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Noura Al-Osaimi Fatima Al-Nefaei

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Noura Al-Osaimi Fatima Al-Nefaei

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    1. Noura Al-Osaimi Fatima Al-Nefaei

    2. Questions

    3. Our System in a Balance

    4. Hypersensitivity reactions: Immune-mediated that cause tissue damage Unexpected Different types. Pseudoallergic (anaphylactoid) reactions Non-immune mediated. Direct release of mediators without prior sensitization period. Vancomycin Red man syndrome? pseudoallergic True IgE-mediated ?anaphylaxis.

    5. Drug idiosyncrasy/intolerance responses Mimic immune-mediated drug reactions Major drugs induce idiosyncrasy: ASA NSAIDs ACEIs

    6. Classification of hypersensitivity reactions Different types of hypersensitivity reactions are distinguished by: The time required for symptoms or skin test reactions to appear after exposure to an antigen On type of Ags Or on the nature of organ involvement. Type I: immediate or anaphylactic hypersensitivity Type II: antibody-dependent cytotoxic hypersensitivity Type III: complex-mediated hypersensitivity Type IV: cell-mediated hypersensitivity

    7. Type I: immediate (anaphylactic hypersensitivity) Most common (20% of population) IgE is made in response to allergen (drug). In allergic individuals, IgE >> those without allergies. Th2 cells >> Th1 cells

    8. How can type I hypersensitivity reactions occur?

    9. Type I: immediate (anaphylactic hypersensitivity)

    10. Type I: immediate (anaphylactic hypersensitivity)

    11.

    12. Diagnostic test for type I Hypersensitivity: skin (prick and intradermal) tests RAST (radioallergosorbent test) Serum tryptase Therapeutic consideration of type I hypersensitivity Discontinue drug. Consider epinephrine, antihistamines, systemic corticosteroids, bronchodilators. patient monitoring, if severe

    13. Type II: antibody-dependent cytotoxic hypersensitivity IgG or IgM is made against normal self Ags foreign Ag looks like cell-surface molecule stimulate Abs (IgG, IgM) response? Abs bind to foreign Ag ? attack cell surface. The results: opsonization of the host cells activation of the classical complement pathway causing MAC lysis of the cells ADCC destruction of the host cells by NK cells.

    14. How can opsonization of the host cells occurs?

    15. Opsonization During Type-II Hypersensitivity

    16. How can MAC lysis of the cells occurs?

    17. MAC Lysis During Type-II Hypersensitivity

    18. ADCC destruction of the host cells by NK cells.

    19. ADCC Destruction During Type-II Hypersensitivity

    20. ADCC Apoptosis by NK Cells During Type II Hypersensitivity

    21. Diseases and problems caused by type II hypersensitivity Autoimmune diseases Rheumatic fever (Abs? damage to joints and heart valves) Idiopathic thrombocytopenia purpura (Abs? destroy platelets) Myasthenia gravis (Abs? destroy NM connections). Graves disease (Abs? stimulate the overproduction of THS) multiple sclerosis (Abs ? oligodendroglial cells that make myelin) Reactions to drugs (penicillin)

    23. Type III hypersensitivity Soluble Ag-Ab (IgG or IgM) complex Activate classical complement pathway. Massive inflammation Influx of neutrophils MAC lysis Aggregation of platelats

    25. Examples of type III hypersensitivity: serum sickness (type I and type III) autoimmune acute glomerulonephritis rheumatoid arthritis systemic lupus erythematosus (SLE) some cases of chronic viral hepatitis the skin lesions of syphilis and leprosy

    26. Diagnosis of type III hypersensitivity ESR, C-reactive protein, Immune complexes Complement studies Antinuclear antibody Tissue biopsy for immunofluorescence studies Therapeutic considerations : Discontinue drug. Consider NSAIDs, antihistamines, or systemic corticosteroids.

    27. Type IV: cell-mediated hypersensitivity Delayed hypersensitivity Cell-mediated (NOT Ab-mediated) T8-lymphocytes become sensitized to Ag ? differentiate into cytotoxic T-lymphocytes Examples: Tuberculin test Contact dermatitis

    28. Type IV: cell-mediated hypersensitivity

    29. Type IV: cell-mediated hypersensitivity

    30. Type IV: cell-mediated hypersensitivity Diagnosis: Patch testing Lymphocyte proliferation assay* Therapeutic considerations: Discontinue drug Consider topical corticosteroids, antihistamines, or systemic corticosteroids if severe.

    31. Antimicrobial drugs

    33. Agents that inhibit synthesis of bacterial cell walls:

    34. Agents that inhibit synthesis of bacterial cell walls: Beta Lactams Penicillins (PCN) Carbapenems monobactams Cephalosporins carbacephems

    35. Toxicity of Beta-lactams: PCN All types (I to IV) of hypersensitivity Low direct toxicity (safe) Carbapenems? seizures Monobactams? <<PCN cross-sensitivity Agents that inhibit synthesis of bacterial cell walls:

    36. Toxicity of Beta-lactams: Cephalosporins? < common Broader spectrum ?opportunistic infections (candidiasis, C. difficile colitis). Agents that inhibit synthesis of bacterial cell walls:

    37. Glycopeptides Vancomycin? ototoxic Cycloserine? CNS toxicity Azole: Ketoconazole? inhibit CYP 3A3/4 Fluconazole? alopecia, hepatitis Bacitracin ? one of the top ten allergens implicated in contact dermatitis. Agents that inhibit synthesis of bacterial cell walls:

    38. Agents act directly on the cell membrane of the microorganism

    39. Agents act directly on the cell membrane of the microorganism polymyxin Polymyxin E (colistin) Polymyxin B Highly nephrotoxic & neurotoxic (only topical) polyene antifungal agents Nystatin ? Rare toxicity (poorly absorbed) Amphotericin B ?Nephrotoxicity (80%)

    40. Agents that affect the function of 30S or 50S ribosomal subunit to cause reversible inhibition of protein synthesis (bacteriostatic)

    43. Agents that bind to 30S ribosomal subunit & alter protein synthesis eventually leads to death (bactericidal)

    44. Aminoglycosides Amikacin Gentamicin Neomycin Main toxicity Ototoxicity Nephrotoxicity neuromuscular blockade.

    45. Agents that affect bacterial nucleic acid metabolism

    46. Rifamycins (Rifampin) Brownish-red or orange discoloration of the body secretions. Induce cyp450 (bad for pts on anticoagulants, oral contraceptives, anti-convulsants) Quinolones Nalidixic acid, Ciprofloxacin, Ofloxacin GI disturbance CNS side effects Anaphylactoid react

    47. Antimetabolites (block essential enzymes of folate metabolism

    48. Antimetabolites Sulfonamides Sulfamethoxazole Sulfadiazine Main toxicity: crystalluria, renal failure, bone marrow suppression Kernicterus in infants Hypersensitivity ? Rashes (photodermatitis, Stevens-Johnsons syndrome). Trimethoprim GI disturbance (nausea, vomiting, and glossitis) Folate antagonism Hypersensitivity ? fever & rash

    49. Antiviral agents

    50. Nucleic acid analogs Selective inhibitors of viral DNA polymerase Acyclovir ? Renal & CNS toxicity Ganciclovir ? Bone marrow & CNS toxicity They cause inflammation or phlebitis Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine ? Bone marrow suppression, CNS toxicity, hepatitis, & GI disturbance

    51. Nonnucleioside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine CNS disturbances (infrequent) Dyslipidemia Severe rash, including Stevens-Johnson syndrome, fever, & hepatotoxicity

    52. Inhibitors of other essential viral enzymes Protease Inhibitors (PI) Saquinavir Not life-threatening toxicity GI distress (diarrhea) Inhibition of cytochrome P-450 Dyslipidemia (leading to treatment discontinuation) Inhibitor of influenza neuraminidase Amantadine CNS toxicity Cardiac disturbance (torsades de pointes) Urinary retention.

    53. Drug of the case TMP/SMZ

    54. Trimethoprim-Sulfamethoxazole (co-trimoxazole) Class: Antibiotic (sulfonamide combination) Mechanism of action Sulfamethoxazole (SMZ) Competitively inhibits the synthesis of dihydropteroic acid from PABA in microorganisms Trimethoprim (TMP) Inhibit the enzymatic reduction of dihydrofolic acid to tetrahydrofolic acid.

    55. Therapeutic uses of TMP/SMZ: Urinary tract infection Shigellosis Otitis media travelers diarrhea

    56. Pharmacokinetic of TMP/SMZ ADME Absorption: both are 90-100% absorbed orally. Distribution: both are widely distributed > lipophilic Metabolism: SMZ extensively metabolized in the liver into N4-acetylated and N4-glucuronidated derivatives Excretion: TMP ? 50-75% as unchanged drug. SMZ ? 85% as metabolites & 10-30% as unchanged drug. Half-life: TMP = 11 h SMZ = 10 h

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    75. Precautions group A beta-hemolytic strep infections elderly patients, AIDS patients patients with possible folate deficiency severe allergies,asthma glucose-6-phosphate dehydrogenase deficiency Autoimmune disease Increase bilirubin & jaundice Additional SOAP Format

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    79. When 2 persons take antibiotic drug, the hypersensitivity reaction not necessarily appear in both, but sometimes hypersensitivity reaction developed within minutes and may lead to death if no immediate treatment. For urinary tract infection the trimethoprim alone is effective and safe than sulfonamide combination, which may lead to death due to its action on bone marrow.

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