drug reaction may be defined as :undesirable clinical manifestations,
consequent to and caused by administration of a particular drug.
reactions may be non immunologic or
Non-immunologic Drug Reactions
reactions are related to different factors mainly:
leads to different side effects depending on the specific drug.
Certain drugs are hepatotoxic as phenothiazine derivatives and
depressant drugs, certain types of antihistamines, griseofulvin,
sulphapyridine, sulphones and chloromycetin.
anti-malarial drugs, sulphones may cause hemolysis.
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.
Immunologic Drug Reaction
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
Some of the drugs inducing urticaria are Aspirin, Penicillin.
Topical sensitizers as local anesthetic, topical antihistamines,
topical antibiotics as neomycin, penicillin, halogenated
sensitizer: Sulfonamides, Naldixic acids, and Chloropromazine.
acrylates in filling materials often also react to epoxy resin
leading to local sensitization of the oral mucosa.
dermatitis: Topical sensitizer, heavy metals, and antibiotics.
eruption: Sulfonamides, barbiturates, and phenolphthalein.
reaction: Antibiotics, phenylbutazone, thiazides, and barbiturates.
multiform: Sulfonamides and others
necrosis: Barbiturates, phenylbutazone and sulfonamides.
Penicillin and cytotoxic drugs.
Zirconium topically in antiperspirant and cosmetics used topically
especially to the axillary folds, bromides, and iodides.
erythematosus -like reaction: Hydrallazine, procainamide.
ACTH, Chloropromazine, Busulphan, metals locally as silver nitrates
in topical medications such as that used topically for treatment of
androgens, corticosteroids, and testosterone.
Cytotoxic drugs, heparin, corticosteroid.
reaction: due to antimalarial drugs, coumarin and phenothiazines.
commonest drugs that may cause skin reactions are:
agents: Topical or systemic antibiotics may cause sensitization.
common topical anti-microbial preparations causing allergic contact
dermatitis are: Neomycin, Framycetin, Virginiamycin, and Bacitricin.
bromosalicylanilides, organic mercury compounds benzyl alcohol,
xanthocillin, sulphonamides, thiuram sulfides, iodine, and bithionol
in shampoos may cause also drug reaction. Systemic antibiotics such
Chloramphenicol, Penicillin and Tetracyclines may cause different
clinical types of skin reactions.
and its derivatives may cause 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 .
:leads to cutaneous eruptions including urticaria, morbilliform, or
maculopapular rashes , fixed drug eruption and serum sickness.
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.
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).
amantadine , tromantadine and idoxuridine can all cause
Phenothiazines are the strongest sensitizers, but all can cause
sensitization when used topically .
is more common than previously thought. Dermatologists and
physicians are often faced with common steroid side effects due to
abuse or misuse of steroids.
feel relief of their skin problem and therefore continue using this
double-wedged medication for longer periods leading later to
unwanted side effects .
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.
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
E and K, and dexpanthenol have all a sensitizing effect in topical
medicaments in susceptible individuals .
used as disinfectants. Quaternary ammonium compounds may cause
and Cetrimide have produced unusual necrotic lesions in some
individuals, especially when used concentrated and under occlusion.
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 .
Fig. 238. Fixed Drug Reaction (Sulfonamides)
Fig. 239. Fixed drug reaction (Phenothiazine)
Fig. 240.Drug Reaction
(Amoxicillin Exfoliative dermatitis)
Fig. 241.Drug Reaction (Corticosteroids)
Fig. 242. Drug Reaction
Fig. 243. Bllous Drug Reaction
Fig. 244. Drug Reaction
Fig. 245. Bllous Drug Reaction
Fig. 246.Drug Reaction (Corticosteroid)
Fig. 247. Fixed Drug Reaction
Fig. 248.Drug Reaction,striae
Fig. 249. Drug Reaction
Fig. 250. Fixed Drug Reaction,
(Trimethoprin and sulfa, Bactrim)
Fig. 251. Drug Reaction, contact dermatitis
Drug reaction (Doxycyclin) Fig.251,c,d,e. Drug reaction due to slimming pills (Sibutramine-Reductil)
reaction. Persistent skin rash that lasts for a long time and recurs
again at the same site when the same drug is taken .
and Phenolphthalein besides other drugs can cause this type of
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 .
Butazolidin and Antipyrine are the commonest drugs causing this
fetal abnormalities. Methotroxates may cause such complications .
syndrome like reaction can be caused by long acting Sulfonamides.
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 .
this may be due to large amounts of mercury that is used in topical
preparations and absorbed from the skin surface .
the use of sulphones for a long period as in dermatitis
herpetiformis and in treatment of leprosy may lead to blood
problems: due to eight-nerve damage as a result of streptomycin and
this can be caused by phenothiazines, methyl testosterone, and
erythromycin osteolate .
hemorrhagic diseases: this is due to bone marrow depression due to
Methotroxates , Grisoefulvin , Butazolidines, Antihistamines,
Novobiocin. Different drugs can cause this problem.
and vitamin B complex can produce black hairy tongue.
causes the blue stain line along the gums.
toothpastes may cause cheilitis and ulcerative stomatitis
lead to direct skin atrophy or pigmentary disorders on repeated use
of potent steroids for a long time, especially in infants and young
inhibitors of lipid synthesis such as ( Triparanol ) lead to
disturbance in keratinization .
Declomycin may cause fragmentation of nails .
Chemotherapy such as Methotroxates may cause complete hair loss.
Excessive vitamine A intake may cause hair falling.
Pathophysiology of drug reactions
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.
and the metabolites of penicillin such as penicilloyl, penicilloate
and penilloate may act as haptens.
the circulating hapten protein 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.
mediators, producing the anaphylaxis state,
secreated by both types of mucosal and connective tissue mast
cells. Histamine produces arteriolar and venous dilation
causing increased vascular permeability.
D2 : is secreated
by mast cells only causing peripheral vasodilatation.
Leukotrienes C4 and D4 :is secreted by by both mast cells
and basophils causing
constriction of coronary and peripheral
arterial circulation .These also increase vascular
peripheral arterial circulation.
activating factor: is secreted by mast cells only , causing
increased vascular permeability and venous dilatation.
Tryptase: the role of mast cells tryptase is unknown .
mediators : are bradykinin producing enzymes, neutral proteases,
cytokines and other substances.
Clinical manifestations of
may occur immediately after exposure to the offending drug or after
The initial symptoms
include : feeling of warmth or impending doom, flushing, tachycardia
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
manifestations include shortness of breath, tightness in the chest,
acute asthma and wheezing.
manifestations include hypotension and cardiac arrest.
manifestations include loss of consciousness, confusion and
manifestations: nausea, vomiting and abdominal cramps.
Stop exposure to the drug causing the reaction .
physiologic saline for all patients with anaphylaxis.
Resuscitation with endotracheal
intubation and advanced cardiac
life support may be necessary in the event of cardiopulmonary
Epinephrine is the treatment of choice in acute anaphylaxis.
counteracts the vasodilattion , bronchoconstriction ane other
manifestations of IgE mediators released from mast cells and
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
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 standard advance
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
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
G.I.T irritation such as nausea and vomiting or
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
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
reactions to antibiotics are due to interaction between the
antibiotic and the immune system.
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.
Cutaneous manifestations: pruritus, flushing ,
urticaria and angioedema.
Cardiovascular manifestations: cardiac arrythmia
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
clarithromacin and azithromycin have
usually low immunologic reaction.
Mode of poisoning: this is
due to: 1)Overdose
due to: prolonged use.
Toxic manifestations: can be grouped under
the following varieties:
disorders: (mainly due to penicillins in hypersensitive
1. Mild reaction: skin rash (erythematous,
maculopapular, vesicular,bullous, exfoliative, purpuric, hgic).
2.Severe reaction: generalized anaphylactoid shock and
disorders: (due to chloramphenicol, tetracycline)
1. Irritation of G.I.T.: leading to anorexia, nausea, and
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),
disorders: (due to chloramphenicol, streptomycin).
Inhibition of bone marrow leading to :
2. leucopenia (or
(with hgic complications).
disorders: (due to streptomycin, neomycin,
8th nerve affection: (by streptomycin)
Auditory symptoms: up to deafness and tinnitis.
Vestibular symptoms: leading to balance disturbances and
2.Grey syndrome: (by chloramphenicol).
is due to affection of basal ganglia leading to
peripheral circulatory failure with pallor and cyanosis
(occurs in young infants
disorders: (by gentamycin, streptomycin; with poor kidney
function) toxic nephritis, resulting in:
disorders: Contact dermatitis; during manufacture (allergic
Toxicity (mainly due to penicillins)
Penicillins are used against Gram+ve and Gram-ve organisms.
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:
Pharyngeal and laryngeal edema, respiratory failure
In the form of :
G.I irritation (nausea, vomiting, colic, diarrhea).
b. Inhibition of intestinal bacterial flora…..
renal damage due to precipitation of toxic substances.
discoloration due to chelation of calcium, this occurs in
children and it is permanent change.
They are broad-spectrum antibiotics used
against systemic infections.
G.I.T.: upsets leading to diarrhea.
Bone Marrow: depression leading to…..
Grey Syndrome: in infants and prematures.
It is a broad-spectrum antibiotic used in
Liver affection: with jaundice.
Allergic manifestations: leading to circulatory failure.
It is used against streptococcal and
G.I.T.: a. Irritation…..
b. Inhibition of intestinal bacterial flora…..
C.N.S.: 8th nerve affction…..
These antibiotics include streptomycin,
gentamycin, kanamycin, and neomycin.
They are used against Gram-ve bacteria,
(streptomycin is used against T.B. bacilli).
a. Adrenaline S.C.
c. Corticosteroids I.V.
d. Penicillinase; reverses anaphylactoid and
delay reactions but not anaphylactic one
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.
For bone marrow depression; folic acid and
iron( in mild cases), blood transfusion( in
e. For renal failure; artificial kidney.
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