MUNI MED Pharmacotherapy in children, elderly, in pregnant women and in lactation Alena Machalová Overview of factors affecting drug effects A. Factors related to drug: Physical and chemical properties Dose Drug form Combination of drugs Food administered together with a drug Repeated administration B. Factors related to organism: Age Gender Weight and body constitution Circadian rhytms Pathological state of organism Genotype/fenotype (Race group/ethnic group) Age Administration of medicinal product (MP) to children to elderly people Administration of MP to children A child is not small adult particularities of PD particularities of PK Changes of PK of drugs in young age - A Higher pH in stomach Large surface area/volume ration + thinner skin -increased skin absorption TABLE 59-3 Oral drug absorption (bioavailability) of various drugs in the neonate compared with older children and adults. Drug Oral Ab»rptlon Acetaminophen Decreased Ampicillin Increased Diazepam Normal Digoxin Normal PenbcHlin G tncreased Phefiübarbifcs! Decieased Phenytoin Decreased 5 ul Fon amides Normal Changes of PK of drugs in young age - D • Higher total body water • Increase of body fat with age • Lower plasma proteins in infants • Unfinished development of HEB —> increased Vd —> obese children - higher risk in drugs not distributed into fat —> higher distribution and lower peak concentrations of protein-bound drugs 4$ Changes of PK of drugs in young age - M • The most complex difference between adults and children • Activity of CYP begins in foetus and increases with age (in 2 y exceeds adult levels) • Glucuronidation takes at least 3 years to mature • Liver blood flow is relatively higher —> higher first pass effect —> without adjustment of dose and dosing intervals there is a risk of cummulation and toxicity especially in newborns 160 140 CO t£> -Prenatal pattern: CYP3A7, FM01, SULT1A3 --Constant pattern: CYP3A5,SULT1A1, TPMT -Postnatal pattern: CYP2C9, 2C19, 2D6, 2E1, 3A4, FM03, most UGTs MED Changes of PK of drugs in young age - E • Decreased GF, but still is more advanced than TS • Decreased TS (aminoglycosides!!) —> preterm infants develop renal excretion pathways more slowly than term neonates porod acetylace glukuronidace konjugace s aminokyselinami 1 glomerulární filtrace tubulární sekrece 10 20 30 2 3 4 5 6 dny měsíce TABLE 59~4 Comparison of elimination half-lives of various drugs in neonates and adults. Nhj rj it j t j 1 Age Neonates t,n (hours) Adults tig {hours) Acetamfnophein 12-5 0.9-2J Diazepam 25-100 40-50 Diyoxin 60-70 30-60 Phenobarbetal 0-5 days 200 64-140 5-15 days 100 1-30 months 50 Phertytoin 0-2 days 60 12-18 3-14 days if; ^| 14-50 days 6 Salicyla:c- 10-15 TheophyLline Neonate 13-26 5-10 Child 3-4 Changes of PD in children Antihistamins: In adult patient sedation (sleppines, tiredness) In children excitation (cramps) Chloramphenicol - gray baby syndrome Salicylates - Reye syndrome Barbiturates - paradoxical reaction (excitation, agressivity) Administration of MP to children Doses are given in calculated SPC or have to be Approximate dose for children = body surface area (m2) x dose for _adult_ 1,7 (m2) Body surface area 7 x age (years) + 45 100 Administration of MP to old people Seniors represent 14% of population but use 35% of drugs „Young" senior 60 - 64y.......83% use medicines „Middle" senior 65 - 74y.......89% use medicines „Old" senior above 75y.......91-98% use medicines Avarage amount of used preparations increase with age Ambulant seniors 4-6 Hospitalised 5-8 prep Administration of MP to old people > physiological changes (organs lose their functional reserve) > worse adaptability to changes in inner or external conditions > poly morbidity (concomitant diseases or chain of diseases) > polypragmasia (administration of many drugs together, risk of drug interactions is increasing) > higher incidence and severity of adverse effects Characteristics of morbidity in old age • Microsymptomatology - asymptomatology (lack of typical symptoms - fever, leucocytosis, silent AMI) • Mono(oligo)symptomatology (tachyfibrillation in thyreotoxicosis) • Non-specific symptoms (tiredness, loss of appetite, weightloss) • Syndrom of secondary impairment (symptoms of another organ than which is the cause of disease e.g. disease of kidney leads to delirant state) • Cascade reaction (chain of diseases) • Atypic reactions to drugs Changes of PD in old age Very variable Tissue hypoxia Dysfunction of regulatory mechanisms Change of sensibility of target structures = hyperergic or paradoxical reactions Changes of PD in old age - examples ATB aminoglycosides: lower doses in case of lower GF (correction according to CL CR) Antihypertensives: orthostatic hypotension, psychical alternations (confusion) Anticoagulants: bleeding from GIT (decreased absorption of vitamin K and decreased synthesis of prothrombin) NSAID: in 25% hematemesis Anticholinergic drugs: higher toxicity, depression, confusion The most often mistakes in prescription in old age underprescribing not prescribing drugs with proven benefit (statins, AD, ACE-I) overprescribing drugs which are not indicated (hypnotics, BZD, peripheral vazodilatants, nootropics ^imperative drugging" prescribing drugs for each disease per se prescription with risk of interactions prescription of drugs with risky profile drugs CI due to comorbidities (|3-blockers + COPD) Drugs not suitable in old age Mark H. Beers, 54, Expert on Drugs Given to Elderly, Dies Feb 28, 2009 Beers1 List — Potentially Inappropriate Medications for the Elder Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of US consensus panel of experts. Arch Intern Med. 2003;163:2716-2724 Gender Women are in general more sensitive to effects of some drugs because of lower weight, but also of lower CL (olanzapine) Specific periods are: menstruation gravidity lactation menopause Pregnancy • slowed stomach and intestinal motility • increased volume of plasma • body water can be raised by up to 8 litres • occupancy rate of plasma proteins by hormones, • relative hypoalbumineamia • increased blood flow through kidneys and increase of GFR • changed liver enzymes activity (some stimulated, some inhibited) Safety of medication in pregnancy Consider - Dose - Lenght of therapy - Ability of drug to cross placentar barrier - Ability of the baby to eliminate the drug - Cummulation of the drug in the baby or in the water - Period of gestation when the drug is administered Safety of medication in pregnancy 1) Period of implantation - all or nothing (14 days) 2) Organogenesis - the most sensitive period to teratogenic effects of drugs (till 12th week) 3) Fetal period - relatively safer when considering teratogenic effects, but risky in toxic eff. 4) Last month of gravidity - long acting drugs can affect newborn ! 5) Lactation Pregnancy and Lactation Labeling Rule FDA Pharmaceutical Pregnancy Categories Category A Adequate and well-controlled human studies demonstrate no risk. Prescription Drug Labeling USE IN SPECIFIC POPULATIONS, Subsections 8.1 to 8.3 PRE PUR LABELING PLLR LABELING Animal studies demonstrate no risk, but no human studies have been performed. Category B OR Animal studies demonstrate a risk, but human studies have demonstrated no risk. Animal studies demonstrate a risk, but no human Category C studies have been performed. Potential benefits may outweigh the risks. Human studies demonstrate a risk. Potential benefits may outweigh the risks. Animal or human studies demonstrate a risk. The risks outweigh the potential benefits. 8*1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.1 Pregnancy 8*2 Lactation . . Females and Males of ■** Reproductive Potential Category D Category X 26 Pregnancy and Lactation Labeling Rule The final rule requires that for the labeling of certain drug products (as described in the "Implementation" section of this document), the subsections "Pregnancy," "Nursing mothers," and "Labor and delivery" be replaced by three subsections entitled "Pregnancy," "Lactation," and "Females and Males of Reproductive Potential." The final rule also requires the removal of the pregnancy categories A, B, C, D, and X from all drug product labeling. - Previous FDA classification was not suitable for practical use - Drugs are no more classified into categories - Detailed characterisation of possible use of the drug in pregnancy or in lactation - Also SPC contains information on influence of the drug on fertility 27 Teratogenic drugs include: remember of "TERATOWA" Thalidomide Epileptic medications (Valproic acid, Phenytoin) Retinoid (Vitamin A) ACE inhibitors, ARBs Third element (Lithium) Oral contraceptives, Hormones Warfarin Alcohol General recommendations Prescription for women in fertile age 1. Prescribe medicines which were tested for teratogenicity 2. Newly registered drugs should be prescribed only if older (time-proven) drugs cannot be used 3. If known teratogenic drug cannot be avoided, contraception is necessary General recommendations Prescription for pregnant women 1. Choose proven medication before pregnancy if chronic therapy is necessary 2. Sudden discontinuation may provoke worsening of the condition with possible severe consequences for both mother and child 3. Prefer monotherapy with the lowest dose possible Lactation Almost all of the drugs given to mother gets into her milk (apart from big molecules), however often in very small amount - depends on characteristics of the molecule (size, lipophility, binding to proteins in mother's plasma, ionisation) - milk is mildly acidic - drugs which cross the barrier easiest are typically small molecules, lipophylic, weak bases and non-ionised Lactation - drugs given to mother only locally or in small amount (nose or eye drops, inhalant sprays, topical preparations applied on small area) do not reach the baby in significant concentrations - the relative infant dose is the dose received via breast milk (mg/kg/day) relative to the mother's dose (mg/kg/day). It is expressed as a percentage. - A relative dose of 10% or above is the notional level of concern, but this is rare (e.g. Lithium) 32 Safety of medication during lactation Possible risk for breast-fed child depends on • Amount of the drug fed in breast-milk to the baby • PK of the drug in the baby (t1/2) • Safety profile of the drug • Health state of the baby General recommendations 1. Adjust time of administrations and feeding - Generally the most suitable pattern is to feed baby 1-3h after administration of the drug (exceptions - amoxicilin 4-6 h, metylprednisolon 8 h, caffeine 0,5 h). 2. The safest is to use drugs, which can be administered once a day 3. In this case the drug should be given after evening feeding, before child's longest sleep 34 Drugs Contraindicated During Breastfeeding • Amiodarone • Hypothyroidism reported • Antineoplastic • Possible immune suppression, agents effect on growth • Chloramph. • (May->idiosyncratic BM supp. at high cone, in breast milk ) • Ergotamine • Vomiting,diarr.,convulsion (dose>migraine) • Gold salts • Possible facial edema in one infant 3 mo. after Rx in mother • Lithium • Severe rash reported • Phenindione • Increased PT & PTT in 1 infant Drugs Contraindicated • Retinoids •Very lipid soluble,wide range of AEs in adult, mutagenic & carcinogenic in animals • Tetracycline •Staining immature teeth, change in (chronic-months) epiphyseal bone growth • Pseudoephedrin •Unpublished result, may inhibit e prolactin & milk production significantly • Radioactives •Temporary cessation of BF, based on presence of radioactivity in milk • Combined oral •Dec.breast milk product0, dec.protein contraceptives & nitrogen content of milk Drugs stimulating milk production = galactogogues Domperidone and metoclopramide - D antagonists - used off-label to stimulate prolactin and enhance milk supply - do not have high evidence of efficacy for this indication, risk of arrhytmias! Other drug increasing milk production - side effects Imipramine, fenothiazin, Sulpirid, haloperidol, reserpin, metyldopa, TSH Drugs decreasing milk production Estrogens, ergot alkaloids (very strong effect) androgens, tamoxifen, bromocriptine, levodopa, barbiturates, apomorphin, diuretics, 1st generation of antihistaminics, pyridoxin (in very high doses) Where to look for information? Product information - SPC State-based obstetric drug information services provide detailed advice on the use of drugs during lactation and should be able to advise about past clinical experience with the drug. 38 Gravidity - European Network of Teratology Information Service (ENTIS) -UKTeratology Information Service (UKTIS) - The Australian categorisation system for prescribing medicines in pregnancy https://www. taa.aov.au/prescribing-medicines-preanancv-database Lactation - Drugs and Lactation Database (LactMed) https://www.ncbi. nlm. nih.gov/books/NBK501922/ 39 LactMed 11 is a freely accessible, well-resourced and peer-reviewed online database. It is updated to keep pace with new information, including published studies and drug approvals. It also incorporates information on complementary treatments. UNI ED Drugs used in dentistry Updated Drugs and Prcgiiimcy Categories 40 Generic Name Local Anesthetics Articai-ne witn epinephrine ll-upitfacame with epinephrine Lidocain? with epinephrine MepLvicaine plain Mepivicaire w.t.*\ levorordefrin Prilocairte plain Priloiaina w^m spinapli fine B*itiüc*irie Topical Peripherally Acting Analgetics Acetaminophen Asjj.lrln Ibuprofen Ketorolac Centrally Acting Opioid Analgesics Brand Name Septocaine Marcame Xylocaine Carbocai-ne Carbocai ne with tteo-Cobefrřn Citnnast ötanest Forta Tylenol Bayer Advilr Motnn Toradol Aleve. AflíprO* Pregnancy catenary 6 e/D5 Potential R"i&k Fetal bradycardia Fetal bradycardia Potential methemoglobinemia PÓtSPVtial rr.LUliamyglobineiniü Potůňttíi iriethůmůalObinů^iiů Postoarium hemorrhage; premaiure closure of ductus arteriosus Postpartum hemorrhage: premature closure of ductus arteriosus Postpartum hemorrhage; prematuie closure of ductu-s arteriosus Postpartum hemorrhage; .premature closure of dyctu-s arteriosus Codeine -.vit h AcetarrtirKrpnen Tylerbít witn Codoififr C/D1 neonatal respLrawy depression, ana opto withdrawal H/drgcGdone with Acetaminophen C/D5 M&onatal respiratory depression and opioid" withdrawal Hydrocodor.e ■ftjtn Ibuprofen vi-njpťofen C/D1 neonatal iresiJ&sifDfV depression and opioid* withdrawal Osycodone Üvyconttn B/CP neonatal respiratory depression and opioid withdrawal Oxycodone with Acetaminophen Percocet C/D1 Meonatal respiratory depression and opioid" withdrawal Oxycodone with Ibuprofen ComturKK C/Ds Neonatal respiratory depresstonand opioid withdrawal: premature closure of ductus arteriosus Tramadol Uitram C Mibi-StiCS Amoxicillin AmaaiE ArnpxjciJlin .irr: C'^viiiJinali* Aygrr.entm r> Azithromycin Zithromax, J-Pa^Sí e Cepl^ale^i n KefteK e ClindaiYrycin Cleocin DoKycydJne Düfya d Tooth discoloration -and inhibition o-f bone development Erythromycin base E-mycin B Avoid estolate salt FluconaEofe Diflucan C Fetal brachycephaly. cleft pala'e. thinning o* bones Gentamicin Garamycin C/D5 Ototoxicity potential in Fetus Molraniovjsole Flagyl MintCyClirtO DyrtiCir., Mirtäiirt :j COrt^Grtat&l iriOt^ONflS ftrtd CnfirViGl hypoplasia Penicillin V Ptn-Vee k r> Tet racycline Te-trstyCliiií1 gen^-nc ■5 Materr>al he palo* icily and enamel hypoplasra: Sedatives/Ann ic-lyci-cs Afprazolam Diazepam Lorazepam MidozOtorTr Triůiůfam Other E3i ph en hy<1 famine Epinephrine řlumazenil Phentolarnine Xanax Valium Ativan Versed Halcion Benadryl Epinephrine Roma?: icon Ora Verse tpoth discoloration Congenital m-alformations, wl Congenital m-alformaticns, wi Congenital malformations, wi Congenital malformations, wi Con^enätüi malFormatio^s. wi thtírawal symptoms thdrawal symptoms ithdrawal symptom* itKornwiil symptoms ítKílríiw^l aymp'Orns Potential iof fetal hyperemia Avoid during later and delivery Avoid during laoo^and delivery 4 D1 = Avoid in thirrd (-runt si er. ĎnKiíin.ílefl D1 df-jo* arc cannric-wil PrcgnAnep C^ntfrpDiy Ď when r^kc-n in thiir-ci (FLmnatar. TABLE 2 Key medication considerations during pregnancy and breast-feeding. AGENT FDA PR" CATEGORY SAFE DURING PREGNANCY? SAFE DURING BREAST-FEEDING? Analgesics and Anti-inf lammatoriest Acetaminophen Aspirin Codeine Glucocorticoids (dexamethasone, Prednison«) Hydrocodone Ibuprofen9 Oxycodone B C/D C c c C/D B Yes Avoid Use with caution Avoid* Use with caution Avoid use in third trimester Use with caution Yes Avoid Yes Yes Use with caution Yes Use with caution Antibiotics11'' Amoxicillin B Yes Yes Azithromycin B Yes Yes Cephalexin B Yes Yes Chlorhexidine (topical) B Yes Yes Clarithromycin C Use with caution Use with caution Clindamycin B Yes Yes Clotrimazole (topical) B Yes Yes Doxycycline D Avoid Avoid Erythromycin B Yes Use with caution Fluconazole C/D Yes (single-dose regimens) Yes Metronidazole B Yes Avoid; may give breast milk an unpleasant taste Nystatin C Yes Yes Penicillin B Yes Yes Terconazole (topical) B Yes Yes Tetracycline D Avoid Avoid Local Anesthetics Articaine C Use with caution Use with caution Bupivacaine c Use with caution Yes Lidotaine {with or without epinephrine) B Yes Yes Mepivacaine (with or without levonordefrin) C Use with caution Yes Prilocaine B Yes Yes Benzocaine (topical) C Use with caution Use with caution Dydonine (topical) c Ves Yes Lidocaine (topical) B Yes Yes Tetracaine (topical) c Use with caution Use with caution Sedatives Benzodiazepines D/X Avoid Avoid Zaleplon c Use with caution Use with caution Zolpidem c Use with caution Yes Emergency Medications Albuterol c Steroid and p^-agonist inhalers Yes are safe Diphenhydramine B Yes Avoid Epinephrine C Use with caution Yes Flumazenil c Use with caution Use with caution Naloxone c Use with caution Use with caution Nitroglycerin c Use with caution Use with caution * FDA PR: U.S. Food and Drug Administration Pregnancy Risk. See Table 1 for FDA PR category definitions. t In the case of combination products (such as oxycodone with acetaminophen). the safety with respect to either pregnancy or breast-feeding is dependent on the highest-risk moiety, In the example of oxycodone with acetaminophen, the combination of these two drugs should be used with caution, because the oxycodone moiety carries a higher risk than the acetaminophen moiety, t Oral steroids should not be withheld from patients with acute severe asthma. § Ibuprofen is representative of all nonsteroidal anti-inflammatory drugs. In breast-feeding patients, avoid cyclooxygenase selective inhibitors such as celecoxib, as few data regarding their safe use in this population are available, and avoid doses of aspirin higher than 100 milligrams because of risk of platelet dysfunction and Reye syndrome. 11 Antibiotic use during pregnancy: The patient should receive the full adult dose and for the usual length of treatment. Serious infections should be treated aggressively. Penicillins and cephalosporins are considered safe. Use higher-dose regimens (such as cephalexin 500 mg three times per day rather than 250 mg three times per day), as they are cleared from the system more quickly because of the increase in glomerular filtration rate in pregnancy. # Antibiotic use during breast-feeding: These agents may cause altered bowel flora and, thus, diarrhea in the baby. If the infant develops a fever, the clinician should take into account maternal antibiotic treatment. Thank you for your attention 42