• Information
  1. Classification of ADRs
  2. Types of Typical Reactions
  3. Exaggeration of Intended Pharmacologic Effect
  4. Secondary Pharmacologic Drug Effects - Side Effects
  5. Toxicity Independent of Known Pharmacologic Effects
  6. Common Clinical Presentations
  7. Drug Induced Hepatitis
  8. Antibiotic Allergies
  9. Drug Induced Lupus Erythematosus
  10. Considerations in Evaluation of ADRs

A. Classification of ADRs [2,3]

1. Dose Related (Augmented)
2. Non-Dose Related (Bizarre)
3. Dose and Time Related (Chronic)
4. Time Only Related (Delayed)
5. Withdrawal (End of Use)
6. Failure of Therapy (Failure)

B. Types of Typical Reactions [3]

1. Related to enhanced predictable pharmacologic effect of drug
   1. Most frequent and can occur in any patient
   2. May be related to drug's primary or secondary pharmacologic use
   3. Accout for ~80% of ADRs
   4. Type A ADRs
2. Unrelated to pharmacologic action - idiosyncratic [8]
   1. These are type B ADRs, less frequently observed than Type A
   2. Often hypersensitivity or allergy (pseudoallergy)
   3. Often unpredictable, and outcome therefore may be severe
   4. Unclear mechanisms in many cases
   5. Blood dyscrasias most likely included here
   6. Likely related to patients genetic makeup and/or comorbid conditions
3. Allergic Drug Reactions
   1. True hypersensitivity reactions (Type B ADRs)
   2. Immune response may be of any of the four hypersensitivity types (see below)
   3. Anaphylactoid (non-specific histamine release) reactions
   4. Idiosyncratic Reactions (above)
   5. Severe cutaneous reactions usually included

C. Exaggeration of Intended Pharmacologic Effect

1. Typically seen with drug overdose
2. Examples
   1. Morphine - respiratory arrest
   2. Insulin - hypoglycemia
3. Abnormal Host Factors
   1. Abnormally high concentration of drug at active site due to subject variability
   2. Decreased volume of distribution (Vd) - often due to abnormal fat stores
   3. Unusual metabolism - particularly hepatic
   4. Excretion abnormal - particularly renal
   5. Electrolyte abnormalities - often aggravate cardiac effects; usually potassium, calcium
4. Steep Dose-Response Curve
   1. Patients are more likely to develop toxicity with small dose increase
   2. Examples include: digoxin, lithium, phenytoin (Dilantin®)
5. Concomittant Drug therapy
   1. Protein binding drug
   2. Metabolism altering drugs
   3. Excretion altering drugs
   4. Drugs acting on same system may demonstrate synergistic toxicity

D. Secondary Pharmacologic Drug Effects - Side Effects

1. Effects caused by same mechanism responsible for drug's primary effect
   1. Aspirin - GI distress and/or renal dysfunction due to prostaglandin inhibition
   2. Anti-neoplastic drugs - anemia, pancytopenia, alopecia
   3. Diuretics - hypokalemia or hyperkalemia (depends on agent)
2. Effects due to other pharmacologic mechanisms
   1. Minoxidil - increased hair growth (unclear mechanism)
   2. Spironolactone - gynecomastia (estrogen like effects)
   3. Heparin - hair loss, thrombocytopenia (autoimmune reaction)
   4. ACE Inhibitors - angioedema due to inhibition of bradykinin and substance P degradation
   5. Warfarin - skin necrosis associated with Protein C deficiency
3. Drug-Induced Methemoglobinemia [6]
   1. Rare consequence of exposure of normal red cells to various oxidizing drugs
   2. Methemogloblin is oxidized hemoglobin (Hb) that cannot properly carry oxygen
   3. Methemoglobin is normally reduced back to Hb by NADH-dependent cytochrome b5-methemoglobin reductase system
   4. Several drugs associated with methemoglobinemia
   5. Dapsone
      1. Nitrates - nitroglycerin, nitroprusside
      2. Sulfonamides
      3. Primaquine
   6. Benzocaine
   7. Increased risk of methemoglobinemia in patients with G6PD deficiency
   8. Treatment with oxygen and drug-binding agents
   9. Methylene blue should be given if symptomatic but not to G6PD deficient persons
   10. Methylene blue reduces methemoglobin to Hb rapidly

E. Toxicity Independent of Known Pharmacologic Effects

1. Type B ADRs
2. Metabolic Enzyme Defects
   1. Hepatic acetylator status: procainamide, hydralazine, sulfa, isoniazid
   2. Mixed function oxidase system - usually cytochrome P450 systems
   3. Epoxide hydrolase deficiency - phenytoin toxicity (hepatotoxic, hypersensitivity)
3. Other Systems
   1. Glucose 6-phosphate dehydrogenase deficiency - hemolysis (sulfa drugs, chloroquine)
   2. Plasma pseudocholinesterase deficiency - succinylcholine toxicity
4. Toxic Reactions
   1. Reactive metabolite which binds to and destroys macromolecules
   2. Results in tissue damage
5. Examples of Type B ADR Syndromes
   1. Isoniazid - hepatitis [16], associated with slow acetylator phenotype for drug (NAT2 gene)
   2. Acetaminophen - liver necrosis associated with glutathione depletion (such as alcoholics)
   3. Sulfa drugs - hepatitis, rash, fever
   4. Statins - drug induced hepatitis, rhabdomyolysis (very uncommon)
   5. Cerivastatin (Baycol®) - withdrawn from market due to fatal rhabdomyolysis [11]
6. Immunologically Mediated Reactions
   1. Linkage of drug to larger macromolecules with stimulation of immune response
   2. Most often seen with penicillins; lesser extent with cephalosporins [10,19]
   3. Likely that many idiosyncratic reactions have an immunological basis
7. Immune response may be of any of the four hypersensitivity types:
   1. Type I: IgE mediated: urticaria, anaphylaxis
   2. Type II: Antibody + Complement mediated: hemolytic anemia, cytopenia, nephritis
   3. Type III: Immune Complex Disease: drug fever, serum sickness, ? cutaneous reaction
   4. Type IV: Delayed Hypersensitivity (DTH): contact dermatitis; multiple subclasses
8. Anaphylactoid and Idiosyncratic Reactions
   1. Aspirin and Nonsteroidal Drugs: mast cell degranulation, as in "triad" asthma
   2. Radiocontrast media: activation of complement system
   3. Ampicillin with Epstein-Barr Virus infection: maculo-papular eruptions
   4. Sulfa drugs (especially in HIV infection): rash
   5. Chloramphenicol: aplastic anemia
   6. Abacavir (Ziagen®) hypersensitivity reaction linked to HLA-B*5701, -DR7, and -DQ3 [14]
   7. Witholding abacavir from white patients with HLA-B*5701 reduced hypersensitivity to 0% [20]
9. Subclassifciation of Type IV (DTH) Drug Reactions [18]
   1. Type IVa: T cells recruit primarily monocytes
   2. Type IVb: T cells recruit primarily eosinophils
   3. Type IVd: T cells recruit primarily neutrophils
   4. Type IVc: cytotoxic CD4+ or CD8+ lymphocytes (pariticipate in all above reactions)
10. Skin Lesions Asssociated with DTH Reactions [18,19]
    1. Maculopapular exanthema - mainly CD4+ perforin+ or granzyme B+ T cells kill keratinocytes
    2. Vessicles and bullae due mainly to cytotoxic CD8+ T cells in epidermis
    3. Eosinophilic infiltrates mainly associated with IL5 and eotaxin production
    4. Mucous membrane involvement usually associated with elevated CRP levels
    5. Systemic symptoms with skin lesions - assess liver function tests, kidney, lung, heart
    6. Skin lesions may be manifestation of severe systemic reaction
    7. Acute necrotizing eosinophilic myocarditis may occur [7]
11. QT Prolongation
    1. Various agents directly prolong the QT and QTc intervals
    2. Usually due to blocking of HERG K+ ion channels in cardiac tissue (HERG channels)
    3. Agents include antiarrhythmics, tricyclic antidepressants, classical antipsychotics, others
    4. QTc prolonging anti-arrhythmic agents include Types IA and IB and III
    5. Moxifloxacin and certain other antibiotics can prolong the QT interval
    6. Terfenadine (Seldane®), astemizole (Hismanal®), cisapride (Propulsid®) withdrawn from market due to QT prolongation
    7. Additional drugs can contribute to QTc prolongation by primarily agent
    8. In most cases, these "contributing" agents inhibit P450 metabolic enzymes
    9. Macrolides can exacerbate QT prolongation: erythromycin, clarithromycin, troleandomycin
    10. Azole antifungals - ketoconazole, fluconazole and others
    11. Digitalis toxicity
12. Genotyping and other pharmacogenomic approaches may lead to avoidance of specific agents in individuals prone to various ADRs [12]

F. Common Clinical Presentations [1]

1. Anaphylaxis
   1. Immunologically mediated or anaphylactoid (direct mast cell release)
   2. Symptoms: hives (urticaria), angioedema, nausea, vomiting, bronchospasm, hypotension
   3. Seen with penicillin, aspirin, sulfa drugs, bee stings, biologicals
   4. Rare with cephalosporins (<0.01%) [10]
   5. Severe hypersensitivity reactions to cetuximab (Erbitux® for various cancers) occur in >3% (or more), higher rates in southern USA [54]
   6. Most patients with hypersensitivity to cetuximab have IgE Abs specific for cetuximab and to the disaccharide galactose-alpha-1,3-galactose [54]
   7. Anaphylactoid: radiocontrast agents, vancomycin, ciprofloxacin
   8. Note that ACE inhibitors cause isolated angioedema (much reduced with AT2R blockers)
2. Hypersensitivity Vasculitis and Serum Sickness
   1. Symptoms: arthralgias, rash, fever
   2. Pulmonary inflammation with eosinophilia, macrophage activation, others may occur
   3. Immune complex deposition may be important
   4. Seen most commonly with penicillin, aspirin, sulfonamides
   5. Predisposition to general hypersensitivity in patients with sulfonamide reactions [17]
3. Cutaneous Reactions
   1. Most common drug hypersensitivity
   2. Idiosyncratic or immune complex
   3. Hives common, treat with diphenhydramine or hydroxyzine, ± glucocorticoids
   4. Maculopapular rash - ampicillin with EBV infection, sulfa drugs (especially in HIV)
   5. Morbilliform or Maculopapular - penicillin or cephalosporin
   6. Erythema multiforme - target-like (bull's-eye) raised maculopapular skin lesions
   7. Stevens-Johnson Syndrome (SJS) - more serious ulcerations with mucosal erruptions
   8. SJS is most commonly seen with sulfa drugs, allopurinol, anticonvulsants [5]
   9. Risk of SJS >3/10,000 whites and >30/10,000 Asians (mainly Chinese) with carbamazepine
   10. Association of SJS and carbamazepine in Asians found with HLA-B*1502 and genetic testing for this allele is recommended for all Asian patients before initiation carbamazepine [22]
4. Cutaneous Reactions in HIV+ Patients [9]
   1. Usually manifests as morbilliform or maculopapular rash
   2. Fever often precedes rash
   3. Fatigue and myalgias
   4. Mucosal ulceration
   5. Features <5% of cases: erythema multiforme major, anicteric hepatitis, hypotension
   6. Very uncommon: acute interstitial nephritis, acute interstitial pneumonitis
5. Drug Induced Hepatitis (see below)
6. Renal
   1. Membranous Glomerulonephritis: gold, NSAIDs, penicillamine, probenecid, antiepileptics
   2. Interstitial Nephritis: sulfonamides, NSAIDs, rifampin, ß-lactams, allopurinol, captopril
   3. Tubular Damage: cisplatin
   4. Renal failure secondary to rhabdomyolysis
7. Pulmonary
   1. Pneumonitis with eosinophilia: nitrofurantoin, methotrexate, NSAIDs, sulfonamides, INH
   2. Asthma: inhaled proteins, ß-lactams, sulfites, NSAIDs, ß-adrenergic receptor blockers
   3. Pulmonary Fibrosis: nitrofurantoin, bleomycin, methotrexate, amiodarone
8. Anemia
   1. Hemolytic anemia is common
   2. Non-immune mechanisms: eg. G6PD deficiency (Antimalarials, Sulfa Drugs, Quinine)
   3. Immune mediated (Coomb's Positive): penicillin, cisplatin, sulfa, methyldopa, quinines
   4. Anemia + granulocytopenia: sulfasalazine, procainamide, penicillins, phenothiazines
   5. Megaloblastic: Folate antagonists Methotrexate, Trimethoprim; also Zidovudine (AZT)
   6. Drug Induced Lupus - procainamide, quinidine, phenytoin, hydralazine
9. Neutropenia
   1. Chemotherapy: nearly all cytotoxic agents
   2. Ganciclovir and valganciclovir
   3. Sulfa Drugs: sulfamethoxazole
   4. Idiopathic: chloramphenicol, ticlopidine, carbamazepine, felbamate, clozapine [9]
   5. NSAIDs: aspirin, indomethacin, others
   6. Antithyroid Agents: propylthiouracil, carbimazole, methimazole
   7. Immunological: quinidine, heparin
10. Thrombocytopenia
    1. Heparin, quinidine - immune mediated reactions
    2. H-2 Antagonists (especially cimetidine) - direct toxicity
    3. Ticlopidine - thrombocytopenia in setting of thrombotic thrombocytopenic purpura (TTP)
    4. Clopidogrel, related to ticlopidine, can also cause TTP
    5. Gold
    6. Sulfonamides
    7. Protamine
11. Eosinophilia
    1. Likely due to drug stimulation of IL5 and/or IL4 and/or chemokines such as eotaxin
    2. Allopurinol, aspirin, ampcillin, carbamazepine, digitalis, phenytoin, gold
    3. Also seen with tricyclic antidepressants, nitrofurantoin
12. Drug Induced Lupus [8]
    1. Not the same as systemic lupus, but has some overlapping features
    2. Musculoskeletal complaints, fever and weight loss (most cases)
    3. Pleuropulmonary involvement (>50%)
    4. Rarely renal, neurologic, or vasculitis symptoms
    5. Cutaneous manifestations are not seen
    6. Antihistone Abs found in ~95% of cases
    7. Anti-ds DNA Abs are not found in drug induced lupus
    8. Commonly seen with minocycline, isoniazid, procainamide, penicillamine, methyldopa
    9. Also with hydralazine, chlorpromazine, TNFa blockers [13]
    10. Stop drug; glucocorticoids only in pleuropulmonary or other severe manifestation
    11. Resolution usually within 4-6 weeks
13. Other
    1. Tinnitis: low doses of aspirin, called "salicylism"
    2. Deafness: aminoglycosides, ethacrynic acid, furosemide (high dose), bleomycin, aspirin
    3. Optic neuritis: ethambutol, isoniazid
    4. Reduced seizure threshhold: tricyclics, lithium, theophylline, vincristine, meperidine, phenothiazines and possibly haloperidol
    5. Protamine: histamine release syndromes, arrhythmias, bronchospasm, thrombocytopenia
    6. Thromboembolic events: oral contraceptives, estrogen replacement therapies, SERMS [9]
    7. Rhabdomyolysis: statins, particularly cerivastatin [11]

G. Drug Induced Hepatitis [15,16]

1. Overview
   1. Most frequent reason for withdrawal of drugs from marketing
   2. >50% of cases of acute liver failure in USA due to drugs
   3. Occur in ~1 in 10,000 persons
   4. Usually with drugs metabolized by liver; cytochrome P450 enzymes usually implicated
   5. Nearly any drug can cause idiopathic hepatitis
   6. Women are more affected than men
2. Several distinct types of idiosyncratic reactions exist
   1. Hepatocellular death
   2. Cholestasis
   3. Microvesicular fatty deposition
   4. Steatohepatitis
   5. Autoimmune - cytotoxic lymphocyte responses
   6. Immunoallergic - IgE response
   7. Granulomatous - macrophages and lymphocytes infiltrate heatic lobule
   8. Fibrosis - activation of stellate cells
   9. Vascular collapse - ischemic necrosis
   10. Oncogenesis
   11. Mixed - cytoplasmic and canalicular injury, direct bile duct injury
3. Hepatocellular Death
   1. Acetaminophen (paracetamol, Tylenol® and others) - associated with doses of >15gm
   2. Isoniazid - mainly only in slow acetylators
   3. Lovastatin (Mevocor®) and other statins
   4. Diclofenac (Voltaren® and others)
   5. Bromfenac (Duract®) - withdrawn from market
   6. Trazadone (Desyrel®)
   7. Nefazodone (Serzone®)
   8. Venlafaxine (Effexor®)
   9. Likely through tumor necrosis factor and fas mediated apoptotic death pathways
4. Cholestasis
   1. Estrogen
   2. Erythromycin
   3. Chlorpromazine
5. Microvesicular Fatty Deposition
   1. Didanosine (Videx®)
   2. Tetracyclines
   3. Aspirin (ASA)
   4. Valproates (Depokene®, Depokote®, others)
6. Steatohepatitis
   1. Amiodarone (Cordarone®)
   2. Tamoxifen (Nolvadex®)
7. Immunoallergic
   1. Halothane
   2. Phenytoin (Dilantin® and others)
   3. Sulfamethoxazole
8. Autoimmune
   1. Nitrofurantoin (Macrobid®, Macrodantin®)
   2. Methyldopa (Aldomet®)
   3. Lovastatin
   4. Minocycline (Minocin®)
9. Granulomatous
   1. Diltiazem (Cardizem® and others)
   2. Sulfa drugs (TMP/SMX, Bactrim®, Septra®, and others)
   3. Quinidine
10. Fibrosis
    1. Methotrexate (Rheumatrex® and others)
    2. Vitamin A overdose
11. Vascular Collapse
    1. Nicotinic Acid (and niacin in high doses)
    2. Cocaine
    3. MDMA (methylenedioxymethamphetamine, "Ecstasy")
12. Oncogenesis
    1. Oral contraceptives
    2. Androgens
13. Mixed Effects
    1. Amoxicillin-clavulanate (Augmentin®)
    2. Carbamazepine (Tegretol®)
    3. Cyclosporine (Neoral®)
    4. Methimazole (Tapazole®)
    5. Troglitazone (Rezulin®) - withdrawn from market [4]
14. Other
    1. Zileuton (Zyflo®)
    2. Tacrine (Cognex®)
    3. Felbamate (Felbatol®)
15. Alcohol ingestion aggravates most reactions
16. Diagnosis [16]
    1. Rule out viral hepatitis
    2. Biliary evaluation - radiographic, usually begin with ultrasound, CT/MRI, ERCP
    3. Rule out autoimmune disease
    4. Rule out alcohol abuse
    5. Metabolic and genetic: ferritin level, iron, ceruloplasmin, alpha1-antitrypsin
    6. Hemodynamic causes: hypotension, shock, heart failure, vascular occlusion

H. Antibiotic Allergies [19]

1. Most allergic reactions to antibiotics are cutaneous
   1. ~2% of cutaneous drug reactions in hospitalized patients due to antibiotics
   2. Prevalence also estimated as 2 cases per 1000 hospitalized patients per year
2. Most reactions are Type IV delayed and Type I immediate hypersensitivities
3. Most common antibiotics associated with ADRs:
   1. Amoxicillin
   2. Trimethoprim-Sulfamethoxazole (TMP-SMX)
   3. Ampicillin
   4. Less common: cephalosporins, macrolides, fluoroquinolones, tetracyclines, vancomycin
4. Most common skin reactions
   1. Maculopupaular skin eruptions
   2. Urticaria
   3. Pruritus
5. Usually days to weeks after initial exposure: "sensitization"
6. On secondary exposure, reaction is within minutes to hours
   1. Secondary exposure may include fever, eosinophilia, other extracutaneous symptoms
   2. Hypotension, bronchospasm, frank anaphylaxis can occur
7. Increased Risk of Allergic Reactions
   1. HIV Infection
   2. Cystic fibrosis
   3. Infectious mononucleosis
8. Diagnosis
   1. Skin testing - allergen specific IgE antibodies (mainly for pencillin allergies)
   2. Skin testing not useful for non-IgE drug reactions
   3. Lymphocyte based testing for T cell reactive allergens approved in Europe, not in USA
9. Treatment and Desensitization
   1. Acute reactions: Supportive, Antihistamines, Glucocorticoids
   2. Desensitization: administer increasing amounts of antibiotics of a period of hours until therapeutic dose is obtained
   3. Desensitization requires continuous presence of drug
   4. Desensitization successful in ~75% of IgE-mediated drug allergies
   5. Patients with sulfonamide antibiotic allergies do not cross react with other sulfur containing drugs such as celecoxib, thiazides, sulfonylureas

I. Drug Induced Lupus Erythematosus (DILE) [41,42]

1. Frequent Associations
   1. Procainamide: ANA+ in 50-75% of patients within 6 months (usually slow acetylators)
   2. Quinidine: ANA+ in ~10% of patients within 12 months
   3. Hydralazine: 10-20% of patients will become ANA+
   4. Isoniazid
   5. Propylthiouracil (PTU)
   6. Chlorpromazine
   7. Penicillamine
2. Less Frequent
   1. alpha-methyl Dopa (Aldomet®)
   2. Phenytoin (Dilantin®)
   3. Minocycline (Minocin®)
   4. Cimetidine
   5. Oral Contraceptives (OCP; questionable)
   6. Griseofulvin
   7. Hydrochlorothiazide
   8. Sulfonamides
   9. Tetracycline
   10. Psoralen-UV-A
   11. Tumor Necrosis Factor alpha (TNFa) blockade - etanercept and infliximab [16]
3. Eiotlogy
   1. Appears to be related to generation of toxic metabolites by activated neutrophils
   2. Myeloperoxidase appeared to be the major enzyme in neutrophils required for activation
   3. Provides a unifying mechanism for lupus-like effects of different types of drugs
   4. In addition, specific antinuclear Abs can bind to keratinocyte surfaces inducing damage
   5. Thus, photoactive drugs may synergize with endogenous autoAbs to induce DILE
4. Presentation and Laboratory
   1. Fever and weight loss, and musculoskeletal complaints in nearly all patients
   2. Pleuropulmonary disease in ~50%
   3. High ANA levels with homogeneous pattern
   4. Anti-Histone Abs in ~95%
   5. ESR elevated, frequently >80mm/hr
   6. Severe SLE manifestations are extremely rare (nephritis, CNS) in DILE
5. Treatment
   1. Stop offending agent
   2. If symptomatic, glucocorticoid therapy for short duration (2-4 weeks)
   3. Antihistamines may also be useful

J. Considerations in Evaluation of ADRs [2]

1. Timing
2. Pattern of Illness
3. Results of Investigations
4. Rechallenge
5. Drug reactions should be reported
6. Laboratory Evaluations [8]
   1. Complete blood count and differential
   2. Liver function tests
   3. Urinalysis (routine and microscopic)
   4. Serum renal function (BUN and creatinine)
   5. Chest radiography for respiratory or thoracic symptoms
   6. Skin biopsy of any rash

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