STUDY - Technical - New Dacian's Medicine
Drug-Induced
Skin Reactions (3)
Translation Draft
So, we're going to go on...
Necrotizing skin vasculitis often presents in the form of palpable purple lesions, which can be generalized or limited to the lower limbs or other declive regions. Urticaria lesions, ulcers and hemorrhagic bubbles also occur. Vasculitis can also affect other organs, including the liver, kidney, brain and joints.
Drugs are just one of the causes of vasculitis. Reactions from immune complexes are likely responsible for drug-induced vasculitis and/ or serum disease. Propyltoiuracil induces a skin vasculitis accompanied by leukopenia and splenomegaly. Changes in direct immunofluorescence in these lesions suggest deposits of immune complexes. Medications involved in vasculitic eruptions include allopurinol, thiazides, penicillin and phenytoin.
The sensitivity reaction to phenytoin (anticonvulsant), one of the many skin reactions induced by it, is an erythematous rash, which subsequently becomes purple and is accompanied by fever, facial and periorbital edema, painful generalized adenopathy, leukocytosis (often with atypical lymphocytes and eosinophils), hepatitis and sometimes nephritis. The skin reaction usually begins 1-3 weeks after cessation of phenytoin and heals rapidly after discontinuation of the drug and treatment with systemic glucocorticoids.
Eruption recurs upon reexposure, and cross-reactions with other aromatic anticonvulsants, including carbamazepine and barbiturates are common. This syndrome apparently results from a hereditary deficiency of epoxidehydrolase, an enzyme necessary for the metabolism of a toxic intermediate aren-oxide that is formed during phenytoin metabolism by the cytochrome P450 system. Although no controlled studies are available, systemic glucocorticoids (prednisone) will reduce signs, symptoms and laboratory changes that attest to serious hypersensitivity reactions to anticonvulsants.
Skin necrosis due to warfarin (rare) usually occurs between day 3 and 10 of warfarin derivatives therapy, usually in women. Injuries are clearly delineated, endured, erythematous and purple and can heal or progress towards the formation of large, irregular hemorrhagic bubbles with final necrosis and slow healing escare formation. The occurrence of the syndrome is not related to the dose of the medicine or the underlying condition.
The predilections are breasts, thighs and buttocks. Evolution is not altered by discontinuation of the drug after the onset of the rash. Similar reactions have been associated with heparin. Warfarin reactions are associated with vitamin K-dependent protein C deficiency with a shorter half-life than other clotting proteins and is partly responsible for controlling fibrinolysis. Because warfarin inhibits the synthesis of vitamin K-dependent coagulation factors, warfarin anticoagulation in individuals with heterozygous protein C deficiency causes a steep collapse in circulating protein C levels, allowing hypercoagulability and thrombosis in the skin microvascularization with consecutive necrosis areas.
Heparin-induced necrosis may have similar clinical characteristics, but it is likely due to heparin-induced platelet aggregation with consecutive occlusion of blood vessels. Warfarin-induced skin necrosis is treated with vitamin K and heparin. Vitamin K cancels out the effects of warfarin, and heparin acts as an anticoagulant. Treatment with protein C concentrate may also be useful in individuals with protein C deficiency, a predisposing factor for the occurrence of these reactions.
There are a few things to be said for uncertain reactions. I'll start with the morbiliform reactions. Morbiliform or maculopapular eruptions may be the most common of all drug-induced reactions. They often begin to appear on the trunk or in traumatized or pressured areas and consist of erythematous macula and papules that are frequently symmetrical and can become confluenced. Damage to mucous membranes, palms and plants is variable, the rash can be associated with moderate to severe pruritus and fever.
Pathology is not clear. A hypersensitivity mechanism has been suggested, although these reactions do not always recur when re-exposure to the drug. Diagnosis is rarely supported by laboratory tests, the distinction between viral exantems being the main problem of differential diagnosis. While these reactions usually require discontinuation of the drug, rashes can sometimes decrease or disappear if the responsible medicine continues to be administered.
Morbiliform reactions usually occur during the first week after initiation of therapy and last 1-2 weeks (however some reactions to certain medications, especially penicillin, may start more than 2 weeks after the start of therapy, and may persist up to 2 weeks after the start of therapy). These rashes are common in patients receiving ampicillin, amoxicillin or allopurinol (trimetoprim-sulfamethoxazole frequently causes reactions in AIDS patients). Morbiliform rashes are usually treated symptomatically.
Oral antihistamines and calming compresses are useful in the treatment of pruritus. Topical antihistamines can also have a favorable effect, as can emollients. Short cures of potent topical glucocorticoids can reduce inflammation and symptoms and are likely helpful. The beneficial effect of systemic glucocorticoids in relation to their risk is less clear for morbiliform eruptions.
Fixed drug reactions are characterized by one or more clearly delineated, erythematous lesions, in which hyperpigmentation occurs after the healing of acute inflammation (at reexposure, the lesion recurs in the same place, hence the name "fixed"). Injuries often affect the face, genitals and oral mucosa and cause burning sensation.
Fixed drug rashes have been associated with phenolphthalein, sulfonamides, tetracycline, phenylbutazone and barbiturates. Although cross-sensitivity appears to occur between different tetraciclinical compounds, cross-sensitivity was not caused when different sulfonamide compounds were administered to patients as part of a challenge test. The evidence of a characteristic mononuclear infiltration of the dermal papillae close to the dermo-epidermic junction can confirm the clinical diagnosis. Extensive degeneration of basal cells can lead to the formation of bubbles and the dispersion of pigment. Even when the lesions are completely healed, melanin-laden macrophages are present in the dermis.
Nodos erythema is a paniculitis characterized by sensitive subcutaneous erythematous nodules, usually arranged on the anterior portion of the legs. Drug hypersensitivity, frequently to oral contraceptives, is one of the causes of this reaction. The mechanism is unknown.
Medicinal eruptions of lichenoids are lichenoid skin reactions, clinically and morphopathologically indistinguishable from the lichen plan, being associated with various drugs and chemicals. Eosinophils in the plan lichen are common when the reaction is drug-induced. Gold and antimalarials are most commonly associated with this eruption. Hypertensive agents, including beta blockers and captopril, also cause a lichenoid reaction.
Bubble rashes are represented by bubbles that accompany a wide variety of skin reactions, especially severe morbiliform rashes, and can be an integral part of phototoxic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (NET) and fixed drug rashes. Nalidixic acid and furosemide cause bullous rashes that cannot be distinguished from primary bullous diseases. Other examples are a pemfigus-like rash found in penicilamine and scar pemfigoid that has been found in clonidine.
Active pustulous exanthemal rashes are also associated with exposure to drugs, especially antibiotics. These rashes can be distinguished from pustulous psoriasis by the faster onset of fever and pustization and by their rapid and spontaneous healing after discontinuation of the drug.
Polymorphic erythema is a self-limiting inflammatory disease of the skin and mucous membranes, characterized by distinctive lesions in the iris or as a "target shooting" sign, usually having acral distribution and often being associated with pharyngeal pain and malaise. Many medicines, including sulfonamide, penicillin, phenytoin and phenylbutazone, can cause polymorphic erythema, with long-acting sulfonamides being best studied. Polymorphic erythema most often has non-medicinal causes, l, most commonly herpes simplex infection.
Stevens-Johnson syndrome (SSJ) is a bullous condition that is usually more serious than polymorphic erythema. In addition to erosions of the mucous membranes, this rash is characterized by small blisters appearing on the purple macles or atypical "targeting" lesions. The total percentage of body surface area represented by the clivat region is less than 10%. The SSJ/ NET overlap is both SSJ and NET, with 10-30% of the cleaved body surface. Fever and altered generalized condition also occur.
Toxic epidermal necrolysis (NET) is the most serious drug skin reaction and can be fatal. Medications are the most common cause in adults. The onset is generally acute and is characterized by necrosis of the epidermis, interested in more than 30% of the body surface. This reaction is most often associated with sulfonamides, aminopenicillins, anticonvulsants, nonsteroidal inflammatory agents of the oxicame group and allopurinol.
From the point of view of drugs of particular interest I'll start with penicillin. The incidence of penicillin reactions is about 1%. Not all adverse reactions are immunological, examples being ampicillin-induced morbiliform eruptions and central nervous system reactions to procain-penicillin. IgG, IgM and IgE antibodies may be produced, with igG and IgM anti-penicillin antibodies playing a role in hemolytic anaemia, while anaphylaxis and serum disease appear to be due to IgE antibodies in serum.
Since penicillin reactions often occur in patients with no history of penicillin allergy, the usefulness of these accurate and easy-to-perform awareness tests is obvious. The current practice is to carry out skin testing with a commercially available preparation containing an antigenic determinant of penicilloyl determination (Pre-pen, Kremers-Urban) and with fresh penicillin and, if possible, with another source of minor determinants (non-penicilloyl), such as expired or base-treated penicillin.
Antibodies to minor determinants are common in patients with anaphylaxis. On average, 27% (10-36%) patients with a positive history of penicillin allergy also have a positive skin test, while 6% (3-10%) of those with a negative history have a positive skin response to penicillin. Penicillin administration in those patients with a positive skin test produces reactions in a large proportion (50-100%), while only a few patients (about 0.5%) with negative skin tests react to the drug and reactions tend to be moderate and occur late.
Since a negative skin test may occur during or immediately after an acute reaction, testing should be carried out either prospectively or several months after an alleged reaction. Up to 80% of patients lose anaphylactic sensitivity and IgE antibodies after a few years. The radioallergosorbent test (RAST) and other is in vitro does not provide any advantage over the properly performed skin testing. A degree of cross-activity exists between penicillin and nonpenicillin beta-lactam antibiotics (e.g. cephalosporins).
About half of patients who react to penicillin skin testing also react to skin testing in cephalosporins, with anaphylaxis in cephalosporins occurring in patients with positive penicillin testing. The benefit of skin testing with penicillin and cephalosporin derivatives, in addition to penicillin, is uncertain (in one study, none of the 120 patients with negative penicillin skin test results reacted to semisynthetic penicillin-resistant derivatives).
In the face of a positive history of penicillin reaction, another medicine should be chosen. If this objective cannot be achieved or is not prudent (e.g. in a pregnant patient with syphilis, in enterococcal endocarditis), skin testing with penicillin is justified. If skin tests are negative, cautious administration of penicillin is acceptable, although some recommend desensitizing these patients.
In those with positive skin tests, desensitization is mandatory if the therapeutic use of beta-lactam antibiotics should be undertaken. Various protocols including oral and parenteral administrations are available. Oral desensitization appears to present a lower risk of serious anaphylactic reactions during desensitization. However, desensitisation carries a risk of anaphylaxis, regardless of how it is performed. After desensitization, many patients experience penicillin-mediated IgE side effects during therapy that do not endanger life. Desensitization is not effective in those with exfoliative dermatitis or morbiliform reactions due to penicillin.
I'll continue in the next post!
So, we're going to go on...
Necrotizing skin vasculitis often presents in the form of palpable purple lesions, which can be generalized or limited to the lower limbs or other declive regions. Urticaria lesions, ulcers and hemorrhagic bubbles also occur. Vasculitis can also affect other organs, including the liver, kidney, brain and joints.
Drugs are just one of the causes of vasculitis. Reactions from immune complexes are likely responsible for drug-induced vasculitis and/ or serum disease. Propyltoiuracil induces a skin vasculitis accompanied by leukopenia and splenomegaly. Changes in direct immunofluorescence in these lesions suggest deposits of immune complexes. Medications involved in vasculitic eruptions include allopurinol, thiazides, penicillin and phenytoin.
The sensitivity reaction to phenytoin (anticonvulsant), one of the many skin reactions induced by it, is an erythematous rash, which subsequently becomes purple and is accompanied by fever, facial and periorbital edema, painful generalized adenopathy, leukocytosis (often with atypical lymphocytes and eosinophils), hepatitis and sometimes nephritis. The skin reaction usually begins 1-3 weeks after cessation of phenytoin and heals rapidly after discontinuation of the drug and treatment with systemic glucocorticoids.
Eruption recurs upon reexposure, and cross-reactions with other aromatic anticonvulsants, including carbamazepine and barbiturates are common. This syndrome apparently results from a hereditary deficiency of epoxidehydrolase, an enzyme necessary for the metabolism of a toxic intermediate aren-oxide that is formed during phenytoin metabolism by the cytochrome P450 system. Although no controlled studies are available, systemic glucocorticoids (prednisone) will reduce signs, symptoms and laboratory changes that attest to serious hypersensitivity reactions to anticonvulsants.
Skin necrosis due to warfarin (rare) usually occurs between day 3 and 10 of warfarin derivatives therapy, usually in women. Injuries are clearly delineated, endured, erythematous and purple and can heal or progress towards the formation of large, irregular hemorrhagic bubbles with final necrosis and slow healing escare formation. The occurrence of the syndrome is not related to the dose of the medicine or the underlying condition.
The predilections are breasts, thighs and buttocks. Evolution is not altered by discontinuation of the drug after the onset of the rash. Similar reactions have been associated with heparin. Warfarin reactions are associated with vitamin K-dependent protein C deficiency with a shorter half-life than other clotting proteins and is partly responsible for controlling fibrinolysis. Because warfarin inhibits the synthesis of vitamin K-dependent coagulation factors, warfarin anticoagulation in individuals with heterozygous protein C deficiency causes a steep collapse in circulating protein C levels, allowing hypercoagulability and thrombosis in the skin microvascularization with consecutive necrosis areas.
Heparin-induced necrosis may have similar clinical characteristics, but it is likely due to heparin-induced platelet aggregation with consecutive occlusion of blood vessels. Warfarin-induced skin necrosis is treated with vitamin K and heparin. Vitamin K cancels out the effects of warfarin, and heparin acts as an anticoagulant. Treatment with protein C concentrate may also be useful in individuals with protein C deficiency, a predisposing factor for the occurrence of these reactions.
There are a few things to be said for uncertain reactions. I'll start with the morbiliform reactions. Morbiliform or maculopapular eruptions may be the most common of all drug-induced reactions. They often begin to appear on the trunk or in traumatized or pressured areas and consist of erythematous macula and papules that are frequently symmetrical and can become confluenced. Damage to mucous membranes, palms and plants is variable, the rash can be associated with moderate to severe pruritus and fever.
Pathology is not clear. A hypersensitivity mechanism has been suggested, although these reactions do not always recur when re-exposure to the drug. Diagnosis is rarely supported by laboratory tests, the distinction between viral exantems being the main problem of differential diagnosis. While these reactions usually require discontinuation of the drug, rashes can sometimes decrease or disappear if the responsible medicine continues to be administered.
Morbiliform reactions usually occur during the first week after initiation of therapy and last 1-2 weeks (however some reactions to certain medications, especially penicillin, may start more than 2 weeks after the start of therapy, and may persist up to 2 weeks after the start of therapy). These rashes are common in patients receiving ampicillin, amoxicillin or allopurinol (trimetoprim-sulfamethoxazole frequently causes reactions in AIDS patients). Morbiliform rashes are usually treated symptomatically.
Oral antihistamines and calming compresses are useful in the treatment of pruritus. Topical antihistamines can also have a favorable effect, as can emollients. Short cures of potent topical glucocorticoids can reduce inflammation and symptoms and are likely helpful. The beneficial effect of systemic glucocorticoids in relation to their risk is less clear for morbiliform eruptions.
Fixed drug reactions are characterized by one or more clearly delineated, erythematous lesions, in which hyperpigmentation occurs after the healing of acute inflammation (at reexposure, the lesion recurs in the same place, hence the name "fixed"). Injuries often affect the face, genitals and oral mucosa and cause burning sensation.
Fixed drug rashes have been associated with phenolphthalein, sulfonamides, tetracycline, phenylbutazone and barbiturates. Although cross-sensitivity appears to occur between different tetraciclinical compounds, cross-sensitivity was not caused when different sulfonamide compounds were administered to patients as part of a challenge test. The evidence of a characteristic mononuclear infiltration of the dermal papillae close to the dermo-epidermic junction can confirm the clinical diagnosis. Extensive degeneration of basal cells can lead to the formation of bubbles and the dispersion of pigment. Even when the lesions are completely healed, melanin-laden macrophages are present in the dermis.
Nodos erythema is a paniculitis characterized by sensitive subcutaneous erythematous nodules, usually arranged on the anterior portion of the legs. Drug hypersensitivity, frequently to oral contraceptives, is one of the causes of this reaction. The mechanism is unknown.
Medicinal eruptions of lichenoids are lichenoid skin reactions, clinically and morphopathologically indistinguishable from the lichen plan, being associated with various drugs and chemicals. Eosinophils in the plan lichen are common when the reaction is drug-induced. Gold and antimalarials are most commonly associated with this eruption. Hypertensive agents, including beta blockers and captopril, also cause a lichenoid reaction.
Bubble rashes are represented by bubbles that accompany a wide variety of skin reactions, especially severe morbiliform rashes, and can be an integral part of phototoxic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (NET) and fixed drug rashes. Nalidixic acid and furosemide cause bullous rashes that cannot be distinguished from primary bullous diseases. Other examples are a pemfigus-like rash found in penicilamine and scar pemfigoid that has been found in clonidine.
Active pustulous exanthemal rashes are also associated with exposure to drugs, especially antibiotics. These rashes can be distinguished from pustulous psoriasis by the faster onset of fever and pustization and by their rapid and spontaneous healing after discontinuation of the drug.
Polymorphic erythema is a self-limiting inflammatory disease of the skin and mucous membranes, characterized by distinctive lesions in the iris or as a "target shooting" sign, usually having acral distribution and often being associated with pharyngeal pain and malaise. Many medicines, including sulfonamide, penicillin, phenytoin and phenylbutazone, can cause polymorphic erythema, with long-acting sulfonamides being best studied. Polymorphic erythema most often has non-medicinal causes, l, most commonly herpes simplex infection.
Stevens-Johnson syndrome (SSJ) is a bullous condition that is usually more serious than polymorphic erythema. In addition to erosions of the mucous membranes, this rash is characterized by small blisters appearing on the purple macles or atypical "targeting" lesions. The total percentage of body surface area represented by the clivat region is less than 10%. The SSJ/ NET overlap is both SSJ and NET, with 10-30% of the cleaved body surface. Fever and altered generalized condition also occur.
Toxic epidermal necrolysis (NET) is the most serious drug skin reaction and can be fatal. Medications are the most common cause in adults. The onset is generally acute and is characterized by necrosis of the epidermis, interested in more than 30% of the body surface. This reaction is most often associated with sulfonamides, aminopenicillins, anticonvulsants, nonsteroidal inflammatory agents of the oxicame group and allopurinol.
From the point of view of drugs of particular interest I'll start with penicillin. The incidence of penicillin reactions is about 1%. Not all adverse reactions are immunological, examples being ampicillin-induced morbiliform eruptions and central nervous system reactions to procain-penicillin. IgG, IgM and IgE antibodies may be produced, with igG and IgM anti-penicillin antibodies playing a role in hemolytic anaemia, while anaphylaxis and serum disease appear to be due to IgE antibodies in serum.
Since penicillin reactions often occur in patients with no history of penicillin allergy, the usefulness of these accurate and easy-to-perform awareness tests is obvious. The current practice is to carry out skin testing with a commercially available preparation containing an antigenic determinant of penicilloyl determination (Pre-pen, Kremers-Urban) and with fresh penicillin and, if possible, with another source of minor determinants (non-penicilloyl), such as expired or base-treated penicillin.
Antibodies to minor determinants are common in patients with anaphylaxis. On average, 27% (10-36%) patients with a positive history of penicillin allergy also have a positive skin test, while 6% (3-10%) of those with a negative history have a positive skin response to penicillin. Penicillin administration in those patients with a positive skin test produces reactions in a large proportion (50-100%), while only a few patients (about 0.5%) with negative skin tests react to the drug and reactions tend to be moderate and occur late.
Since a negative skin test may occur during or immediately after an acute reaction, testing should be carried out either prospectively or several months after an alleged reaction. Up to 80% of patients lose anaphylactic sensitivity and IgE antibodies after a few years. The radioallergosorbent test (RAST) and other is in vitro does not provide any advantage over the properly performed skin testing. A degree of cross-activity exists between penicillin and nonpenicillin beta-lactam antibiotics (e.g. cephalosporins).
About half of patients who react to penicillin skin testing also react to skin testing in cephalosporins, with anaphylaxis in cephalosporins occurring in patients with positive penicillin testing. The benefit of skin testing with penicillin and cephalosporin derivatives, in addition to penicillin, is uncertain (in one study, none of the 120 patients with negative penicillin skin test results reacted to semisynthetic penicillin-resistant derivatives).
In the face of a positive history of penicillin reaction, another medicine should be chosen. If this objective cannot be achieved or is not prudent (e.g. in a pregnant patient with syphilis, in enterococcal endocarditis), skin testing with penicillin is justified. If skin tests are negative, cautious administration of penicillin is acceptable, although some recommend desensitizing these patients.
In those with positive skin tests, desensitization is mandatory if the therapeutic use of beta-lactam antibiotics should be undertaken. Various protocols including oral and parenteral administrations are available. Oral desensitization appears to present a lower risk of serious anaphylactic reactions during desensitization. However, desensitisation carries a risk of anaphylaxis, regardless of how it is performed. After desensitization, many patients experience penicillin-mediated IgE side effects during therapy that do not endanger life. Desensitization is not effective in those with exfoliative dermatitis or morbiliform reactions due to penicillin.
I'll continue in the next post!
A good weekend, fun,
restful, full of understanding, love and gratitude!
Dorin, Merticaru