropenia, influence on growth?, cancerogenesis? Abused drugs – (amphetamine, cocaine, heroin, marijuana, LSD, alcohol, nicotine) – influence of CNS, maternal behavior Ergot alcaloids – (bromocriptine decreases lactation, ergotamine – risk of vomiting, diarrhea, cramps) Iodides – risk of struma, hypothyreosis Radioactive isotopes Gold Lithium – high concentration in maternal milk, possible influence of CNS Estrogens (oral contraceptives) Thiouracile – risk of struma, thyreosuppression, agranulocytosis

Drugs deserving increased caution Drugs affecting CNS – antidepressants, antipsychotics, benzodiazepines Drugs with recorded serious ADRs aspirin (metabol. acidosis), atenolol (beta-blocker), carbamazepine (sedation, hyperexcitability, cholestat. hepatitis), clemastine (hyperexcitability, drowsiness), phenobarbital (sedation, methaemoglobinemia), sulfasalazine (bloody diarrhea), metronidazole (potentially cancerogenic), TTC

Safe drugs during pregnancy

Antibiotics/chemotherapeutics amoxicilline, phenoxymethylpenicilline, benzylpenicilline, chloramphenicol, ciprofloxacine, clindamycine, doxycycline, gentamicine, nitrofurantoin, metronidazole or vancomycine easily cross to maternal milk according to available data, tetracyclins, chloramphenicol or aminoglycosides, eventually quinolones, can be used in specific cases, but mostly contraindicated

Antihypertensives ACE inhibitors, methyldopa, beta-blockers or calcium ion channel blockers are compatible with breastfeeding, i.e. they do not decrease blood pressure of children

Antihistaminics risk of irritability of children

Caffeine in common doses fully compatible with breastfeeding higher doses => risk of insomnia or irritation of children (half-life of caffeine: 3 to 7 hours)

NSAIDs, acetaminophen Ibuprofen – compatible with breast-feeding, Acetylsalicylic acid – compatible with breast-feeding expect of higher doses (risk of metabolic acidosis), Paracetamol – compatible with breast-feeding. Currently, it is discussed in relation with increased of higher prevalence of allergic rhinoconjunctivitis

PREDNISON IN PAEDIATRIC PRAXIS AND ITS MAGISTRALITER PREPARATION 17

Indications of prednisone Respiratory system Allergy Nephrology Oncology Rheumatology Haematology Dermatology Endocrinology Ophthalmology Gastroenterology Immunology Common dosis pro infantibus ranges from 5 to 60 mg/day

Corticosteroids for children available in the Czech Republic Prednisone Prednison tbl. 5 a 20 mg Rectodelt rect. supp. 100 mg ----------------------------- Methyl-prednizolone: Medrol tbl., Solu-Medrol i.v. Dexamethasone: Dexamethason supp. (IVLP) Dexamed, Dexona inj. Fortecortin tbl. Hydrocortisone Hydrokortison inj., tbl. Oral dose 5.0 mg prednisone is equal to 5.0 mg prednisolone, 4.0 mg triamcinolonu, 0.6 mg betamethasone, 0.75 mg dexamethasone a 20.0 mg hydrocortisone

F-CH vlastnosti p.o. kortikoidů Hodnocení 1-5 (1-nejhorší, 5-nejlepší), dospělí dobrovolníci Testování obdobné testování vína Kortikoid Aroma Chuť Chuť po požití Prednison 1mg/ml 1,8 1,31 1,27 Prednizolon 1mg/ml 1,83 2,51 2,52 Dexamethason 0,5mg/5ml 2,37 2,19 2,22 Prednison po čichové i chuťové stránce špatně tolerovaný, přetrvává hořká chuť po požití – zvracení, dávení u dětí – negativní vliv na compliance při dlouhodobém užívání. A taste comparison of three different liquid steroid preparations: prednisone, prednisolone and dexamethasone, John C.Mitchell a koll., Academic Emergency Meicine; april 2003;Vol.10, No.4

Lékové formy kortikoidů pro kojence a batolata - období do 2 let věku Tablety – „drcené“: - Hořká chuť - Provokace dávení, zvracení Čípky: - Provokace defekace - Interindividuální absorpce Parenterální formy - Invazivní podávání Suspenze: - Krytí hořké chuti - Lepší aplikovatelnost - Přesné dávkování

Prednisone suspension Raitt, J. R., Hotaling, W. H.: Preparation of stable prednisone suspension, Amer. J. Hosp. Pharm. 30:923-924 (Oct.) 1973.

Technologický postup Příprava suspenzního vehikula Příprava korigencia 3% vodný roztok tragacant-acacie sliz funkce: strukturální stabilizátor technologie: řízené botnání (?) anýzová silice funkce: korigens odoru Příprava korigencia Sirupus simplex a Sirupus aurantii (2:1) Příprava prednisonové suspenze

Prescription Rp. Prednisoni plv.…………………………..1,0 g Natrii benzoati 0,1%..............40,0 ml Tragacant-acacii mxt……………….20,0 ml Tragacant 3% Acacia 3% Natrii benzoat 0,1% Anisi (foeniculi) ol. 0,025% Sirupi ad…………………..…….100,0 ml Sirupi simplicis 67 % Sirupi aurantii 33 %

Koncentrace prednison susp. Prednisonová suspenze: 10 mg/1 ml Při dávkování 5–60mg/den odpovídá 0,5–6,0 ml suspenze

Stabilita Konzervans: 0,1% natrium benzoat (výhoda: užití suspenze i u dětí alergických na parabeny) Použitelnost: 1 měsíc (garantováno studií – viz výše) Uchovávání: v chladu (2–8 °C)

Economic evaluation 1.50 Kč 0.95 Kč Vial (100 ml) CZK 1 189,75 2 161,88 3 152,59 4 150,88 5 147,51 6 147,09 7 145,23 8 143,83 9 142,74 10 141,86 Total price Price per 5 mg Prednison tbl 20x5mg 30.10 Kč 1.50 Kč Prednison susp. 100ml 189.75 Kč 0.95 Kč

Useful URLs LACTMED: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT TOXNET: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT WHO: http://whqlibdoc.who.int/hq/2002/55732.pdf AAP: http://www.aap.org/healthtopics/breastfeeding.cfm http://www.medscape.com/viewarticle/464551_2

Questions for independent work: Try to decide: which of molecules will be transfered into maternal milk easier – warfarin or sumatriptan (based on plasma protein-binding?) Try to find decide, how salicylates (i.e. acetylsalicylic acid etc.) cross into maternal milk Try to find/recommend oral antiseptic drug compatible with both breast-feeding and pregnancy (AISLP, Micromedex etc.) What kind of drugs (active substance/plants) are used/recommended in order to stimulate lactation? Prescribe 10 suppositories with domperidone for infant (Dosis Therapeutica Singula = 10 mg)

Brand Content Dosage Bylinný čaj s jestřabinou pro kojící maminky Meduňková nať, plod kopru, plod fenyklu, nať jestřabiny a nať dobromyslu 2–3x denně po celé období kojení Čaj pro kojící matky Nať jestřabiny, plod kmínu, fenyklu, nať meduňky, zlatobýlu, violky trojbarevné, list jitrocele. ČAJánek Na podporu kojení Nať jestřabiny lékařské, květ ibišku súdánského, plod fenyklu, listy maliníku, nať levandule lékařské Laktační – bylinný čaj porcovaný fenykl plod, anýz plod, kopr plod, aronie plod, kmín plod, jestřabina nať, mateřídouška nať, kopřiva list, heřmánek květ 3x denně po celé období kojení Laktační – bylinný čaj sypaný dtto 3 x denně po celé období kojení. Nálev se připravuje z obsahu 1 čajové lžičky přelitím 1/4 l vroucí vody a nechá se v zakryté nádobě 15 min odstát. Laktofyt – bylinný sirup voda, cukr, bylinné extrakty z anýzu, fenyklu, kmínu, pískavce, bazalky, meduňky a ibišku, kyselina jablečná, sorban draselný Užívá se jako sirup s vodou dle chuti. WELEDA Čaj pro podporu kojení kopřiva, semena anýzu, fenyklu a kmínu 3–6x denně po celé období kojení