Learning Objectives: 1. Relation of drugs and lactation 2. Factors modifying passage of drugs in milk 3. Effects of drugs on milk production 4. Role of lactation on drugs excretion This lecture was done by: 5. Drug safety during lactation / use of Abdullah Saleh Bawazir safe drugs 6. Drugs contraindicated during lactation And reviewed by: Tuqa Alkaff Lactaon: • Breast feeding is very important because breast milk is the healthiest form of milk for babies. • It provides the baby with immunoglobulins (IgA, IgM) that are essenal for protecon against gastroenteris.

Drugs & Lactaon: . Most drugs administered to breast feeding woman are detectable in milk. . The concentraon of drugs achieved in breast milk is usually low (< 1 %). . However, even small amounts of some drugs may be of significance for the suckling child. (all the execratory mechanisms are going down in babies)

Pediatric populaon are classified into: • Newborn: less than one month old – Preterm neonates: born before 38 weeks of pregnancy (it's the harmful stage) – Full-term neonates: 38-42 weeks of gestaonal age • Infants (babies): 1 month – 12 months of age • Children: 1 -12 years of age – Toddler (young child): 1-5 years – Older child: 6-12 years • Adolescent: 13-18 years 2

Pharmacokinecs in pediatric: • Higher gastric PH • Higher concentraon of free drug • Higher percenrage of body water • Neonate’s especially premature babies have limited capacity for metabolism and excreon. • Neonates have very limited rate of metabolism due to immaturity of liver enzymes. • Renal clearance is less efficient: ( decrease Renal blood flow – decrease GFR). • The epithelium of the breast alveolar cells is most permeable to drugs during the 1st week postpartum, so drug transfer to milk may be greater during the 1st week of an infant’s life.

Physiologic Differences between Neonates and Adults of Pharmacokinec Importance (Hilligoss 1980)

Neonate Adult

Gastric acid output (mEq/10kg/hr) 0.15 ↓ 2 Gastric emptying me (min) 87 ↑ 65 Total body water 78 ↑ 60 (% of body weight) 12 ↓ Adipose ssue (% of b.wt.) 12-25

3.7 ↓ Serum albumin (gm/dL) 4.5

Glomerular filtraon rate (ml/min/m2) 3 11 ↓ 70

Factors that affect passage of drugs into breast milk:

Factors related to drugs

Molecular weight: Lipid solubility of the drug: pH of drug: weight:Very small molecules (< 200 Daltons) such Lipid soluble drugs pass as alcohol, equilibrate rapidly between plasma more freely into .pH of milk is slightly more acidic than and breast milk via the aqueous channels the breast milk than water maternal blood. surrounding alveoli. soluble drugs.can easily .Weak basic drugs tend to concentrate Large molecules drugs (>800 Daltons) are less cross any membrane in breast milk and become trapped likely to be transferred to breast milk than low Degree of ionizaon: secondary to ionizaon. molecular weight. .Ionized form of drugs are Insulin: MW > 6,000 daltons less likely to be transferred .Weak acidic drugs don't enter the Heparin: MW 40,000 daltons into breast milk. milk to a significant extent and tend to Monoclonal anbodies, pass very poorly into milk .e.g., heparins pass poorly be concentrated in plasma.maternal aer the first 1st week postpartum. into breast milk circulaon The epithelium of the breast alveolar cells is most

permeable to drugs during the 1st week Plasma protein binding of postpartum, so drug transfer to milk may drugs be greater during the 1st week of an infants life. Drugs circulate in maternal Volume of distribuon Transfer of drug from circulaon in unbound (free) or bound forms to maternal blood to milk is low with drugs that have albumin. large volume of distribuon (Vd)to prevent from Only unbound form gets staying from blood.let it stay in ssues. into maternal milk. Half life of drug Definion of good protein binding > 90% Avoid the use of drugs with long half lives 4 e.g. warfarin also heparin short half life (t ½) are preferable. could be prescribed Oxazepam vs diazepam

Factors that affect passage of drugs into breast milk:

Factors related to mother

Route of administraon (to minimize exposure of drug) Health status Breaseeding is contraindicated .Route of administraon affect the concentraon of the in case of: drug in maternal blood. Mother HIV

Acve, untreated TB in mother .Maternal use of topical preparaons (creams, nasal sprays or inhalers) are expected to carry less risk to a Herpes on breast breased infant than systemically administered drugs. Use of illegal drugs by mother Time of breaseeding Certain medicaons .The concentraon of the drug in the milk at the me of feeding. .Lactang mother should take medicaon just aer nursing and 3-4 hours before the next feeding.(injecon-minutes) (to allow me for drug to be cleared from the mother’s blood – drug concentraon in milk will be low). . 5

Factors that affect passage of drugs into breast milk:

Factors related to neonates Age -Body weight(premature lower body weight than mature)- Health status The amount of a drug to which the baby is exposed as a result of breast feeding depends on: The amount of milk consumed. The amount of drug absorbed from GI. The ability of the baby to eliminate the drug.

Age & Health status Special cauons are required in - Premature infants - Low birth weight(even those with full term-gestaon) - Infants with G6PD deficiency- Infants with impaired ability to metabolize /excrete drugs e.g. hyperbilirubinemia.(physiological jaundice) Pathological condions

Neonatal hyperbilirubinemia Neonatal Methemoglobinemia Premature infants or infants with inherited  Infants under 6 months of age are G6PD(found in RBC’s membrance(anoxidant) parcularly deficiency are suscepble to oxidizing drugs that can prone to develop methemoglobinemia upon cause → hemolysis of RBCS →↑ bilirubin exposure to some oxidizing drugs. (hyperbilirubinemia) →↑ Kernicterus(go BBB) Examples for oxidizing drugs:  Methemoglobin is an oxidized form of Anbiocs6 sulfonamides, trimethoprim hemoglobin that has a decreased affinity for Anmalarials: Primaquine oxygen → ssue hypoxia.

Drugs contraindicated during lactaon:

Ancancer CNS acng Lithium (an Atenolol Radioaph Potassium drugs drugs manic Drug) armaceu iodide cals Risk of Growth Amphetamine, high concentraon of Risk of Radioacve risk of retardaon heroin, cocaine , the drug will pass with Bradycradia and iodine Hypothyroidism Doxorubicin, BZDs , the milk and appear Hypoglycemia cyclophosphamid Bulbutarates & as skin rash on the e, methotrexate even Smoking baby Chloramphenic ol antibiotic Remember gray baby syndrome

Drugs that can suppress lactaon: (does not produce harmful acons) >> reduce prolacn Levodopa Bromocripn Androgens Estrogen,combi Thiazide Ergot e ned oral diurecs derivaves contracepves (dopamine precursor). (dopamine that contain high- an Migraine Dopamine will Inhibit agonists ). dose of estrogen and Drugs Prolacn leading to Same Acon as a progesn.take mini Milk Suppression Dopamine pills or progestrins only 7 Also, Pyridoxine, and MAO inhibitors suppress lactaon Drugs to be avoided during lactaon:

Barbiturates: Benzodiazepi Anthyroid Hormonal Analgesics : Anbiocs: Phenobarbito nes: drugs: contracepv Aspirin Tetracyclines ne diazepam carbamizole es: estrogen only

Note: These drugs are contraindicated also but they can be used under some restricons when there’s no other choice Dopamine antagonists: they smulate prolacn secreon (Hyper-Prolacnemia) such as: like an- Drugs that can augment lactaon: physicocs,have risk parkinsonism Metoclopramide Haloperidol Phenothiazin Methyl dopa Theophylline Domperidone (anemec) (anpsychoc) e (anhypertensive (used in (anemec) drug) asthma) *preferred in Has narrow pregnancy also therapuc index Note:  Infant with G6PD deficiency may develop hemolysis and hyperbilirubinemia with

sulphonamides8 and anmalarial drug primaquine  Some anbiocs are contraindicated in lactang women e.g. chloramphenicol Antibiotics

Penicillins No significant adverse effect Ampicillin allergic reacons, diarrhea (!st prescribed) amoxacillin Cephalosporins If she’s allergic to penicllins or the baby has diarreah Macrolides erythromycin No significant adverse effect clarithromycin Alteraons to infant bowel flora hyperbilirubinemia -neonatal jaundice Should be avoided in premature Sulfonamides (co-trimoxazole) infants or infants with G6PD deficiency

Quinolones Theorecal risk of arthropathies Should be avoided Chloramphenicol “Gray baby” syndrome avoid Tetracyclines Absorpon by the baby is probably prevented by chelaon with milk calcium. Avoid due to possible risk of teeth discoloraon.theorically not proven hyperbilirubinemia -neonatal jaundice Should be avoided in premature Sulfonamides infants or infants with G6PD deficiency

(co-trimoxazole) 9 Sedative/hypnotics Barbiturates Lethargy, sedaon, poor suck reflexes with prolonged (phenobarbitone) use.(addicon to mom&baby)

Benzodiazepines Single use of low doses is probably safe. Diazepam Lethargy, sedaon in infants with prolonged use.

Lorazepam

Oral contraceptives Non hormonal method should be used Avoid estrogens containing pills Estrogens ↓ milk quanty Progesn only pills or minipills are preferred for birth control. 10 Antidiabetics

Insulin safe Oral andiabecs compable Meormin avoid due to lacc acidosis

Analgesics Paracetamol safe

Ibuoprofen compable

Aspirin avoid due to theorecal risk of Reye's syndrome

11 Anthyroid drugs Propylthiouracil May suppress thyroid funcon in infants. Carbimazole Methimazole Propylthiouracil should be used rather potassium iodide than carbimazole or methimazole. Ancoagulants Safe, not present in breast milk. Heparin Warfarin can be used, very small quanes found in breast milk, monitor the infant's prothrombin me during treatment. Warfarin

Anconvulsants Preferable over others

Carbamazepine Compable with breaseeding

Phenytoin Amounts entering breast milk are not sufficient to produce adverse effects Valproic acid Infants must be monitored for CNS depression Lamotrigine avoid Andepressants SSRI Paroxene is the preferred SSRI in breaseeding women.

12 Cytotoxic drugs Breast feeding should be avoided Iodine (radioacve) Permanent hypothyroidism in infant Breast-feeding is contraindicated Lithium Large amounts can be detected in milk

avoid CVS drugs Atenolol Risk of bradycardia and hypoglycemia

avoid

13 Drugs of choice in lactation

Anbiocs Cephalosporins, penicillins are safe Avoid: chloramphenicol, quinolones, sulphonamides and tetracyclines

Andiabecs Insulin – oral andiabecs are safe Avoid: meormin

Ancoagulants Heparin – warfarin Analgesics Acetaminophen (paracetamol) Anthyroid drugs Propylthiouracil is preferable over others

Anconvulsants Carbamazepine - phenytoin Oral contracepves Progesn only pills or minipills are preferred for birth control.

Anasthmacs Inhaled corcosteroids – prednisone

14 General consideraons to minimize risk to nursing infant:  The safest drug should be chosen.  Route of administraon (topical, local, inhalaon) instead of an oral form.  Poorest oral bioavailability o Inhaler Restricted to the Respiratory system o Topical Restricted to the Skin  Lowest lipid solubility.  Shortest half-life  Highest protein-binding ability.  Lactang mother should take medicaon just aer nursing and 3-4 hours before the next feeding.  Infants should be monitored for adverse effects e.g. feeding, sedaon, irritability, rash, etc.

Drugs with no safety data should be avoided or lactaon should be disconnued. Cauons required in: 1. Premature infants at high risk of developing side effects 2. Low birth weight 3. Infants with impaired ability to metabolize/excrete drugs eg. sick babies 4. Infants with G6PD deficiency

15 Summary

To minimize the ADRs of the drugs in lactaon we use a drug having these characters : • non lipid soluble (water soluble) → ionized • High molecular weight • acidic drug • Summary: • Short half life • high volume of distribuon Drugs of choice in lactaon: • Anbiocs: Cephalosporins, penicillins are safe Avoid: chloramphenicol, quinolones, sulphonamides and tetracyclines • AnDiabecs: Insulin – oral andiabecs are safe Avoid: meormin • Ancoagulant: Heparin – warfarin • Analgesics: Acetaminophen ( paracetamol ) • Anthyroid: Propylthiouracil is preferable over others • Anconvulsants: Carbamazepine - phenytoin • Oral contracepve: Progesn only pills or minipills are preferred for birth control. • AnAsthmacs: Inhaled corcosteroids - prednisone

16

1. Which one of the following drugs should be avoided during lactaon : A. Chloramphenicol B. Insulin C. Erythromycin D. Penicillin

2. Which one of the following drugs can be given during lactaon : A. Quinolones B. Sulphonamides C. L-dopa D. Heparin

Answers: 1-A, 2-D 3- Which one of the following drugs increases the risk of growth retardaon: A. Amphetamine B. Doxorubicin C. Atenolol D. Potassium Iodide

4- Which one of the following drugs Appear as skin rash on the baby : A. Lithium B. Cocaine C. L-dopa D. Penicillin

Answers: 3-B, 4-A 5- A newborn baby with G6PD deficiency presented with hemolysis and yellowish appearance. Which of the following drugs the mother are taking that could cause his symptoms: A. Chloramphenicol B. Erythromycin C. Primaquine D. Propylthiouracil

6- Which one of the following drugs is safe in a lactang mother that don’t want to have another child : A. Combined oral contracepve B. Minipills C. L-dopa D. Atenolol

Answers: 5-C, 6-B [email protected]