CHAPTER 30

 
An adverse drug reaction may be defined as undesirable clinical manifestations, consequent to, and caused by administration of a particular drug.

Drug reactions may be non immunologic or immunologic .

1. Non-immunologic Drug Reactions

   Non-immunological reactions are related to different factors mainly:

   Overdose: leads to different side effects depending on the specific drug. Certain drugs are hepatotoxic as phenothiazine derivatives and erythromycin osteolate.

   Bone marrow depressant drugs, certain types of antihistamines, grisoefulvin, sulphapyridine, sulphones and chloromycetin.

   Aspirin, anti-malarial drugs, sulphones may cause hemolysis.

   Cumulative : certain drugs may have cumulative side effects . Other drugs may cause different reactions such as the yellowish skin discoloration due to Atabrine intake or the slate gray color due to silver compound intake. Hypervitaminosis A may lead to periosteal swelling in children and hair fall.

2. Immunologic Drug Reaction

   Drug reactions may arise as a result of immunological drug allergy.

   This type of drug reaction is the most common. Drugs may induce different skin reactions simulating most various skin diseases. Immanologic drug reaction may present with different skin manifestations. Some of these are:

   Urticaria: Some of the drugs inducing urticaria are Aspirin, Penicillin.

   Eczema: Topical sensitizers as local anesthetic, topical antihistamines, topical antibiotics as neomycin, penicillin, halogenated salicylanilides.

   Oral sensitizer: Sulfonamides, Naldixic acids, and Chloropromazine.

   Epoxy acrylates in filling materials often also react to epoxy resin leading to local sensitization of the oral mucosa.

   Serum sickness: Penicillin

   Exfoliative dermatitis: Topical sensitizer, heavy metals, and antibiotics.

   Fixed drug eruption: Sulfonamides, barbiturates, and phenolphthalein.

   Exanthemata reaction: Antibiotics, phenylbutazone, thiazides, and barbiturates.

   Erythema multiform: Sulfonamides and others

   Epidermal necrosis: Barbiturates, phenylbutazone and sulfonamides.

   Purpura: Penicillin and cytotoxic drugs.

   Granuloma: Zirconium topically in antiperspirant and cosmetics used topically especially to the axillary folds, bromides, and iodides.

   Lupus erythematosus -like reaction: Hydrallazine, procainamide.

   Hyperpigmentation: ACTH, Chloropromazine, Busulphan, metals locally as silver nitrates in topical medications such as that used topically for treatment of burns.

   Hirsutism: androgens, corticosteroids, and testosterone.

   Alopecia: Cytotoxic drugs, heparin, corticosteroid.

   Phototoxic reaction: due to antimalarial drugs, coumarin and phenothiazines.

   The commonest drugs that may cause skin reactions are:

   Antimicrobial agents:Topical or systemic antibiotics may cause sensitization.

   The most common topical anti-microbial preparations causing allergic contact dermatitis are: Neomycin, Framycetin, Virginiamycin, and Bacitricin.

   Chloro- and bromosalicylanilides, organic mercury compounds benzyl alcohol, xanthocillin, sulphonamides, thiuram sulfides, iodine, and bithionol in shampoos may cause also drug reaction. Systemic antibiotics such as.

   Minocycline, Chloramphenicol, Penicillin and Tetracyclines may cause different clinical types of skin reactions.

   Ampicillin and its derivatives may elicit morbilliform rash.  The eruption appears on the extremities that may become generalized. The onset may be immediate , occuring in patients treated with Ampicillin . Usually skin rash develops after one week from the onset of therapy. Re-exposure of such patients to Ampicillin and other penicillin derivatives is contra-indicated.Ampicillin in such cases may cause  anaphylactic reaction .

   Amoxicillin :leads to cutaneous eruptions including urticaria, morbilliform, or maculopapular rashes , fixed drug eruption and serum sickness.

   Hydroxyquinolines: Sterosan and Vioform (Chinoform), as well as esters of hydroxybenzoic acids (Nipagins, Parabens) Chloroacetamide and Chloroxylenol have sensitizing capacity. Less common sensitizers are quaternary ammonium salts in eardrops and antiperspirants.

Antimycotic agents

Most of the organic compounds used as antimycotics have sensitizing properties, e.g. hydroxyquinolines, esters of hydroxybenzoic acid, Jadit (photosensitizer), thiuram sulfides, organic mercury compounds, dichlorophene, tolnaftate, nystatin and various other halogenated phenols compounds (photosensitizers).

Antiviral agents

Acyclovir , amantadine , tromantadine and idoxuridine can all cause sensitization .

Antihistamines

The Phenothiazines are the strongest sensitizers, but all can cause sensitization when used topically .

Corticosteroids

Sensitization is more common than previously thought. Dermatologists and physicians are often faced with common steroid side effects due to abuse or misuse of steroids.

Patients feel relief of their skin problem and therefore continue using this double-wedged medication for longer periods leading later to unwanted side effects .

Local anesthetics

Derivatives of P-aminobenzoic acid such as benzocaine, amethocaine, procaine and dibucaine are strong sensitizers. Mepivacaine (carbocaine) and lidocaine (lignocaine, Xylocaine) seem to be rare sensitizers.

Non-steroid anti-inflammatory drugs

The propionic acid derivatives, such as ketoprofen, ibuprofen, ibuproxam and tiaprofenic acids, cause contact and photocontact dermatitis, with cross-reactivity. Topical benzydamine is also a contact and photocontact sensitizer.

Vitamins

Vitamins A, E and K, and dexpanthenol have all a sensitizing effect in topical medicaments in susceptible individuals .

Quaternary ammonium compounds

They are used as disinfectants.Quaternary ammonium compounds may cause sensitization .

Dequalinium and Cetrimide have produced unusual necrotic lesions in some individuals, especially when used concentrated and under occlusion.

Ointment and cream bases

Lanolin, cetyl, oleyl and stearyl alcohol, ethylene, hexylene and parabens propylene glycol, linnet wax, white and yellow petrolatum, sesame and olive oils, perfume, polidocanol and preservatives are known to be sensitizers. Ethylenediamine can cause also skin sensitization .

SPECIAL DRUG REACTIONS

Fixed drug reaction. Persistent skin rash that lasts for a long time and recurs again at the same site when the same drug is taken .

Sulfonamides and Phenolphthalein besides      other drugs can cause this type of reaction .

Toxic epidermal necrolysis

This is a serious reaction especially in young age. Wide spread erythematous and bullous reaction and desquamation occurs, where the skin surface separates into sheets. Constitutional symptoms may be severe and the condition may be fatal .

Sulfonamides, Butazolidin and Antipyrine are the commonest drugs causing this syndrome .

Abortion and fetal abnormalities. Methotroxates may cause such complications .

Stevens-Johnson syndrome like reaction can be caused by long acting Sulfonamides.

Teeth changes: Tetracycline taken by pregnant women or given to infants may lead to hypoplasia of tooth enamel and staining of teeth. The permanent teeth can be affected in children , with fibrocystic disease of the pancreas .

Polyneuropathy: this may be due to large amounts of mercury that is used in topical preparations and absorbed from the skin surface .

Hemolysis : the use of sulphones for a long period as in dermatitis herpetiformis and in treatment of leprosy may lead to blood hemolysis.

Hearing problems: due to eight-nerve damage as a result of streptomycin and colimycin .

Hepatotoxicity: this can be caused by phenothiazines, methyl testosterone, and erythromycin osteolate .

Anemia and hemorrhagic diseases: this is due to bone marrow depression due to Methotroxates , Grisoefulvin , Butazolidines, Antihistamines, Novobiocin. Different drugs can cause this problem.

Mucous membranes changes:

Antibiotics and vitamin B complex can produce black hairy tongue.

Bismuth causes the blue stain line along the gums.

Fluorinated toothpastes may cause cheilitis and ulcerative stomatitis

Skin changes

Glucocorticoids lead to direct skin atrophy or pigmentary disorders on repeated use of potent steroids for a long time, especially in infants and young children .

Certain inhibitors of lipid synthesis such as ( Triparanol ) lead to disturbance in keratinization .

Nails . Declomycin may cause fragmentation of nails .

Hair. Chemotherapy such as Methotroxates may cause complete hair loss. Excessive vitamine A intake may cause hair falling.

                        Pathophysiology of drug reactions

Low molecular weight drugs such as penicillin cannot induce an immune response at the beginning of exposure and these are called “ Haptens”. After repeated intake of such  drugs these haptens bind to endogenous proteins such as serum globulins forming hapten -protein complex which becomes antigenic causin production og IgE antibodies in susceptible patients.

Penicillin itself and the metabolites of penicillin such as penicilloyl, penicilloate and penilloate may act as haptens.

Combination of the circulating haptenprotein antigen with IgE antibody bound to the mast cells and basophils causing cell degranulation through a calcium – dependent mechanism with release of vasoactive mediators, producing the anaphylactic state.

The vaso-active mediators, producing the anaphylaxis state,  include:

Histamine: secreated by both types of mucosal and connective tissue mast cells.Histamine produces arteriolar and venous dilation  causing increased vascular permeability.

Prostaglandin D2 : is  secreated by mast cells only causing peripheral vasodilatation.

 Leukotrienes C4 and D4 :is secreated by by both mast cells and basophils  causing  constriction of  coronary and peripheral  arterial circulation .These also increase vascular permeability  and  peripheral arterial circulation.

Platelet activating factor: is secreated by mast cells only , causing increased vascular permeability and venous dilatation.

 Tryptase: the role of mast cells tryptase is unknown .

The other mediators : are bradykinin producing enzymes, neutral proteases, cytokines and other substances.

                            Clinical manifestations of anaphylaxis

Manifestations may occur immediately after exposure to the offending drug or after few minutes.

·        The initial symptoms include : feeling of warmth or impending doom, flushing, tachycardia and pruritus.

·        Urticaria is the most common manifestation and may be accompanied by congestion and swelling of the mucous membranes of the eyes, nose, mouth,lips and tongue with a feeling of a lump in the throat which may lead to angioedema of the larynx, epiglotis. These manifestations may lead to respiratory stridor and suffocation.

·        Respiratory manifestations include shortness of breath, tightness in the chest, acute asthma and wheezing.

·        Cardiac manifestations include hypotension and cardiac arrest.

·        Neurological manifestations include loss of consciousness, confusion and seizures.

·        Gastrointestinal manifestations: nausea, vomiting and abdominal cramps.

                                  Treatment  of Drug Reaction

A. General measures

1.      Stop exposure to the drug causing the reaction .

2.     IV  normal physiologic saline for all patients with anaphylaxis.

3.     Maintain airway.

4.     Resuscitation with endotracheal  intubation and  advanced  cardiac life support may be necessary in the event of cardiopulmonary arrest.

B. Specifc measures

1.      Epinephrine is the treatment of choice in acute anaphylaxis.

Epinephrine counteracts the vasodilattion , bronchoconstriction ane other manifestations of IgE mediators released from mast cells and basophils.

·        Patients presenting with skin rash only and mild manifestations of anaphylaxis  can be given 0.3 ml of aquous epinephrine 1:1000 subcutaneous route  to an adult or 0.01 mg/kg to a child.

 This can be repeated every 15-30 minutes when required.

·        Shock or cardiac arrest: epinephrine 1:10,000 may be given IV, as an initial  adult dose of 5-10 ml and can be repeated every 5 minutes as indicated and according to the patient’s response.

·       Cases with severe hypotension , continuous intravenous drip of epinephrine may be necessary using the standerd advancec cardiac life support protocol. The recommended drip dose for adults is 1 mg of epinephrine 1:1000 dilution or I ml to be added to 500ml of normal saline, to give a concentration of 2 microgram/ml.

·        Patients with shock may need vasopressor drugs such as dopamine.

·        In elderly patients or those under Β-blocker therapy,  0.5 mg of glucagon for children or 1 mg for the adults may be indicated and repeated when required.

·        Oxygen supplemental is often indicated for patients with cardiac or respiratory symptoms.

·       Asthmatic patients need I.V aminophylline (adult dose 6 mg/kg loading dose over 30 minutes, followed by a maintenance dose of 0.5 –1 mg/kg/hr).

·       Antihistamines including H1-blockers such as diphenhydramine (Benadryl) or hydroxazine (Atarax) ,25-50 mg I.V (for children we give 1 mg/kg I.V.

      H2-blockers such as cemitidine (Tagamet) , 300 mg I.V for adults  and   (4mg/kg for children).

·       Corticosteroides such as methylprednisolone (125mg I.V in adults or 1 mg/kg for children or hydrocortisone(250-500 mg in an adult of 4-8 mg/kg in children as an initial loading dose may prevent recurrence of anaphylaxis and bronchospasm.

                                     Sulphonamides Drug Reaction

1.Short acting sulphonamides may cause :

·        G.I.T irritation such as nausea and vomiting or

·         C.N.S symptoms such as headache, dizziness, and mental depression.

·        Cyanosis due to formation of sulph-methemoglobinaemia.

·        Allergic skin reaction such as fixed drug eruption, articaria, and perpura.

·        Severe toxicity may lead to renal damage presenting with hematouria, oligouria, and anuria.

·        Bone marrow depression leading to anemia and thrombocytopenia and agranulocytosis.

·        Liver damage leading to toxic hepatitis and jaundice.

·        RBC’s affection causes hemolysis.

·        Hypospermia due to gonadal affection.

·        Toxic polyneuritis and memory disorders.

2.Long acting sulphonamides lead to :

·        fixed drug reaction and Steven Johnson Syndrome fever pneumonitis

·        peritonitis and toxic polyneuritis.

   Toxic manifestations of antimicrobial and chemotherapeutic drugs.

·        Hypersensitivity and direct toxicity reaction to Pencillin and  Sulphonamides

·        Anaphylaxis is the common cause of death which is mainly due to penicillin, sulphonamides, erythrocin and macrolides.

Anaphylaxis is the most common cause of  IgE mediated anaphylaxis and that  is mainly due to penicillin, followed by B-lactam and others. Anaphylaxis occurs more commonly after exposure to parenteral antibiotics.

Hypersensitivity reactions to antibiotics are due to interaction between the antibiotic and the immune system.

The  manifestations of Sulphonamides drug reactioins are:

·        Vascultis: These manifestations include small bood vessels vasculitis .These manifestations are self-limiting and subside with withdrawal of the drug.

The type of reaction in sulphamethoxazole is type  1V cell-mediated delayed hypersensitivity reaction.

Clinical finding in anaphylaxis:

·        Cutaneous manifestations: pruritus, flushing , urticaria and angioedema.

·        Cardiovascular manifestations: cardiac arrythmia and palpitation.

·        Pulmonary manifestations: increased mucous secreations with rhinorrhea, laryngeal edema, wheezing,  and bronchorrha which causes nasal congestions , hoarseness ,lump of throat, shortness of breath, dyspnea, stridor and respiratory arrest .

·        General manifestations: conunctival edema diaphoresis, vomiting ,diarrhea and abdominal cramps.

Hypersensitivity to Macrolides

Erythromycin, clarithromacin and azithromycin have  usually low immunologic reaction.

                                             Antibiotic poisoning

Mode of poisoning: this is  usually accidental

1. Acute: due to: 1)Overdose

                               2)Hypersensitivity

2. Chronic: due to: prolonged use.

Toxic manifestations: can be grouped under the following varieties:

1. Allergic disorders: (mainly due to penicillins in hypersensitive patients)

        1. Mild reaction: skin rash (erythematous, maculopapular, vesicular,bullous, exfoliative, purpuric, hgic).

        2.Severe reaction: generalized anaphylactoid shock and death.

2. G.I. disorders: (due to chloramphenicol, tetracycline)                                                                                                  

                           1. Irritation of G.I.T.: leading to anorexia, nausea, and vomiting.

         2. Inhibition of intestinal bacterial flora:

      With diminished synthesis of vit.B complex leading to      inflammation of mucous membrane as (glossitis, stomatitis, enteritis (diarrhea), colitis, anositis (difficult defaecation), sore throat.

3. Blood disorders: (due to chloramphenicol, streptomycin).

              Inhibition of bone marrow leading to :

         1. anaemia (aplastic).

         2. leucopenia (or agranulocytosis).

         3. thrombocytopenia (with hgic complications).

4. Nervous disorders: (due to streptomycin, neomycin, chloramphenicol).

         1.   8^th nerve affection: (by streptomycin)

a.      Auditory symptoms: up to deafness and tinnitis.

b.      Vestibular symptoms: leading to balance disturbances and vertigo.

                     2.Grey syndrome: (by chloramphenicol).

                                  It is due to affection of basal ganglia leading to                    peripheral circulatory failure with pallor and cyanosis (occurs in young   infants and prematures).

5. Renal disorders: (by gentamycin, streptomycin; with poor kidney function) toxic nephritis, resulting in:

·        Oliguria.

·        Albuminuria.

·        Haematuria.

·        Casts.

6. Skin disorders: Contact dermatitis; during manufacture (allergic rash…..)

1.Acute Toxicity (mainly due to penicillins)  

         Penicillins are used against Gram+ve and Gram-ve organisms. Penicillins     include benzylpenicillin, phenoxypenicillin, cloxacillin and ampicillin.

Forms of toxicity:

         1. Anaphylactic shock: (occurs within seconds to minutes).

In the form of pallor which is followed immediately by cyanosis, wheezes, pulmonary edema, respiratory failure and death.

   2. Delayed reaction: In the form of:

·        Skin rash.

·        Fever.

·        Pharyngeal and laryngeal edema, respiratory failure and death.

   3.Anaphylactoid reaction:

In the form of :

·        G.I irritation (nausea, vomiting, colic, diarrhea).

·        Convulsions.

·        Pulmonary edema.

2.Chronic toxicity

A. Tetracyclins:

                  1.   G.I.T.: a. Irritation…..

                                     b. Inhibition of intestinal bacterial flora…..

                  2.   Kidney: renal damage due to precipitation of toxic substances.

                  3.   Teeth: discoloration due to chelation of calcium, this occurs in         

                  children and it is permanent change. 

They are broad-spectrum antibiotics used against systemic infections.

B.  Chloramphenicol:

1.      G.I.T.: upsets leading to diarrhea.

2.      Bone Marrow: depression leading to…..

3.      Grey Syndrome: in infants and prematures.

It is a broad-spectrum antibiotic used in enteric fever.

C. Erythromycin:

1.      Liver affection: with jaundice.

2.      Allergic manifestations: leading to circulatory failure.

It is used against streptococcal and pneumococcal infections.

D.  Aminoglycoside antibiotics:

1.      G.I.T.: a. Irritation…..

                   b. Inhibition of intestinal bacterial flora….. 

2.      C.N.S.: 8^th nerve affction…..

These antibiotics include streptomycin, gentamycin, kanamycin, and neomycin.

They are used against Gram-ve bacteria, (streptomycin is used against T.B. bacilli).

Treatment:

1.    of acute toxicity:

                                    a. Adrenaline S.C.

                                                 b. Antihistamines.

                                                 c. Corticosteroids I.V.

                                                 d. Penicillinase; reverses anaphylactoid and       

                                                     delay reactions but not anaphylactic one

2.    of chronic toxicity:

                        a. Stop the drug.

                        b. For G.I. irritation; milk and bismuth     

                                       carbonate.  

                                                       c. For sore throat and stomatitis; Vit. B complex

                                                           and antiseptic measures to mouth.

                                                        d. For bone marrow depression; folic acid and

                                                            iron( in mild cases), blood transfusion( in

                                                            severe cases).

                                                        e. For renal failure; artificial kidney.

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