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Teratogenicity dr.elza

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Teratogenicity dr.elza

  1. 1. DRUG INTERACTION By Dr . Elza Emmanuel
  2. 2. DEFINITION MODIFICATION OF RESPONSE TO ONE DRUG BY ANOTHER WHEN THEY ARE ADMINISTERED SIMULTANIOUSLY OR IN QUICK SUCCESSION ie, THE EFFECTS OF ONE DRUG ARE AFFECTED BY THE EFFECT OF ANOTHER DRUG.
  3. 3.  Severity of drug interacton in most cases is highly unpredictable  The doctor must know which drugs are not to be prescribed concurrently
  4. 4. PRECIPITANTDRUG-THE DRUG THAT PRECIPITATE AN INTERACTION OBJECTDRUG-THE DRUG WHOSE ACTION IS AFFECETED
  5. 5. MECHANIISM OF DRUG INTERACTION 1. Pharmacokinetic 2. Pharmacodynamic
  6. 6. PHARMACOKINETIC INTERACTIONS  These interactions alter the concentration of the object drug at its site of action by affecting its absorption,distribution,metabolism or excretion
  7. 7. ABSORPTION  Due to formation of insoluble &poorly absorbed complexes in the gut lumen  Eg:Btw Tetracyclines & calcium/iron salts  Can be minimized by administering two drugs with a gap of 2-3 hours
  8. 8. DISTRIBUTION  Due to displacement of one drug from its binding sites on plasma proteins by another drug  Eg:Quinidine & Digoxin
  9. 9. METABOLISM  Certain drugs reduce or enhance the rate of metabolism of other drugs  Eg:Microsomal enzyme inducers like barbiturates, rifampicin can cause contraceptive failure
  10. 10. EXCRETION  Important in case of drugs actively secreted by tubular transport mechanisms  Eg:Probenacid inhibits tubular secretion of penicillins &cephalosporins and prolongs their plasma t1/2
  11. 11. PHARMACODYNAMIC INTERACTIONS  These interactions are due to modification of action of one drug at the target site by another drug independent of change in its concentration  This results in  Enhanced response-SYNERGISM  Attenuated response-ANTAGONISM  Abnormal response
  12. 12. EXAMPLES  Fall in BP & MI due to use of sildinafil by patients receiving organic nitrates  Severe hyperkalaemia by concurrent use of ACE inhbitors & K+ sparing diuretics  Additive ototoxicity due to use of aminoglycoside in patient receiving furosemide
  13. 13. DRUG INTERACTIONS BEFORE ADMINISTRATION  Certain drugs react with each other and get inactivated if their solutions are mixed before administration  Eg:Penicilln G/Ampicillin +Gentamicin  Thiopentone sodium+Succinylcholine
  14. 14. ADVERSE DRUG REACTION
  15. 15. EXPECTED UNDESIRABLE EFFECTS TYPE A ADRS
  16. 16. SIDE EFFECTS  These are undesirable effects which are observed even with the therapeutic doses of the drug  They are usually mild and manageable  Eg:Promethazine has antiallergic action - Desirable effect,but it also produces sedation in therapeutic doses-Side effect
  17. 17. SECONDARY EFFECTS  These are indirect consequences of the main pharmacodynamic action of the drug  Eg:Development of superinfection after suppression of bacterial flora by antibiotics
  18. 18. TOXICITY  These are exaggerated form of side effects which occur due to overdoses or after prolonged use of the drug  Eg:Bleeding due to high doses of heparin
  19. 19. UNEXPECTED UNDESIRABLE EFFECTS/ TYPE B ADRS/ BIZZARRE EFFECTS
  20. 20. DRUG ALLERGY[HYPERSENSITIVITY REACTIONS]  Allergic responses to drug occur when there has been previous exposure to drug & when this sensitised individual is re-exposed to the same drug again  Drugs may elicit Type I,II,III & IV Hypersensitivity reactions.
  21. 21. TYPE I HSR  Allergy develops with in minutes & lasts for 2-3 hour  Drug causes formation of tissue sensitizing IgE antibodies that are fixed to mast cells or leucocytes.  The subsequent exposure to drug degranulates mast cells or activates leucocytes with release of chemical mediators [histamine,serotonin] of allergy  The patient if untreated suddenly passes into anaphylactic shock.  Eg:Anaphylaxis after parenteral administration of penicillin or radiocontrast media
  22. 22. TYPE II HSR  It results when a drug binds to RBC & is recognised by IgG Ab.  The Ag-Ab reaction triggers the lysis of RBC by complement activation /action of cytotoxic T cell/phagocytosis by macrophages.  Results within 72 hr of drug administration  Eg:Drug induced Thrombocytopenia,SLE after quinidine use
  23. 23. TYPE III HSR  Ag-Ab form complexes which are deposited on vascular endothelium & activate complement  Eg:Glomerularnephritis after giving NSAID
  24. 24. TYPE IV HSR  These reactions are mediated by sensitised T cells following contact with an antigen  Sensitised T cells results in release of cytokines which activate macrophages,granulocytes & natural killer cells  Eg:Contact dermatitis ,Photosensitivity.
  25. 25. GENETICALLY DETERMINED ADVERSE EFFECTS  Drug reactions in some individuals may be qualitatively different from effects usually observed from majority of subjects  The mechanism is of genetic origin  Eg:The genotype with atypical pseudocholine esterases cannot hydrolyse succinylcholine,in that case even the therapeutic dose of sccinylcholine leads to prolonged respiratory failure
  26. 26. IDIOSYNCRATIC DRUG RESPONSES  These are harmful & sometimes fatal reactions that occur in a small minority of individuals,for which the cause is yet poorly understood.  Eg:Malignant Hyperthermia on using halothane ,succinylcholine
  27. 27. TYPE –C [CHRONIC EFFECTS]  Adverse effects that are associated with prolonged use of drug.  Eg:Cushing syndrome after chronic use of prednisolone
  28. 28. TYPE-D[DELAYED EFFECTS]  Adverse effects that occur in patients years after treatment or effects appearing in their children who did not receive the treatment  Eg:Clear cell carcinoma of vagina in the daughters of women who took diethylstilbesterol during pregnancy
  29. 29. TERATOGENICITY By Dr . Elza Emmanuel
  30. 30. DEFINITION Capacity of a drug to cause fetal abnormalities when administered to pregnant mother.
  31. 31. The placenta does not strictly constitute a barrier and any drug can cross it to a greater or lesser extent.
  32. 32. FACTORS THAT DETERMINE THE EFFECTS OF TERATOGENS 1. Point in development when drug exposure occurs 2. Duration of exposure 3. Susceptibility of fetus 4. Dose reaching fetus
  33. 33. Drugs can affect fetus at 3 stages
  34. 34. 1. Fertilization & implantation - conception to 17 days- failure of pregnancy 2. Organogenesis-18 to 55 days- deformities -MOST VULNERABLE PERIOD 3. Growth & development- 56 days onwards-developmental & functional abnormalities.
  35. 35. MECHANISM OF TERATOGENICITY  Poorly understood  Multifactorial 1.Drugs directly affect the process of differentiation 2.Drugs may interfere with the passage of oxygen & nutrients through placenta 3.Deficiency of a critical substance
  36. 36. FDA USE-IN-PREGNANCY RATINGS
  37. 37. CATEGORY -A Controlled studies show no risk Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy.
  38. 38. CATEGORY -B No evidence of risk in humans Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a possibility.
  39. 39. CATEGORY-C Risk cannot be ruled out . Adequate, well- controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk.
  40. 40. CATEGORY - D Positive evidence of risk Studies in humans, or investigational or post- marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective
  41. 41. CATEGORY - X Contraindicated in pregnancy Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk that clearly outweighs any possible benefit to the patient.
  42. 42. CLASSIFICATION BASED ON TERATOGENIC POTENTIAL Category Characteristics Examples A Controlled human studies show no risk Folic Acid Thyroxine B Animal studies OK no human data Paracetamol, Erythromycin C Animal studies not OK no human Data Rifampicin Morphine D Evidence for risk +++ Benefits outweigh risk Antiepileptics X Evidence for risk +++ Risks outweigh benefits Thalidomide Retinoids
  43. 43. COMMON TERATOGENIC DRUGS Alchohol Androgens Anticonvulsants Antineoplastics Iodides Isotretinoin Lithium Methimazole Tetracyclines Warfarin
  44. 44. THALIDOMIDE -A LESSON IN MEDICINE PHOCOMELIA : THIS ABNORMALITY ('SEAL LIMBS') CONSISTS OF AN ABSENCE OF DEVELOPMENT OF THE LONG BONES OF THE ARMS AND LEGS
  45. 45. THALIDOMIDE  Developed in Germany in 1954  Promoted as a tranquiliser and anti emetic  Taken by thousands of pregnant women  Resulted in >10,000 children with birth deformities  Withdrawn in 1961  Has found new uses as an immune modulator & for multiple myeloma
  46. 46. LESSONS FROM THALIDOMIDE  The placental barrier is not effective against most orally administered drugs Animal teratogenic testing can be misleading
  47. 47. PHENYTOIN  Cleft lip/palate,  microcephaly,  mental retardation
  48. 48. VALPROATE NEURAL TUBE DEFECT
  49. 49. ISOTRETINOIN Mental retardation and learning disabilities Eye & ear deformities Cleft lip, cleft palate & other facial abnormalities Heart defects Microcephaly & Hydrocephaly
  50. 50. FETAL ALCOHOL SYNDROME
  51. 51. FETAL WARFARIN SYNDROME Saddle nose; retarded growth; defects of limbs, eyes, central nervous system
  52. 52. YELLOW STAINING OF THE TEETH IN A CHILD EXPOSED TO MATERNAL TETRACYCLINE IN UTERO
  53. 53. DIETHYLSTILBESTROL In 1971, DES was shown to cause clear cell carcinoma, a rare vaginal tumor in girls and women who had been exposed to this drug in utero.
  54. 54. ANTIBIOTICS • Category A: None available • Category B: Penicillins Cephalosporins clindamycin erythromycin metronidazole- 2nd & 3rd trimesters, contraindicated 1st trimester azithromycin acyclovir
  55. 55. GASTROINTESTINAL TRACT • Category A: Doxylamine • Category B: rabeprazole dicyclomine sucralfate bisacodyl loperamide lactulose pantoprazole metoclopramide ranitidine ondansetron
  56. 56. ALLERGIC DISORDERS • Category A: Doxylamine • Category B: chlorpheniramine Cyproheptadine montelukast levocetirizine cetirizine
  57. 57. Category X testosterone estradiol (dipyridamole/aspirin) 3rd trimester simvastatin lovastatin Misoprostol Thalidomide Isotretinoin
  58. 58. TAKEHOME MESSAGES Avoid all drugs during pregnancy unless compelling reasons exist. Folate therapy during pregnancy can reduce spontaneous as well as drug induced malformations.
  59. 59. THANKYOU

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