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Drugs used in special age groups like children, elderly and preganancy

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Drugs used in special age groups like children, elderly and preganancy

  1. 1. Drugs used in special age groups like Children, Elderly and Pregnant Women DR.ROOPALI SOMANI PG RESIDENT MRMC GULBARGA
  2. 2. Contents  Introduction  Drug therapy in Pediatrics  Drug therapy in Pregnancy  Drug therapy in Elderly
  3. 3. Introduction  Clinical responses achieved following drug administration are influenced by o Age of the patient o Relative maturity of particular organ system that is targetted  Age dependent changes in body functions are known to alter pharmacokinetic parameters which determine each compound’s duration of action, extent of drug-receptor interaction, and the drug’s rate of absorption, metabolism and excretion. These differences are important from the therapeutic point of view.
  4. 4. Drug therapy in Paediatrics  Pharmacokinetic process in Paediatric patients Absorption 2. Distribution 3. Biotransformation 4. Elimination  Pharmacodynamic process in pediatric patients  Paediatric dosage forms and compliance 1.
  5. 5. Pharmacokinetic process in pediatric patients I. II. III. IV. V. Absorption: GI factors altering drug absorption: Prolonged gastric emptying time and irregular gut motility interfere with achievement of peak plasma conc of drug Reduced transit time in upper intestine Presence of food decreases absorption of paracetamol, penicillin and ampicillin. High protein diet and low carbohydrate diet increases clearance of theophylline Absorption of lipid soluble drugs reduced in infants as they have low conc of lipase and bile acid .
  6. 6. Oral drug absorption of various drugs in neonate compared with older children and adults Drug Oral absorption Acetaminophen Ampicillin Diazepam Digoxin Penicillin G Sulfonamides Phenobarbital Phenytoin Decreased Increased Normal Normal Increased Normal Decreased Decreased
  7. 7. PARENTERAL ROUTE  Absorption from IM and SC routes is erratic due to low proportion of skeletal mass and fat respectively. Perfusion is diminished to muscles in premature infants eg- digoxin, gentamicin & kanamycin.  IV route should be prefered in serious condition.  Absorption from rectum is adequate eg: diazepam and theophylline
  8. 8. PERCUTANEOUS ROUTE  Drugs are readily absorbed from intact skin as the stratum corneum is thin and skin is well hydrated. Therefore lower dose of drug is required when administered through this route.  Excessive percutaneous absorption has resulted in significant toxicities eg: absorption of hexachlorophene used in soaps has resulted in brain damage and death.  Absorption of napthalene has produced hemolytic anaemia and jaundice esp in infants with G6P deficiency
  9. 9. DISTRIBUTION  Factors determinig distribution of drugs are: a. b. c. d. e. Size of body water compartments Plasma protein binding Degree of development of blood brain barrier Ph and composition of body fluids and tissues Blood flow and tissue specificity for tissue receptor site
  10. 10. Size of body water compartments  Total body water content is high in children ranging from 65% in older children to 80% in neonates, resulting in higher dose of drug in neonates, if calculated on the basis of body weight eg:- aminophylline, digoxin, aminoglycosides, frusemide.  A or in extracellular fluid space such as in diarrhoea and nephrotic syndrome result in higher or reduced plasma conc of drugs. Hence dose needs to be adjusted accordingly.  Dose of drugs calculated on the basis of body surface area Eg: anticancer, immunomodulators, ibuprofen ( hepatic disorders), aminoglycosides ( renal disorders)
  11. 11. Plasma protein binding  Albumin α-glycoprotein and lipoproteins are important plasma proteins.  Higher fraction of unbound (free) drug due to: 1. Reduced concentration of plasma proteins in infancy 2. Decreased affinity for drug binding eg: digoxin, theophylline, 3. High conc of endogenous compounds such as bilirubin, hormones transferred through placenta, free fatty acids which compete with drugs for binding . Eg; phenytoin 4. Disease states leading to reduced plasma proteins eg: PEM, nephrotic syndrome. 5. Decreased binding in disease states.
  12. 12. Blood brain barrier  Blood brain barrier is not well developed, so drug penetration is more in CNS eg: unconjugated bilirubin, lipid soluble drugs, morphine.  Acidosis, hypoxia, hypothermia and hypoglycaemia often associated in disease states in newborn and infants confound the problem leading to enhanced penetration.
  13. 13. Biotransformation of drugs  Drug metabolizing enzymes are immature in neonates, so drug     metabolizing capacity limited. Phase 1 oxidation reaction and glucoronidation are immature at birth hence increased toxicity eg: chloramphenicol produces gray baby syndrome. Plasma esterases are reduced in infants leading to prolonged apnoea due to succinylcholine. Sulfation reaction more active in infants and children leading to more toxic metabolite of paracetamol. Drug metabolism is faster for certain drugs after 1st year of life leading to reduced t ½. Eg; theophylline, phenytoin, carbamazapine, phenobarbitone.
  14. 14.  Enzyme induction: clinically used to treat neonatal jaundice by using phenobarbitone  Therapeutic effect of drug decreases due to reduced plasma conc of drugs in neonate born to mother who is receiving enzyme inducer like phenobarbitone.
  15. 15. Elimination  GFR is low and tubular transport not fully developed at term, gradually increases in about 5-7 months and by 1 year function reaches to adult level .  Hence dose of drugs eliminated by kidney should be reduced in infants eg: aminoglycosides, diuretics.  t1/2 of theophylline and prednisolone are reduced due to high plasma clearance. t1/2 of ampicllin, digoxin and certain drugs increased due to reduced renal clearance  In patients with renal insufficiency dosage guides are based on serum creatinine levels.
  16. 16. Drug Plasma half life ( hours) Neonate Adult Diazepam Plasma t1/2 of some of the drugs in neonate and adult 25-100 40-50 Phenobarbital 0-5 days 5-15 days 1-30 months 200 100 50 64-140 Digoxin 60-70 30-60 Paracetamol 2.25 0.9-2.2 Salicylate 4.5-11 10-15 Theophylline 13-26 10-15
  17. 17. Age related maturation of selected systems System Age adult level attained 1. Gastric acid production 3 months 2. Gastric emptying 6-8 months 3. Hepatic metabolism • 5 months-5 yr • 4. Phase I enzyme reactive Phase II enzyme reactive 3-6 months Excretion Glomerular filtration 3-5 months Tubular secretion 6-9 months Renal blood flow 5-12 months
  18. 18. Pharmacodynamic alterations  Response of drug may be different in pediatric age group and     adults though mechanism of action is same. Possibly due to immature receptors or neurotransmitters system. Antihistaminics and barbiturates cause paradoxical excitement while amphetamine decreases abnormal hyperactivity in children Sensitivity to succinyl choline reduced while response to dtubocurarine enhanced. Premature infants are less sensitive to vasoconstrictive action of adrenaline and mydriatic action of phenylephrine. Indomethacin is used for closure of patent ductus arteriosus, while alprostadil is used to keep it open.
  19. 19. Adverse drug reactions Glucocorticoids affect the growth and development due to premature fusion of epiphysis Delayed development of bone and teeth occur due to tetracycline beacuse of their affinity to calcium containing tissues. Drug Reaction furosemide nephrocalcinosis Indomethacin Renal failure, bowel perforation Adrenocorticoids Increased intracranial pressure, growth suppression Tetracyclins Discoloured teeth Phenobarbital Hyperactivity, impaired intellectual development Phenytoin Thickened skull coarse features Chloramphenicol Grey baby syndrome Aspirin Reye syndrome in viral fever Valproic acid Fetal hepatotoxicity Hyperosmolar drugs Intraventricular haemorrhage Fluroroquinolones Juvenile arthropathy Pediatric specific adverse drug Sulphonamides Kernicterus in neonates reactions
  20. 20. Pediatric drug dosage  Dose calculation on the basis of age, surface area and weight Based on age (young’s rule)  Dose Adult dose x Age ( years) Age +12 Based on weight  Dose = Adult dose x weight(kg) 150
  21. 21. DRUGS USED IN ELDERLY  Pharmacokinetic changes Absorption 2. Distribution 3. Metabolism 4. Elimination  Pharmacodynamic changes  Major drug groups  Adverse drug reactions in elderly 1.
  22. 22. PHARMACOKINETIC CHANGES  Absorption: factors affecting GI absorption 1. altered nutritional habits 2. Greater consumption of non prescription drugs 3. Slower gastric emptying time DISTRIBUTION: Reduced lean body mass 2. Reduced body water 3. Increased fat 4. Decreased serum albumin 5. Increased α- acid glycoprotein These changes alter the loading dose of drug. 1.
  23. 23. Changes related to aging that affect pharmacokinetics of drugs Variable Young adult (20-30 years) Older adult (60-80 years) Body water (% of body weight) 61 53 Lean body mass 19 12 Body fat 26-33 (women) 18-20 (men) 38-45 36-38 Serum albumin(g/dl) 4.7 3.8 Kidney weight(%of young adult) 100 80 Hepatic blood flow(%of young adult) 100 55-60
  24. 24. Metabolism o Metabolizing capacity of liver is decreased only for certain drugs. o Greatest changes are seen in phase I reactions o Conjugation reactions are not significantly affected o Decreased hepatic blood flow causes i. ii. slower metabolic inactivation of drug Decreased first pass metabolism of drugs Eg: neuroleptics,TCA. o Decreased induction of hepatic enzymes with drugs eg- rifampicin o Decline with age of the liver’s ability to recover from injury o Malnutrition and diseases that affect hepatic function are more common in elderly
  25. 25. Effect of age on hepatic clearance of some drugs Age related decrease in hepatic clearance found No age-related difference found Alprazolam Ethanol Barbiturates Isoniazid Clobazam Lidocaine Diazepam Lorazepam Flurazepam Nitrazepam Imipramine Oxazepam Nortriptyline Prazocin Propanolol Salicylate Theophylline Warfarin Tolbutamide
  26. 26. Elimination • 1) 2) 3)     Renal parameters reduced are: Renal blood flow Glomerular filtration Tubular secretion Serum creatinine level may be in normal range Toxicity may result with drugs mainly eliminated through kidney and having narrow therapeutic index eg: lithium, digoxin. Lungs are important for excretion of volatile drugs. As a result of reduced respiratory capacity and increased incidence of active pulmonary disease in elderly, parenteral anaesthetic agents are preferred over inhalational. In patients with renal insufficiency dosing schedule based on serum creatinine level and creatinine clearance level
  27. 27. Formula for dose calculation in renal insufficiency Normal therapeutic dose Dose for a case of renal insufficiency Serum creatinine level (mg/dl) CORRECTED DOSE = NORMAL DOSE X PATIENT’S CREATININE CL NORMAL CREATININE CL
  28. 28. Cockcroft- Gault formula If only the adult dose is known for drug that requires renal clearance , correction can be made using this formula Creatinine clearance (ml/min) (140-age) x weight(kg) 72 x serum creatinine (mg/dl)
  29. 29. Pharmacodynamics Pharmacodynamic changes with age include receptor alterations(change in number and sensitivity), impaired signal transduction and decreased homeostatic regulation. Response decreased Response increased •Reduced sensitivity of Response to β agonists and β baroreceptors ,more chances of blockers is reduced due to reduced number of β receptors orthostatic/postural hypotension •Enhanced response to sedativehypnotics and more respiratory depression . •Intolerance to digitalis •Greater response to coumarin
  30. 30. Factors affecting the occurence of ADR in elderly patients Prior disease Ageing Impaired organ function Altered drug concentration Altered end organ response Decreased homeostatic regulation Adverse drug reaction Multiple disease states Multiple drug administration Altered compliance
  31. 31. Adverse drug reactions in elderly  Overall incidence of ADR is 2-3 times found in young adults  Commonly used drugs causing unwanted adverse effect: 1. 2. 3. 4. 5. 6. Postural hypotension-TCA, levodopa, bromocriptine Constipation-anticholinergics, antidepressants, nifedipine Urinary incontinence- β blockers, diuretics, labetolol, antipsychotics. Depression-antipsychotics, anxiolytics,methydopa Confusional stateanticholinergics, antihistaminics, theophylline, β blockers, anticonvulsants. Loss of postural reflexes (fall)benzodiazepines, neuroleptics, antihistaminics, antidepressants.
  32. 32. Major drug groups DRUGS TO BE AVOIDED Reasons SAFER ALTERNATIVES Diazepam, barbiturates, Prolonged half life due to decreased hepatic and renal clearance Oxazepam. Lorazepam, alprazolam Indomethacin, piroxam CNS side effects Ibuprofen, Cox-2 inhibitors Phenothiazine analogues Haloperidol analogues Greater risk of extrapyrmidal side effects and postural hypotension Thioridazine, olanzapine, risperidone, aripiprazole Tricyclic antidepressants Anticholinergic side effects SSRI Tacrine for alzheimer’s CNS toxicity because of anticholinergic activity Donepezil, rivastigmine, galantamine Propanolol, methyldopa, for hypertension Postural hypotension, propanolol should not be given in asthamatics Thiazides in low doses, selective β1 blocker , CCB, ACE inhibitor Platelet inhibitorsdipyridamole Coronary steal phenomenon Clopidogrel or aspirin
  33. 33. Drugs used in pregnancy  Physiological changes during pregnancy  Pharmacodynamics  Teratogenic actions  Common problems in pregnancy and safe drugs
  34. 34. Physiological changes during pregnancy  Pharmacokinetic changes  Absorption  Distribution  Metabolism  Elimination  Factors affecting placental drug transfer and drug effects
  35. 35. Pharmacokinetic changes  Absorption: Gut motility is reduced but no significant effect on absorption, onset may be delayed 2. Vasodilatation leads to increased tissue perfusion, absorption on IM administration is highly effective  Distribution: 1. Total body water due to haemodilution, so large volume of distribution for water soluble drugs 2. Plasma albumin concentration 3. Increased body fat acts as a reservior of lipid soluble drugs 1.
  36. 36.  Metabolism Hepatic metabolism is increased though blood flow to liver 2. Drugs metabolized by liver have increased clearance 1.  Elimination 1. Renal blood flow is doubled hence rapid elimination of drugs excreted by kidney eg: amoxycillin, and if it is used to treat systemic infection its dose should be doubled but for the treatment of UTI, as amoxycillin gets concentrated in urine there is no need to change the dose
  37. 37. Factors affecting placental transfer of drugs  Critical factors affecting placental drug transfer and drug affects on the fetus include 1. The physiochemical properties of drug 2. Rate at which drug crosses placenta and amount of drug reaching fetus 3. Duration of exposure to the drug 4. Distribution characteristics in different fetal tissues 5. Stage of placental and fetal development at the time of exposure 6. Effect of drug used in combination
  38. 38.  Lipid solubility 1. 2. Drug passage across placenta depends on lipid solubility and degree of drug ionisation eg: thiopental, being lipid soluble diffuses readily across placenta Impermeability of placenta to polar compounds is relative rather than absolute . If high enough maternal-fetal concentration gradients are achieved, polar compounds croses the placenta in measurable amounts.eg: salicylate
  39. 39. Molecular size and ph  Molecular weight influences the rate of transfer and amount of transfer  Drugs having molecular weight 250-500 cross easily, those with mol weight 500-1000 cross with more difficulty  Drugs with mol wt >1000 cross very poorly Eg: choice of heparin as an anticougulant is based on this property, because it is very large and polar ,heprin is unable to cross placenta  Placenta contains drug transporters which can carry large molecules to the fetus eg: maternal antibodies  Ion trapping of weakly basic drugs having pKa >7.4
  40. 40.  Placental transporters: p-glycoprotein encoded by MDR1 gene pumps back into the maternal circulation a variety of drugs eg: vinblastine, doxirubicin. 2. Viral protease inhibitors are substrates of P- glycoprotein. 3. Glyburide is effluxed by BCRP transporter as well as by MRP3  Protein binding A. Degree of protein binding affects the rate of transfer across placenta B. Lipid soluble drugs are not much affected by plasma protein binding and is more dependent on placental blood flow C. Differential protein binding- eg sulfonamides, barbiturates, phenytoin 1.
  41. 41. Placental and fetal drug metabolism  Mechanism of placental metabolism 1. Placenta is semipermeable 2. It is a site of metabolism, several types of oxidation reaction are 3. known to occur( hydroxylation, N-dealkylation, demethylation). Eg: Phenobarbitol is oxidised by this way. Metabolic capacity of placenta may lead to productin of more toxic metabolite eg: ethanol. Fetal metabolism 1. Drugs enter fetal circulation via umblical veins. 40-60% of umblical venous blood passes through the fetal liver, hence a drug maybe partially metabolized before reaching general fetal circulation 2. Drug present in umblical artery may be shunted through the placenta to the umblical vein and into the liver again
  42. 42. Effect of drug on stage of foetal development  The foetal age, drug dosage and potency determine the magnitude and seriousness of a drug on foetal development .  Drugs given during embryonic or zygotic stage(before the 20th day of gestation) may have an all or none effect, either killing the embryo or not affecting it all.  Drugs given during organogenesis (4-10 weeks)may produce 1. No measurable effect 2. Abortion 3. A sublethal gross anatomic defect 4. A permanent subtle metabolic or functional defect
  43. 43. Effect of drugs in late preganancy Effect Likely drug Masculinization Sex hormones Foetal goiter Effect of drugs during labour Effect Drug Respiratory depression Opoid analgesics Sedatives and GA Antithyroid drugs Tooth and bone development Tetracyclins Foetal distress ( due to reduced uterine blood flow) Growth retardation Corticosteriods Prolongation of labour Sedatives and GA Onset of labour is delayed, impaired cns development NSAIDS eg aspirin, indomethacin Hypotonia bezodiazepines Floppy baby syndrome Lithium
  44. 44. Drugs with significant teratogenic effects Drug Trimester Effect ACE Inhibitors All Renal damage Carbamazepine First Neural tube defects Clomipramine Third Neonatal lethargy, hypotonia, cyanosis Lithium First, third Ebstein’s anamoly Methotrexate First Multiple congenital malformation Methythiouracil All Hypothyroidism Phenytoin All Fetal hydantoin syndrome Valproic acid All Neural tube defects Warfarin First Second Third Hypolastic nasal bridge, CNS malformation Risk of bleeding
  45. 45. Pharmacodynamics  Maternal drug actions Endocrine environment appropriate for pregnancy alters the effect of drugs on reproductive tissues such as breast and uterus 2. Cardiac glycosides and diuretics may be required for heart failure precipitated by increased cardiac work loaad during pregnancy 3. Insulin may be required to control blood sugar level in pregnancy induced diabetes mellitus 1.
  46. 46. Effect of drug on foetus  Therapeutic effect: drugs are administered to pregnant women targeting foetus Corticosteroids: used for lung maturation 2. Phenobarbitone: prevents neonatal jaundice 3. Zidovudine or nevirapine: inhibits transmission of AIDS to foetus from mother 1.  Predictable toxic effect: 1. 2. 3. Opoids : respiratory depression ACE inhibitors: congenital anomalies Diethylstilboesterol: vaginal carcinoma in female offspring
  47. 47. Teratogenic effect  Teratogen : any drug or substance is labelled teratogen if: 1. It produces characteristic sites of malformation with selectivity for certain organs 2. Exerts its effect at a particular stage of fetal development 3. Shows a dose dependent incidence Teratogenic mechanism: poorly understood 1. Indirect action: vasoconstriction leads to reduced uterine blood supply and thus fetal anoxia. Eg: prostagladin analogues, ergot alkaloids 2. Direct action on process of differentiation eg: vitamin A analogues produce significant teratogenic effect by altering the normal process of differentiation. 3. Deficiency of a critical substance may cause abnormality eg: spina bifida due to folic acid deficiency
  48. 48.  Continuous exposure to a teratogen may produce cumulative effect or may affect multiple organs which are undergoing development eg: chronic alcohol consumption leads to undergoing development, facial abnormalities  Direct action: eg : thalidomide when administerd during 4-8 weeks causes phacomelia as arms and legs are developed in this period
  49. 49. FDA category/rating of drugs in pregnancy Category Risk Example A No foetal risk shown in controlled human studies Folic acid B Animal studies have not demonstrated a fetal risk , but there are no controlled studies in pregnant women Metronidazole C Studies in animals have revealed adverse effect on fetus Most of the drugs (teratogenic or embryocidal ). Drugs should be given only if the potential benefits justifies the potential risk to the fetus D Fetal risk shown in human studies, but the benefits from Phenytoin use in pregnant women may be acceptable despite the risk( eg; if drug is needed in life threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective) X Proved teratogen, contraindicated in pregnancy Thalidomide
  50. 50. Common problems in pregnancy and safe drugs            Nausea and vomiting: pyridoxine, meclizine diphendyramine Constipation: mild purgative like senna Peptic ulcer: sucralfate, H2 blockers Haematopoitic: iron and folic acid used Urinary tract infections: ampicillin ,amoxycillin,cefurixime axetil Other infections: βlactam antibiotics, cephalosporins, Malaria: chloroquine, quinine, proguanil Amoebiasis: metronidazole and diloxanide furoate Worm infestation: piperazine citrate, pyrantel pamoate Fungal infection: miconazole, clotrimazole, nystatin HIV infection: none of the anti HIV drugs are safe, but zidovudine and nevirapine are considered safe  Tuberculosis : INH and ethambutol are safe. If third drug is needed then rifampicin
  51. 51.          Diabetes mellitus: insulin Hypothyroidism : thyroxine Thyrotoxicosis : propylthiouracil Hypertension :α methydopa , emergency- hydralzine , β blockers – labetolol, atenolol Thromboembolic disease: heparin Headache & inflammatory condition: paracetamol, avoid other Nsaids Epilepsy: sodium valproate and phenytoin must be avoided, carbamazepine used in lower dose Migraine: paracetamol, propanolol, amitriptyline Antidepressants: amitriptyline amd imipramine
  52. 52. References  Bertram and katzung’s .Basic and clinical Pharmacology 12th edition.  S D seth , Vimlesh seth. Textbook of Pharmacology 3rd edition.  S K Srivatsava. A complete textbook of medical Pharmacology  H L Sharma, K K Sharma. Principles of Pharmacology 2nd edition.

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